PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (665914)

Clipboard (0)
None

Related Articles

1.  GAD2 on Chromosome 10p12 Is a Candidate Gene for Human Obesity 
PLoS Biology  2003;1(3):e68.
The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11–12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of γ-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681–0.972], p = 0.0049) and an at-risk SNP (−243 A>G) for morbid obesity (OR = 1.3, 95% CI [1.053–1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (χ2 = 7.637, p = 0.02). In the murine insulinoma cell line βTC3, the G at-risk allele of SNP −243 A>G increased six times GAD2 promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The −243 A>G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic β cells, we analyzed GAD65 antibody level as a marker of β-cell activity and of insulin secretion. In the control group, −243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of β-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity.
A large case-control study, family-based genetic analyses, and functional data suggest that variation in the GAD2 gene affects eating behavior and insulin metabolism
doi:10.1371/journal.pbio.0000068
PMCID: PMC270019  PMID: 14691540
2.  Prospective Analysis of Genetic Polymorphisms and Risk of Recurrence in Renal Cell Cancer 
The lancet oncology  2012;14(1):81-87.
Summary
Background
Germline genetic polymorphisms may affect the risk of recurrence in patients with localized renal cell carcinoma (RCC). Our aim was to investigate the association of genetic polymorphisms with RCC recurrence.
Patients and Methods
We analyzed germline DNA samples extracted from 554 (discovery cohort of 403 and an independent validation cohort of 151) patients with localized RCC treated at Dana-Farber/Harvard Cancer Center (DF/HCC) and of European-American ancestry (Caucasians). The discovery cohort was selected from a prospective database at Dana-Farber/Harvard Cancer Center and the validation cohort was identified from the Brigham and Women’s Hospital surgery and pathology department records. Single nucleotide polymorphims (SNPs) residing in 70 genes involved in RCC pathogenesis including the VHL/HIF/VEGF, PI3K/AKT/mTOR pathways, and genes involved in immune regulation and metabolism were genotyped for the discovery cohort (total 285 SNPs successfully genotyped and assessable for analysis). The analyses of genotype associations with recurrence free survival (RFS) were assessed using Cox proportional hazards model, Kaplan-Meier method and logrank test. False discovery rate (FDR) q-value was used to adjust for multiple comparisons in selecting potential SNPs with RFS association. The finding from the discovery cohort was validated in an external independent cohort.
Findings
We report the significant association between genotype variants of SNP rs11762213 (c.144G>A; p.Ala48Ala, located in exon two c-MET) and primary analysis endpoint of RFS using both univariate and multivariable analysis. Specifically, patients carrying one or two copies of the minor (risk) allele had an increased risk of recurrence or death (hazard ratio (HR) =1·86, 95% confidence interval (CI), 1·17,2·95; p=0·0084) in the multivariate analysis adjusted for clinical and pathological factors. The median RFS for carriers of the risk allele was 19 months (95%CI: 9,*) compared to 50 months (95%CI: 37,75) for homozygotes of the non-risk allele. The significant association was validated using data from the validation cohort with a HR of 2·45 (95%CI: 1·01,5·95; p=0·048), although of borderline significance. The rs11762213 results in a synonymous aminoacid change in cMET gene. * unable to estimate due to small sample.
Interpretation
Patients with localized RCC and c-MET polymorphism (rs11762213) may have an increased risk of recurrence after nephrectomy. If these results are further validated, it may be incorporated in future prognostic tools, potentially aiding in the design of adjuvant clinical trials with c-MET inhibitors, and clinical management.
Funding
This project is funded by the Conquer Cancer Foundation and ASCO under a Career Development Award (CDA) for Dr. Choueiri, The Trust Family Research for Kidney cancer for Dr. Choueiri and the NIH/NCI Kidney cancer SPORE.
doi:10.1016/S1470-2045(12)70517-X
PMCID: PMC3769687  PMID: 23219378
localized renal cell cancer; nephrectomy; recurrence free interval; genetic polymorphisms; single nucleotide polymorphisms; MET; VEGF
3.  Association Study of 182 Candidate Genes in Anorexia Nervosa 
We performed association studies with 5,151 SNPs that were judged as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN) based on location under reported linkage peaks, previous results in the literature (182 candidate genes), brain expression, biological plausibility, and estrogen responsivity. We employed a case–control design that tested each SNP individually as well as haplotypes derived from these SNPs in 1,085 case individuals with AN diagnoses and 677 control individuals. We also performed separate association analyses using three increasingly restrictive case definitions for AN: all individuals with any subtype of AN (All AN: n = 1,085); individuals with AN with no binge eating behavior (AN with No Binge Eating: n = 687); and individuals with the restricting subtype of AN (Restricting AN: n = 421). After accounting for multiple comparisons, there were no statistically significant associations for any individual SNP or haplotype block with any definition of illness. These results underscore the importance of large samples to yield appropriate power to detect genotypic differences in individuals with AN and also motivate complementary approaches involving Genome-Wide Association (GWA) studies, Copy Number Variation (CNV) analyses, sequencing-based rare variant discovery assays, and pathway-based analysis in order to make up for deficiencies in traditional candidate gene approaches to AN.
doi:10.1002/ajmg.b.31082
PMCID: PMC2963154  PMID: 20468064
single nucleotide polymorphisms; probands; anorexia nervosa; bulimia nervosa
4.  Polymorphisms in the SUFU gene are Associated with Organ Injury Protection and Sepsis Severity in Patients with Enterobacteriacea Bacteremia 
Background
Organ injury including acute kidney injury (AKI) and acute lung Injury (ALI) are major contributors to mortality and morbidity in the setting of sepsis. Hedgehog pathway has been recognized as an important mediator in repair of organ injury. There are some clinical predictors associated with the development of organ injury in sepsis; however few host genetic risk factors have been identified and candidate genes for organ injury susceptibility and severity are largely unknown.
Methods
A prospective cohort study in a tertiary care hospital included 250 adult hospitalized patients with Enterobacteriacea bacteremia. We selected a panel of 69 tagging SNPs for genes in the Hedgehog signaling pathway using the TagSNP functionality of the SNPInfo web server and designed a panel on the GoldenGate Veracode genotyping assay (Illumina). We confirmed Illumina data using Taqman allelic discrimination assays. We assessed SNPs in combination with clinical variables for associations with outcomes and organ injury.
Results
Significant associations were identified using logistic regression models, controlling for age, race and gender. From the 69 tagging SNPs, 5 SNPs were associated with renal function and 2 with APACHEII score after false discovery rate correction. After multivariate analysis SNPs rs10786691 (p=0.03), rs12414407 (p=0.026), rs10748825 (p=0.01), and rs7078511 (p=0.006), all in the suppressor of fused homolog (SUFU) gene, correlated with renal function. Likewise, SUFU SNPs rs7907760 (p=0.009) and rs10748825 (p=0.029) were associated with APACHEII score. SNPs rs12414407 and rs1078825 are in linkage disequilibrium (LD) with rs2296590, a SNP in the 5′-UTR region that is within a predicted transcription factor bind site for CCAAT-enhancer-binding proteins. In multivariate analyses functional SNP rs2296590 was correlated with renal function (p=0.004) and APACHEII score (p=0.049).
Conclusions
Host susceptibility factors play an important role in sepsis development and sepsis related organ injury. Polymorphisms in the SUFU gene (encoding for a negative regulator of the hedgehog signaling pathway) are associated with protection from Enterobacteriacea bacteremia related organ injury and sepsis severity.
doi:10.1016/j.meegid.2013.03.025
PMCID: PMC3669235  PMID: 23538333
Gram negative sepsis; organ injury; polymorphism; SUFU
5.  Associations of glutamate decarboxylase genes with initial sensitivity and age-at-onset of alcohol dependence in the Irish Affected Sib Pair Study of Alcohol Dependence 
Drug and alcohol dependence  2008;101(1-2):80-87.
Background
The relation of γ-aminobutyric acid (GABA) to alcohol dependence (AD) has been widely studied. Several previous studies suggest that GABA may be involved in alcohol withdrawal, tolerance, and the symptoms that form an AD diagnosis. The genes coding for glutamate decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis, are of potential interest for their association to ethanol consumption and AD. There are two isoforms of GAD, GAD1 and GAD2, which were reported to be associated with AD in males of Han Taiwanese (GAD1) and Russian (GAD2) ancestry. The present study examined the association of the two GAD isoforms with AD and relevant alcohol-related traits in the Irish Affected Sib Pair Study of Alcohol Dependence [Prescott, C.A., Sullivan, P.F., Myers, J.M., Patterson, D.G., Devitt, M., Halberstadt, L.J., Walsh, D., Kendler, K.S., 2005. The Irish Affected Sib Pair Study of Alcohol Dependence: study methodology and validation of diagnosis by interview and family history. Alcohol.-Clin. Exp. Res. 29 (3) 417–429].
Methods
Participants were recruited in Ireland, including 575 independent cases who met DSM-IV AD criteria and 530 controls, screened for heavy drinking. We first conducted case-control analyses of the GAD genes with AD and, within the cases, examined associations with age at onset of AD, withdrawal symptoms, and two quantitative measures: initial sensitivity and tolerance (based on scales from the Self-Rating of the Effects of Ethanol) [Schuckit, M.A., Smith, T.L., Tipp, J.E., 1997. The self-rating of the effects of alcohol (SRE) form as a retrospective measure of the risk for alcoholism. Addiction 92, 979–988]. A total of 29 SNPs were genotyped for GAD1 and GAD2 using the Illumina GoldenGate protocols. Statistical procedures were implemented to control for false discovery rates (FDR).
Results
Nine of 29 markers with minor allele frequencies less than 0.01 were removed from standard analysis; the remaining 20 markers were all in Hardy-Weinberg equilibrium. Three markers in the intronic regions of GAD1 were associated with initial sensitivity to alcohol (P = 0.002); the associations remained significant after a FDR based correction for multiple testing. In addition, one marker located 3 kb upstream of GAD1 exhibited association with age at onset of AD (P = 0.0001). Gender specific effects were observed in results of both single marker and haplotype analyses.
Conclusion
We found no evidence for the association of GAD genes with AD but significant association of GAD1 with initial sensitivity and age at onset of AD. Our findings suggest that the underlying pathophysiology regulated by genes like GAD1 may be more directly related to the component processes that form AD than to the clinical disorder.
doi:10.1016/j.drugalcdep.2008.11.009
PMCID: PMC2844896  PMID: 19111404
GABA; Initial sensitivity; Response to ethanol; Withdrawal; Gender difference
6.  Genetic Polymorphisms in Host Antiviral Genes: Associations with Humoral and Cellular Immunity to Measles Vaccine 
Vaccine  2011;29(48):8988-8997.
Host antiviral genes are important regulators of antiviral immunity and plausible genetic determinants of immune response heterogeneity after vaccination. We genotyped and analyzed 307 common candidate tagSNPs from 12 antiviral genes in a cohort of 745 schoolchildren immunized with two doses of measles-mumps-rubella vaccine. Associations between SNPs/haplotypes and measles virus-specific immune outcomes were assessed using linear regression methodologies in Caucasians and African-Americans.
Genetic variants within the DDX58/RIG-I gene, including a coding polymorphism (rs3205166/Val800Val), were associated as single-SNPs (p≤0.017; although these SNPs did not remain significant after correction for false discovery rate/FDR) and in haplotype-level analysis, with measles-specific antibody variations in Caucasians (haplotype allele p-value=0.021; haplotype global p-value=0.076). Four DDX58 polymorphisms, in high LD, demonstrated also associations (after correction for FDR) with variations in both measles-specific IFN-γ and IL-2 secretion in Caucasians (p≤0.001, q=0.193). Two intronic OAS1 polymorphisms, including the functional OAS1 SNP rs10774671 (p=0.003), demonstrated evidence of association with a significant allele-dose-related increase in neutralizing antibody levels in African-Americans. Genotype and haplotype-level associations demonstrated the role of ADAR genetic variants, including a non-synonymous SNP (rs2229857/Arg384Lys; p=0.01), in regulating measles virus-specific IFN-γ Elispot responses in Caucasians (haplotype global p-value=0.017). After correction FDR, 15 single-SNP associations (11 SNPs in Caucasians and 4 SNPs in African-Americans) still remained significant at the q-value<0.20.
In conclusion, our findings strongly point to genetic variants/genes, involved in antiviral sensing and antiviral control, as critical determinants, differentially modulating the adaptive immune responses to live attenuated measles vaccine in Caucasians and African-Americans.
doi:10.1016/j.vaccine.2011.09.043
PMCID: PMC3941984  PMID: 21939710
Single Nucleotide Polymorphisms; Haplotypes; Antiviral genes; Measles vaccine; Immunity
7.  Whole Genome Sequencing versus Traditional Genotyping for Investigation of a Mycobacterium tuberculosis Outbreak: A Longitudinal Molecular Epidemiological Study 
PLoS Medicine  2013;10(2):e1001387.
In an outbreak investigation of Mycobacterium tuberculosis comparing whole genome sequencing (WGS) with traditional genotyping, Stefan Niemann and colleagues found that classical genotyping falsely clustered some strains, and WGS better reflected contact tracing.
Background
Understanding Mycobacterium tuberculosis (Mtb) transmission is essential to guide efficient tuberculosis control strategies. Traditional strain typing lacks sufficient discriminatory power to resolve large outbreaks. Here, we tested the potential of using next generation genome sequencing for identification of outbreak-related transmission chains.
Methods and Findings
During long-term (1997 to 2010) prospective population-based molecular epidemiological surveillance comprising a total of 2,301 patients, we identified a large outbreak caused by an Mtb strain of the Haarlem lineage. The main performance outcome measure of whole genome sequencing (WGS) analyses was the degree of correlation of the WGS analyses with contact tracing data and the spatio-temporal distribution of the outbreak cases. WGS analyses of the 86 isolates revealed 85 single nucleotide polymorphisms (SNPs), subdividing the outbreak into seven genome clusters (two to 24 isolates each), plus 36 unique SNP profiles. WGS results showed that the first outbreak isolates detected in 1997 were falsely clustered by classical genotyping. In 1998, one clone (termed “Hamburg clone”) started expanding, apparently independently from differences in the social environment of early cases. Genome-based clustering patterns were in better accordance with contact tracing data and the geographical distribution of the cases than clustering patterns based on classical genotyping. A maximum of three SNPs were identified in eight confirmed human-to-human transmission chains, involving 31 patients. We estimated the Mtb genome evolutionary rate at 0.4 mutations per genome per year. This rate suggests that Mtb grows in its natural host with a doubling time of approximately 22 h (400 generations per year). Based on the genome variation discovered, emergence of the Hamburg clone was dated back to a period between 1993 and 1997, hence shortly before the discovery of the outbreak through epidemiological surveillance.
Conclusions
Our findings suggest that WGS is superior to conventional genotyping for Mtb pathogen tracing and investigating micro-epidemics. WGS provides a measure of Mtb genome evolution over time in its natural host context.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Tuberculosis—a contagious bacterial disease that usually infects the lungs—is a major public health problem, particularly in low- and middle-income countries. In 2011, an estimated 8.7 million people developed tuberculosis globally, and 1.4 million people died from the disease. Tuberculosis is second only to HIV/AIDS in terms of global deaths from a single infectious agent. Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is readily spread in airborne droplets when people with active disease cough or sneeze. The characteristic symptoms of tuberculosis include persistent cough, weight loss, fever, and night sweats. Diagnostic tests for the disease include sputum smear analysis (examination of mucus coughed up from the lungs for the presence of M. tuberculosis), mycobacterial culture (growth of M. tuberculosis from sputum), and chest X-rays. Tuberculosis can be cured by taking several antibiotics daily for at least six months, although the recent emergence of multidrug-resistant M. tuberculosis is making tuberculosis harder to treat.
Why Was This Study Done?
Although efforts to reduce the global burden of tuberculosis are showing some improvements, the annual decline in the number of people developing tuberculosis continues to be slow. To develop optimized control strategies, experts need to be able to accurately track M. tuberculosis transmission within human populations. Because M. tuberculosis, like all bacteria, accumulates genetic changes over time, there are many different strains (genetic variants) of M. tuberculosis. Genotyping methods have been developed that identify different bacterial strains by examining specific regions of the bacterial genome (blueprint), but because these methods examine only a small part of the genome, they may not distinguish between related transmission chains. That is, traditional strain genotyping methods may not be able to determine accurately where a tuberculosis outbreak started or how it spread through a population. In this longitudinal cohort study, the researchers compare the ability of whole genome sequencing (WGS), which is rapidly becoming widely available, and traditional genotyping to provide information about a recent German tuberculosis outbreak. In a longitudinal cohort study, a population is followed over time to analyze the occurrence of a specific disease.
What Did the Researchers Do and Find?
During long-term (1997–2010) population-based molecular epidemiological surveillance (disease surveillance that uses molecular techniques rather than reports of illness) in Hamburg and Schleswig-Holstein, the researchers identified a large tuberculosis outbreak caused by M. tuberculosis isolates of the Haarlem lineage using classical strain typing. The researchers examined each of the 86 isolates from this outbreak using WGS and classical genotyping and asked whether the results of these two approaches correlated with contact tracing data (information is routinely collected about the people a patient with tuberculosis has recently met so that these contacts can be tested for tuberculosis and treated if necessary) and with the spatio-temporal distribution of outbreak cases. WGS of the isolates identified 85 single nucleotide polymorphisms (SNPs; genomic sequence variants in which single building blocks, or nucleotides, are altered) that subdivided the outbreak into seven clusters of isolates and 36 unique isolates. The WGS results showed that the first isolates of the outbreak were incorrectly clustered by classical genotyping and that one strain—the “Hamburg clone”—started expanding in 1998. Notably, the genome-based clustering patterns were in better accordance with contact tracing data and with the geographical distribution of cases than clustering patterns based on classical genotyping, and they identified eight confirmed human-to-human transmission chains that involved 31 patients and a maximum of three SNPs. Finally, the researchers used their WGS results to estimate that the Hamburg clone emerged between 1993 and 1997, shortly before the discovery of the tuberculosis outbreak through epidemiological surveillance.
What Do These Findings Mean?
These findings show that WGS can be used to identify specific strains within large tuberculosis outbreaks more accurately than classical genotyping. They also provide new information about the evolution of M. tuberculosis during outbreaks and indicate how WGS data should be interpreted in future genome-based molecular epidemiology studies. WGS has the potential to improve the molecular epidemiological surveillance and control of tuberculosis and of other infectious diseases. Importantly, note the researchers, ongoing reductions in the cost of WGS, the increased availability of “bench top” genome sequencers, and bioinformatics developments should all accelerate the implementation of WGS as a standard method for the identification of transmission chains in infectious disease outbreaks.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001387.
The World Health Organization provides information (in several languages) on all aspects of tuberculosis, including the Global Tuberculosis Report 2012
The Stop TB Partnership is working towards tuberculosis elimination; patient stories about tuberculosis are available (in English and Spanish)
The US Centers for Disease Control and Prevention has information about tuberculosis, including information on tuberculosis genotyping (some information in English and Spanish)
The US National Institute of Allergy and Infectious Diseases also has detailed information on all aspects of tuberculosis
The Tuberculosis Survival Project, which aims to raise awareness of tuberculosis and provide support for people with tuberculosis, provides personal stories about treatment for tuberculosis; the Tuberculosis Vaccine Initiative also provides personal stories about dealing with tuberculosis
MedlinePlus has links to further information about tuberculosis (in English and Spanish)
Wikipedia has a page on whole-genome sequencing (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001387
PMCID: PMC3570532  PMID: 23424287
8.  Germline Predictors of Androgen Deprivation Therapy Response in Advanced Prostate Cancer 
Mayo Clinic Proceedings  2012;87(3):240-246.
Objective
To evaluate whether germline variations in genes involved in sex steroid biosynthesis and metabolic pathways predict time to treatment failure for patients with advanced prostate cancer undergoing androgen deprivation therapy (ADT), because there are few known clinical predictors of response.
Patients and Methods
In a cohort of 304 patients with advanced prostate cancer undergoing ADT, we genotyped 746 single-nucleotide polymorphisms (SNPs) from 72 genes from germline DNA (680 tagSNPs from 58 genes and 66 candidate SNPs from 20 genes [6 genes common in both]). Association with the primary end point of time to ADT failure was assessed using proportional hazards regression models at the gene level (for genes with tagging SNPs) and at the SNP level. False discovery rates (FDRs) of 0.10 or less were considered noteworthy to account for multiple testing.
Results
At the gene level, TRMT11 showed the strongest association with time to ADT failure (P<.001; FDR=0.008). Two of 4 TRMT11 tagSNPs were associated with time to ADT failure. Median time to ADT failure for rs1268121 (A>G) was 3.05 years for the AA, 4.27 years for the AG, and 6.22 years for the GG genotypes (P=.002), and for rs6900796 (G>A), it was 2.42 years for the GG, 3.52 years for the AG, and 4.18 years for the AA genotypes (P<.001). No other gene level or SNP level tests had an FDR of 0.10 or less.
Conclusion
Genetic variation in TRMT11 was associated with time to ADT failure. Confirmation of these preliminary findings in an independent cohort is needed.
doi:10.1016/j.mayocp.2011.09.009
PMCID: PMC3538410  PMID: 22386179
9.  Interactions between Environmental Factors and Polymorphisms in Angiogenesis Pathway Genes in Esophageal Adenocarcinoma Risk: A Case-Only Study 
Cancer  2011;118(3):804-811.
BACKGROUND
Gastroesophageal reflux symptoms (GERD), higher body mass index (BMI), smoking, and genetic variants in angiogenic pathway genes have been individually associated with increased risk of esophageal adenocarcinoma (EA). However, how angiogenic gene polymorphisms and environmental factors jointly affect EA development remains unclear.
METHODS
Using a case-only design (n = 335), we examined interaction between 141 functional/tagging angiogenic SNPs and environmental factors (GERD, BMI, smoking) in modulating EA risk. Gene-environment interactions were assessed by a two-step approach. First, we applied random forest (RF) to screen for important SNPs that had either main or interaction effects. Second, we used case-only logistic regression (LR) to assess the effects of gene-environment interactions on EA risk, adjusting for covariates and false-discovery rate (FDR).
RESULTS
RF analyses identified three sets of SNPs (17 SNPs-GERD, 26 SNPs-smoking, and 34 SNPs-BMI) that had the highest importance scores. In subsequent LR analyses, interactions between 3 SNPs (rs2295778 of HIF1AN, rs133376 of TSC2, and rs2519757 of TSC1) and GERD, 2 SNPs (rs2295778 of HIF1AN, rs2296188 (VEGFR1) and smoking, and 7 SNPs (rs2114039 of PDGRFA, rs2296188 of VEGFR1, rs11941492 of VEGFR1, rs3756309 of PDGFRB, rs7324547 of VEGFR1, rs17619601 of VEGFR1, and rs17625898 of VEGFR1) and BMI were significantly associated with EA development (all FDR ≤0.10). Moreover, these interactions tended to have a SNP dose-response effects for increased EA risk with increasing number of combined risk genotypes.
CONCLUSIONS
These findings suggest that genetic variations in angiogenic genes may modify EA susceptibility through interactions with environmental factors in a SNP dose-response manner.
doi:10.1002/cncr.26325
PMCID: PMC3193872  PMID: 21751195
Esophageal adenocarcinoma; angiogenesis pathway genes; gene-environment interaction; case-only analysis
10.  Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation 
PLoS Medicine  2013;10(12):e1001577.
In this paper, Choi and colleagues analyzed levels of mitochondrial DNA in two prospective observational cohort studies and found that increased mtDNA levels are associated with ICU mortality, and improve risk prediction in medical ICU patients. The data suggests that mtDNA could serve as a viable plasma biomarker in MICU patients.
Background
Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients.
Methods and Findings
Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6–15.8, p = 1×10−7) and ME ARDS (OR 8.4, 95% CI 2.9–24.2, p = 9×10−5) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10−4) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers.
Conclusions
Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Intensive care units (ICUs, also known as critical care units) are specialist hospital wards that provide care for people with life-threatening injuries and illnesses. In the US alone, more than 5 million people are admitted to ICUs every year. Different types of ICUs treat different types of problems. Medical ICUs treat patients who, for example, have been poisoned or who have a serious infection such as sepsis (blood poisoning) or severe pneumonia (inflammation of the lungs); trauma ICUs treat patients who have sustained a major injury; cardiac ICUs treat patients who have heart problems; and surgical ICUs treat complications arising from operations. Patients admitted to ICUs require constant medical attention and support from a team of specially trained nurses and physicians to prevent organ injury and to keep their bodies functioning. Monitors, intravenous tubes (to supply essential fluids, nutrients, and drugs), breathing machines, catheters (to drain urine), and other equipment also help to keep ICU patients alive.
Why Was This Study Done?
Although many patients admitted to ICUs recover, others do not. ICU specialists use scoring systems (algorithms) based on clinical signs and physiological measurements to predict their patients' likely outcomes. For example, the APACHE II scoring system uses information on heart and breathing rates, temperature, levels of salts in the blood, and other signs and physiological measurements collected during the first 24 hours in the ICU to predict the patient's risk of death. Existing scoring systems are not perfect, however, and “biomarkers” (molecules in bodily fluids that provide information about a disease state) are needed to improve risk prediction for ICU patients. Here, the researchers investigate whether levels of circulating cell-free mitochondrial DNA (mtDNA) are associated with ICU deaths and whether these levels can be used as a biomarker to improve risk prediction in ICU patients. Mitochondria are cellular structures that produce energy. Levels of mtDNA in the plasma (the liquid part of blood) increase in response to trauma and infection. Moreover, mtDNA activates molecular processes that lead to inflammation and organ injury.
What Did the Researchers Do and Find?
The researchers measured mtDNA levels in the plasma of patients enrolled in two prospective observational cohort studies that monitored the outcomes of ICU patients. In the Brigham and Women's Hospital Registry of Critical Illness study, blood was taken from 200 patients within 24 hours of admission into the hospital's medical ICU. In the Molecular Epidemiology of Acute Respiratory Distress Syndrome study (acute respiratory distress syndrome is a life-threatening inflammatory reaction to lung damage or infection), blood was taken from 243 patients within 48 hours of admission into medical and non-medical ICUs at two other US hospitals. Patients admitted to medical ICUs with a raised mtDNA level (3,200 or more copies of a specific mitochondrial gene per microliter of plasma) had a 7- to 8-fold increased risk of dying within 28 days of admission compared to patients with mtDNA levels of less than 3,200 copies/µl plasma. There was no evidence of an association between raised mtDNA levels and death among patients admitted to non-medical ICUs. The addition of an elevated mtDNA level to a clinical model for risk prediction that included the APACHE II score and biomarkers that are already used to predict ICU outcomes improved the net reclassification index (an indicator of the improvement in risk prediction algorithms offered by new biomarkers) of 28-day mortality among medical ICU patients in both studies.
What Do These Findings Mean?
These findings indicate that raised mtDNA plasma levels are associated with death in medical ICUs and show that, among patients in medical ICUs, measurement of mtDNA plasma levels can improve the prediction of the risk of death from the APACHE II scoring system, even when commonly measured biomarkers are taken into account. These findings do not indicate whether circulating cell-free mtDNA increased because of the underlying severity of illness or whether mtDNA actively contributes to the disease process in medical ICU patients. Moreover, they do not provide any evidence that raised mtDNA levels are associated with an increased risk of death among non-medical (mainly surgical) ICU patients. These findings need to be confirmed in additional patients, but given the relative ease and rapidity of mtDNA measurement, the determination of circulating cell-free mtDNA levels could be a valuable addition to the assessment of patients admitted to medical ICUs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001577.
The UK National Health Service Choices website provides information about intensive care
The Society of Critical Care Medicine provides information for professionals, families, and patients about all aspects of intensive care
MedlinePlus provides links to other resources about intensive care (in English and Spanish)
The UK charity ICUsteps supports patients and their families through recovery from critical illness; its booklet Intensive Care: A Guide for Patients and Families is available in English and ten other languages; its website includes patient experiences and relative experiences of treatment in ICUs
Wikipedia has a page on ICU scoring systems (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001577
PMCID: PMC3876981  PMID: 24391478
11.  Racial differences in the association of CD14 polymorphisms with serum total IgE levels and allergen skin test reactivity 
Background
The CD14 C-159T single nucleotide polymorphism (SNP) has been investigated widely as a candidate genetic locus in patients with allergic disease. There are conflicting results for the association of the CD14 C-159T SNP with total serum immunoglobulin E (IgE) levels and atopy. There are limited data regarding the association of the CD14 C-159T SNP in subjects of African ancestry. The aim of the study was to determine whether the C-159T SNP and other CD14 SNPs (C1188G, C1341T) were associated with total serum IgE levels and with allergy skin test results in nonatopic and atopic subjects; as well as in Caucasian and African American subjects.
Methods
A total of 291 participants, 18–40 years old, were screened to determine whether they were atopic and/or asthmatic. Analyses were performed to determine the association between CD14 C-159T, C1188G, or C1341T genotypes with serum IgE levels and with the number of positive skin tests among Caucasian or African American subjects.
Results
We found no significant association of serum total IgE level with CD14 C-159T, C1188G, or C1341T genotypes within nonatopic or atopic subjects. Subjects with CD14-159 T alleles had significantly more positive allergen skin tests than subjects without CD14-159 T alleles (P = 0.0388). There was a significant association between the CD14 1188 G allele, but not the CD14 1341 T allele, with the number of positive skin-test results in Caucasians, but not in African Americans.
Conclusion
These results support a possible association between CD14 polymorphisms and atopy. CD14-159 T or CD14 1188 G alleles were associated with atopic disease. For subjects with CD14 1188 G alleles, the association with atopic disease was stronger in Caucasians compared to African Americans.
doi:10.2147/JAA.S42695
PMCID: PMC3699133  PMID: 23836995
total serum immunoglobulin E; IgE; skin prick test; SPT; CD14-159T; single nucleotide polymorphism; SNP; lipopolysaccharide; LPS; endotoxin
12.  Transcobalamin 2 variant associated with poststroke homocysteine modifies recurrent stroke risk 
Neurology  2011;77(16):1543-1550.
Objectives:
The Vitamin Intervention for Stroke Prevention trial found an association between baseline poststroke homocysteine (Hcy) and recurrent stroke. We investigated genes for enzymes and cofactors in the Hcy metabolic pathway for association with Hcy and determined whether associated single nucleotide polymorphisms (SNPs) influenced recurrent stroke risk.
Methods:
Eighty-six SNPs in 9 candidate genes (BHMT1, BHMT2, CBS, CTH, MTHFR, MTR, MTRR, TCN1, and TCN2) were genotyped in 2,206 subjects (83% European American). Associations with Hcy measures were assessed using linear regression models assuming an additive genetic model, adjusting for age, sex, and race and additionally for baseline Hcy when postmethionine load change was assessed. Associations with recurrent stroke were evaluated using survival analyses.
Results:
Five SNPs in the transcobalamin 2 (TCN2) gene were associated with baseline Hcy (false discovery rate [FDR]–adjusted p = 0.049). TCN2 SNP rs731991 was associated with recurrent stroke risk in the low-dose arm of the trial under a recessive model (log-rank test p = 0.009, hazard ratio 0.34). Associations with change in postmethionine load Hcy levels were found with 5 SNPs in the cystathionine β-synthase (CBS) gene (FDR-adjusted p < 0.031).
Conclusions:
TCN2 variants contribute to poststroke Hcy levels, whereas variants in the CBS gene influence Hcy metabolism. Variation in the TCN2 gene also affects recurrent stroke risk in response to cofactor therapy.
doi:10.1212/WNL.0b013e318233b1f9
PMCID: PMC3198974  PMID: 21975197
13.  Genome-Wide Association Analyses Identify SPOCK as a Key Novel Gene Underlying Age at Menarche 
PLoS Genetics  2009;5(3):e1000420.
For females, menarche is a most significant physiological event. Age at menarche (AAM) is a trait with high genetic determination and is associated with major complex diseases in women. However, specific genes for AAM variation are largely unknown. To identify genetic factors underlying AAM variation, a genome-wide association study (GWAS) examining about 380,000 SNPs was conducted in 477 Caucasian women. A follow-up replication study was performed to validate our major GWAS findings using two independent Caucasian cohorts with 854 siblings and 762 unrelated subjects, respectively, and one Chinese cohort of 1,387 unrelated subjects—all females. Our GWAS identified a novel gene, SPOCK (Sparc/Osteonectin, CWCV, and Kazal-like domains proteoglycan), which had seven SNPs associated with AAM with genome-wide false discovery rate (FDR) q<0.05. Six most significant SNPs of the gene were selected for validation in three independent replication cohorts. All of the six SNPs were replicated in at least one cohort. In particular, SNPs rs13357391 and rs1859345 were replicated both within and across different ethnic groups in all three cohorts, with p values of 5.09×10−3 and 4.37×10−3, respectively, in the Chinese cohort and combined p values (obtained by Fisher's method) of 5.19×10−5 and 1.02×10−4, respectively, in all three replication cohorts. Interestingly, SPOCK can inhibit activation of MMP-2 (matrix metalloproteinase-2), a key factor promoting endometrial menstrual breakdown and onset of menstrual bleeding. Our findings, together with the functional relevance, strongly supported that the SPOCK gene underlies variation of AAM.
Author Summary
Menarche is a physical milestone in a woman's life. Age at menarche (AAM) is related to many common female health problems. AAM is mainly determined by genetic factors. However, the specific genes and the associated mechanisms underlying AAM are largely unknown. Here, taking advantage of the most recent technological advances in the field of human genetics, we identified multiple genetic variants in a gene, SPOCK, which are associated with AAM variation in a group of Caucasian women. This association was subsequently confirmed not only in two independent groups of Caucasian women but also across ethnic boundaries in one group of Chinese women. In addition, SPOCK has a function in regulating a key factor involved in menstrual cycles, MMP-2, which provides further support to our findings. Our study provides a solid basis for further investigation of the gene, which may help to reveal the underlying mechanisms for the timing of menarche and for AAM's relationship with women's health in general.
doi:10.1371/journal.pgen.1000420
PMCID: PMC2652107  PMID: 19282985
14.  Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study 
Human Reproduction (Oxford, England)  2013;28(6):1695-1706.
STUDY QUESTION
Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study?
SUMMARY ANSWER
We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry.
WHAT IS KNOWN ALREADY
Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations.
STUDY DESIGN, SIZE, DURATION
A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM.
MATERIALS, SETTING, METHODS
SNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P < 0.01 for ANM analyses and P < 0.017 for AM analyses.
MAIN RESULTS AND THE ROLE OF CHANCE
We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends.
LIMITATIONS, REASONS FOR CAUTION
Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings.
WIDER IMPLICATIONS OF THE FINDINGS
The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research.
STUDY FUNDING/COMPETING INTEREST(S)
The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI) and U01HG004801 (Coordinating Center), and their respective NHGRI ARRA supplements. The authors report no conflicts of interest.
doi:10.1093/humrep/det071
PMCID: PMC3657124  PMID: 23508249
menopause; menarche; genome-wide association study; race/ethnicity; single nucleotide polymorphism
15.  Domestic Violence and Perinatal Mental Disorders: A Systematic Review and Meta-Analysis 
PLoS Medicine  2013;10(5):e1001452.
Louise Howard and colleagues conduct a systematic review and meta-analysis to estimate the prevalence and odds of experience of domestic violence experience among women with antenatal and postnatal mental health disorders.
Please see later in the article for the Editors' Summary
Background
Domestic violence in the perinatal period is associated with adverse obstetric outcomes, but evidence is limited on its association with perinatal mental disorders. We aimed to estimate the prevalence and odds of having experienced domestic violence among women with antenatal and postnatal mental disorders (depression and anxiety disorders including post-traumatic stress disorder [PTSD], eating disorders, and psychoses).
Methods and Findings
We conducted a systematic review and meta-analysis (PROSPERO reference CRD42012002048). Data sources included searches of electronic databases (to 15 February 2013), hand searches, citation tracking, update of a review on victimisation and mental disorder, and expert recommendations. Included studies were peer-reviewed experimental or observational studies that reported on women aged 16 y or older, that assessed the prevalence and/or odds of having experienced domestic violence, and that assessed symptoms of perinatal mental disorder using a validated instrument. Two reviewers screened 1,125 full-text papers, extracted data, and independently appraised study quality. Odds ratios were pooled using meta-analysis.
Sixty-seven papers were included. Pooled estimates from longitudinal studies suggest a 3-fold increase in the odds of high levels of depressive symptoms in the postnatal period after having experienced partner violence during pregnancy (odds ratio 3.1, 95% CI 2.7–3.6). Increased odds of having experienced domestic violence among women with high levels of depressive, anxiety, and PTSD symptoms in the antenatal and postnatal periods were consistently reported in cross-sectional studies. No studies were identified on eating disorders or puerperal psychosis. Analyses were limited because of study heterogeneity and lack of data on baseline symptoms, preventing clear findings on causal directionality.
Conclusions
High levels of symptoms of perinatal depression, anxiety, and PTSD are significantly associated with having experienced domestic violence. High-quality evidence is now needed on how maternity and mental health services should address domestic violence and improve health outcomes for women and their infants in the perinatal period.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Domestic violence—physical, sexual, or emotional abuse by an intimate partner or family member—is a major public health problem and although more common in women, can also affect men. Due to the nature of the problem, it is difficult to collect accurate figures on the scale of domestic violence, but a study by the World Health Organization in ten countries found that 15%–71% of women aged 15–49 years reported physical and/or sexual violence by an intimate partner at some point in their lives. Women experiencing domestic violence have significant short- and long-term health problems, particularly regarding their mental health: experience of domestic violence can lead to a range of mental health disorders such as depression, psychosis, eating disorders, and even suicide attempts.
Why Was This Study Done?
As perinatal mental health disorders are among the commonest health problems in pregnancy and the postpartum period, and given the rate of domestic violence during pregnancy (previous studies have suggested a domestic violence prevalence of 4%–8% during pregnancy and the postnatal period), it is plausible that there may be a link between perinatal mental health disorders and having experienced domestic violence. Indeed, previous reviews have suggested the existence of such an association but were limited by the small number of included studies and focused on depression only, rather than the full range of antenatal and postnatal mental health disorders. So in this study the researchers systematically reviewed published studies to provide more robust estimates of the prevalence of having experienced domestic violence among women with antenatal and postnatal mental health disorders; the researchers also used a meta-analysis to estimate the odds (chance) of having experienced domestic violence among women with antenatal and postnatal mental health disorders.
What Did the Researchers Do and Find?
The researchers searched multiple databases and hand searched three relevant journals using key search terms to identify all types of relevant studies. Using specific criteria, the researchers retrieved and assessed over 1,000 full papers, of which 67 met the criteria for their systematic review. The researchers assessed the quality of each selected study and included only those studies that used validated diagnostic instruments and screening tools to assess mental health disorders in their calculations of the pooled (combined) odds ratio (OR) through meta-analysis.
Using these methods, in cross-sectional studies (studies conducted at one point in time), the researchers found that women with probable depression in the antenatal period reported a high prevalence and increased odds of having experienced partner violence during their lifetime (OR = 3), during the past year (OR = 2.8), and during pregnancy (OR = 5). The results were similar for the postnatal period. The evidence was less robust for anxiety disorders: among women with probable anxiety in the antenatal period, the researchers found an OR of 2.9 of having experienced lifetime partner violence. The odds were less in the postnatal period (OR = 1.4) In their analysis of longitudinal studies (follow-up studies over a period of time), the researchers found an increased odds of probable postnatal depression both among women who reported having ever experienced partner violence in their lifetime (OR = 2.9) and among women who reported having experienced partner violence during pregnancy (OR = 3.1). The researchers also found a combined prevalence estimate of 12.7% for probable depression during the postnatal period following experiences of partner violence during pregnancy. Because of limited data, the researchers could not calculate an OR of the association between probable antenatal depression and later experiences of partner violence.
What Do These Findings Mean?
These findings suggest that women with high levels of symptoms of perinatal mental health disorders—antenatal and postnatal anxiety, depression, and post-traumatic stress disorder—have a high prevalence and increased odds of having experienced domestic violence both over their lifetime and during pregnancy. However, these findings cannot prove causality, they fail to show a two-way association (that is, perinatal mental health disorders leading to subsequent domestic violence), and no information on other perinatal mental disorders, such as eating disorders and puerperal psychosis, was available. The variation of the quality of the included studies also limits the results, highlighting the need for high-quality data to suggest how maternity and mental health services could address domestic violence and improve health outcomes for women and their infants in the future. Nevertheless, this study emphasizes the importance of identifying and responding to possible domestic violence among women attending antenatal and mental health services.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001452.
The World Health Organization provides information and statistics about violence against women and also about mental health disorders during pregnancy
The UK Royal College of Psychiatrists has information for professionals and patients about mental health disorders during pregnancy
doi:10.1371/journal.pmed.1001452
PMCID: PMC3665851  PMID: 23723741
16.  Expectations for Recovery Important in the Prognosis of Whiplash Injuries 
PLoS Medicine  2008;5(5):e105.
Background
Individuals' expectations on returning to work after an injury have been shown to predict the duration of time that a person with work-related low back pain will remain on benefits; individuals with lower recovery expectations received benefits for a longer time than those with higher expectations. The role of expectations in recovery from traumatic neck pain, in particular whiplash-associated disorders (WAD), has not been assessed to date to our knowledge. The aim of this study was to investigate if expectations for recovery are a prognostic factor after experiencing a WAD.
Methods and Findings
We used a prospective cohort study composed of insurance claimants in Sweden. The participants were car occupants who filed a neck injury claim (i.e., for WAD) to one of two insurance companies between 15 January 2004 and 12 January 2005 (n = 1,032). Postal questionnaires were completed shortly (average 23 d) after the collision and then again 6 mo later. Expectations for recovery were measured with a numerical rating scale (NRS) at baseline, where 0 corresponds to “unlikely to make a full recovery” and 10 to “very likely to make a full recovery.” The scale was reverse coded and trichotomised into NRS 0, 1–4, and 5–10. The main outcome measure was self-perceived disability at 6 mo postinjury, measured with the Pain Disability Index, and categorised into no/low, moderate, and high disability. Multivariable polytomous logistic regression was used for the analysis. There was a dose response relationship between recovery expectations and disability. After controlling for severity of physical and mental symptoms, individuals who stated that they were less likely to make a full recovery (NRS 5–10), were more likely to have a high disability compared to individuals who stated that they were very likely to make a full recovery (odds ratio [OR] 4.2 [95% confidence interval (CI) 2.1 to 8.5]. For the intermediate category (NRS 1–4), the OR was 2.1 (95% CI 1.2 to 3.2). Associations between expectations and disability were also found among individuals with moderate disability.
Conclusions
Individuals' expectations for recovery are important in prognosis, even after controlling for symptom severity. Interventions designed to increase patients' expectations may be beneficial and should be examined further in controlled studies.
Lena Holm and colleagues show that in people who had a whiplash injury after a car crash there was an association between expectation of disability and actual disability six months later.
Editors' Summary
Background
The disability associated with injury is a major source of distress for patients, and can be costly to the health care system and employers when persons fail to recover quickly and are unable to return to work. Finding ways to help people recover quickly and get back to optimal health is important. Some of the most common injuries causing disability and time off work result from whiplash—the sudden hyperextension or “whipping” of the neck, which can occur from a motor vehicle crash. It has long been recognized that psychological factors (such as the ability to cope, how “in control” one feels about one's life) are as important as physical symptoms in how disabling an injury can be. There is now growing evidence that a person's feelings about their ability to recover from injury plays a part in actual recovery. Studies from Europe and North America have shown with conditions like low back pain and minor head injury that a patient's feelings about the possibility of getting better are related to how well they do. Less is known about how important these psychological factors are in recovery from disorders due to whiplash associated disorders.
Why Was This Study Done?
The authors wanted to find out whether there was a relationship between people's expectations for their recovery from whiplash associated disorders and their actual recovery six months later. So, for example, they wondered if a person with whiplash who felt they were very unlikely to recover from their injury, actually did not recover (and vice versa).
What Did the Researchers Do and Find?
The authors had access to an unusual set of health information—insurance claims by people who had been involved in car collisions to two insurance companies in Sweden. They identified about 1,000 adult insurance claimants over one year and mailed them a questionnaire that asked for details about the collision as well as information about the claimant: their demographic profile, health history, and the types of pain and symptoms experienced since the crash. The questionnaire also asked the claimant how likely they thought they were to make a full recovery from their injuries.
For those who said they had whiplash associated disorders, the authors followed up with another questionnaire six months later, which asked for information about any disability, pain, or other symptoms that the claimant was still experiencing because of the injury. Of those who had completed the first questionnaire, 82% were followed up.
Only about a quarter of claimants with whiplash associated disorders said they expected to make a full recovery. Perhaps not surprisingly, those with only mild pain, compared to those with intense pain, were more likely to think so. Persons who said they were less likely to make a full recovery were four times more likely to report high levels of disability six months later. Even for persons (or individuals) people with moderate levels of disability six months after injury, their expectations for recovery were similarly linked to how well they did: the lower the expectations for recovery, the higher the disability. These findings were true even after taking into account how severe signs and symptoms the person had, and how well the person was coping psychologically.
What Do These Findings Mean?
The findings indicate that those with the lowest expectations for recovery after their whiplash injury will have the poorest recovery, and those with the highest expectations will have the best recovery. They also suggest that a patient's expectations about getting better are as important as his or her physical symptoms. The authors say that the more we can influence patients to believe they will make a full recovery, the better chance they will have to recover completely. This means that it may be beneficial for healthcare providers to give support and/or education to patients with whiplash associated disorders that increases their positive feelings toward recovery. The authors call for more studies into whether these types of targeted interventions would be of benefit.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050105.
Information about research on injuries and rehabilitation can be found at the Web sites of organisations devoted to studying the health of workers, such as the Institute for Work and Health in Canada, the Finnish Institute of Occupational Health, and the US National Institute for Occupational Safety and Health
The Wikipedia entry for medical aspects of whiplash describes the four grades of whiplash disorder, but does not cover the debate about the credibility of whiplash disorder (please note that Wikipedia is an online encyclopedia that anyone can edit)
The Sjukvardsradgivningen Web site provides information about whiplash-related disorders, common signs and symptoms, recovery and prognosis, and treatments (in Swedish)
doi:10.1371/journal.pmed.0050105
PMCID: PMC2375948  PMID: 18479182
17.  Calibrating the Performance of SNP Arrays for Whole-Genome Association Studies 
PLoS Genetics  2008;4(6):e1000109.
To facilitate whole-genome association studies (WGAS), several high-density SNP genotyping arrays have been developed. Genetic coverage and statistical power are the primary benchmark metrics in evaluating the performance of SNP arrays. Ideally, such evaluations would be done on a SNP set and a cohort of individuals that are both independently sampled from the original SNPs and individuals used in developing the arrays. Without utilization of an independent test set, previous estimates of genetic coverage and statistical power may be subject to an overfitting bias. Additionally, the SNP arrays' statistical power in WGAS has not been systematically assessed on real traits. One robust setting for doing so is to evaluate statistical power on thousands of traits measured from a single set of individuals. In this study, 359 newly sampled Americans of European descent were genotyped using both Affymetrix 500K (Affx500K) and Illumina 650Y (Ilmn650K) SNP arrays. From these data, we were able to obtain estimates of genetic coverage, which are robust to overfitting, by constructing an independent test set from among these genotypes and individuals. Furthermore, we collected liver tissue RNA from the participants and profiled these samples on a comprehensive gene expression microarray. The RNA levels were used as a large-scale set of quantitative traits to calibrate the relative statistical power of the commercial arrays. Our genetic coverage estimates are lower than previous reports, providing evidence that previous estimates may be inflated due to overfitting. The Ilmn650K platform showed reasonable power (50% or greater) to detect SNPs associated with quantitative traits when the signal-to-noise ratio (SNR) is greater than or equal to 0.5 and the causal SNP's minor allele frequency (MAF) is greater than or equal to 20% (N = 359). In testing each of the more than 40,000 gene expression traits for association to each of the SNPs on the Ilmn650K and Affx500K arrays, we found that the Ilmn650K yielded 15% times more discoveries than the Affx500K at the same false discovery rate (FDR) level.
Author Summary
Advances in SNP genotyping array technologies have made whole-genome association studies (WGAS) a readily available approach. Genetic coverage and the statistical power are two key properties to evaluate on the arrays. In this study, 359 newly sampled individuals were genotyped using Affymetrix 500K and Illumina 650Y SNP arrays. From these data, we obtained new estimates of genetic coverage by constructing a test set from among these genotypes and individuals that is independent from the SNPs and individuals used to construct the arrays. These estimates are notably smaller than previous ones, which we argue is due to an overfitting bias in previous studies. We also collected liver tissue RNA from the participants and profiled these samples on a comprehensive gene expression microarray. The RNA levels were used as a large-scale set of quantitative traits to calibrate the relative statistical power of the commercial arrays. Through this dataset and simulations, we find that the SNP arrays provide adequate power to detect quantitative trait loci when the causal SNP's minor allele frequency is greater than 20%, but low power is less than 10%. Importantly, we provide evidence that sample size has a greater impact on the power of WGAS than SNP density or genetic coverage.
doi:10.1371/journal.pgen.1000109
PMCID: PMC2432039  PMID: 18584036
18.  Polymorphic variants in TSC1 and TSC2 and their association with breast cancer phenotypes 
Breast cancer research and treatment  2010;125(3):10.1007/s10549-010-1062-1.
TSC1 acts coordinately with TSC2 in a complex to inhibit mTOR, an emerging therapeutic target and known promoter of cell growth and cell cycle progression. Perturbation of the mTOR pathway, through abnormal expression or function of pathway genes, could lead to tumorigenesis. TSC1 and TSC2 expression is reduced in invasive breast cancer as compared with normal mammary epithelium. Because single nucleotide polymorphisms (SNPs) in regulatory genes have been implicated in risk and age at diagnosis of breast cancers, systematic SNP association studies were performed on TSC1 and TSC2 SNPs for their associations with clinical features of breast cancer. TSC1 and TSC2 haplotypes were constructed from genotyping of multiple loci in both genes in healthy volunteers. SNPs were selected for further study using a bioinformatics approach based on SNP associations with drug response in NCI-60 cell lines and evidence of selection bias based on haplotype frequencies. Genotyping for five TSC1 and one TSC2 loci were performed on genomic DNA from 1,137 women with breast cancer. This study found that for TSC1 rs7874234, TT variant carriers had a 9-year later age at diagnosis of estrogen receptor positive (ER+), but not ER−, ductal carcinomas (P = 0.0049). No other SNP locus showed an association with age at diagnosis, nor any other breast cancer phenotype. TSC1 rs7874234 is hypothesized to be functional in ER+ breast cancer because the T allele, but not the C allele, may create an estrogen receptor element (ERE) site, resulting in increased TSC1 transcription and subsequent inhibition of mTOR.
doi:10.1007/s10549-010-1062-1
PMCID: PMC3876413  PMID: 20658316
Breast cancer risk; SNP; TSC1/TSC2; Case study
19.  Maternal and family factors and child eating pathology: risk and protective relationships 
Background
Previous studies have found associations between maternal and family factors and child eating disorder symptoms. However, it is not clear whether family factors predict eating disorder symptoms specifically, or relate to more general child psychopathology, of which eating disorder symptoms may be one component. This study aimed to identify maternal and family factors that may predict increases or decreases in child eating disorder symptoms over time, accounting for children’s body mass index z-scores and levels of general psychological distress.
Methods
Participants were 221 mother-child dyads from the Childhood Growth and Development Study, a prospective cohort study in Western Australia. Participants were assessed at baseline, 1-year follow-up and 2-year follow-up using interview and self-report measures. Children had a mean age of 10 years at baseline and 46% were male. Linear mixed models and generalised estimating equations were used to identify predictors of children’s eating disorder symptoms, with outcome variables including a global index of eating disorder psychopathology, levels of dietary restraint, levels of emotional eating, and the presence of loss of control (‘binge’) eating.
Results
Children of mothers with a current or past eating disorder reported significantly higher levels of global eating disorder symptoms and emotional eating than other children, and mothers with a current or past eating disorder reported significantly more concern about their children’s weight than other mothers. Maternal concern about child weight, rather than maternal eating disorder symptoms, was significant in predicting child eating disorder symptoms over time. Family exposure to stress and low maternal education were additional risk factors for eating disorder symptoms, whilst child-reported family satisfaction was a protective factor.
Conclusions
After adjusting for relevant confounding variables, maternal concern about child weight, children’s level of family satisfaction, family exposure to stress, and maternal education are unique predictors of child eating disorder symptoms.
doi:10.1186/2050-2974-2-11
PMCID: PMC4012547  PMID: 24808944
Eating disorders; Children; Loss of control eating; Family; Risk factors; Protective factors; Running head; Family factors and eating pathology
20.  Intimate Partner Violence and Incident Depressive Symptoms and Suicide Attempts: A Systematic Review of Longitudinal Studies 
PLoS Medicine  2013;10(5):e1001439.
Karen Devries and colleagues conduct a systematic review of longitudinal studies to evaluate the direction of association between symptoms of depression and intimate partner violence.
Please see later in the article for the Editors' Summary
Background
Depression and suicide are responsible for a substantial burden of disease globally. Evidence suggests that intimate partner violence (IPV) experience is associated with increased risk of depression, but also that people with mental disorders are at increased risk of violence. We aimed to investigate the extent to which IPV experience is associated with incident depression and suicide attempts, and vice versa, in both women and men.
Methods and Findings
We conducted a systematic review and meta-analysis of longitudinal studies published before February 1, 2013. More than 22,000 records from 20 databases were searched for studies examining physical and/or sexual intimate partner or dating violence and symptoms of depression, diagnosed major depressive disorder, dysthymia, mild depression, or suicide attempts. Random effects meta-analyses were used to generate pooled odds ratios (ORs). Sixteen studies with 36,163 participants met our inclusion criteria. All studies included female participants; four studies also included male participants. Few controlled for key potential confounders other than demographics. All but one depression study measured only depressive symptoms. For women, there was clear evidence of an association between IPV and incident depressive symptoms, with 12 of 13 studies showing a positive direction of association and 11 reaching statistical significance; pooled OR from six studies = 1.97 (95% CI 1.56–2.48, I2 = 50.4%, pheterogeneity = 0.073). There was also evidence of an association in the reverse direction between depressive symptoms and incident IPV (pooled OR from four studies = 1.93, 95% CI 1.51–2.48, I2 = 0%, p = 0.481). IPV was also associated with incident suicide attempts. For men, evidence suggested that IPV was associated with incident depressive symptoms, but there was no clear evidence of an association between IPV and suicide attempts or depression and incident IPV.
Conclusions
In women, IPV was associated with incident depressive symptoms, and depressive symptoms with incident IPV. IPV was associated with incident suicide attempts. In men, few studies were conducted, but evidence suggested IPV was associated with incident depressive symptoms. There was no clear evidence of association with suicide attempts.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Depression and suicide are responsible for a substantial proportion of the global disease burden. Depression—an overwhelming feeling of sadness and hopelessness that can last for months or years—affects more than 350 million people worldwide. It is the eleventh leading cause of global disability-adjusted life-years (a measure of overall disease burden), and it affects one in six people at some time during their lives. Globally, about a million people commit suicide every year, usually because they have depression or some other mental illness. Notably, in cross-sectional studies (investigations that look at a population at a single time point), experience of intimate partner violence (IPV, also called domestic violence) is strongly and consistently associated with both depressive disorders and suicide. IPV, like depression and suicide, is extremely common—in multi-country studies, 15%–71% of women report being physically assaulted at some time during their lifetime. IPV is defined as physical, sexual, or psychological harm by a current or former partner or spouse; men as well as women can be the victims of IPV.
Why Was This Study Done?
It may seem obvious to assume that IPV is causally related to subsequent depression and suicidal behavior. However, cross-sectional studies provide no information about causality, and it is possible that depression and/or suicide attempts cause subsequent IPV or that there are common risk factors for IPV, depression, and suicide. For example, individuals with depressive symptoms may be more accepting of partners with characteristics that predispose them to use violence, or early life exposure to violence may predispose individuals to both depression and choosing violent partners. Here, as part of the Global Burden of Disease Study 2010, the researchers investigate the extent to which experience of IPV is associated with subsequent depression and suicide attempts and vice versa in both men and women by undertaking a systematic review and meta-analysis of longitudinal studies that have examined IPV, depression, and suicide attempts. A systematic review uses predefined criteria to identify all the research on a given topic, meta-analysis combines the results of several studies, and longitudinal studies track people over time to investigate associations between specific characteristics and outcomes.
What Did the Researchers Do and Find?
The researchers identified 16 longitudinal studies involving a total of 36,163 participants that met their inclusion criteria. All the studies included women, but only four also included men. All the studies were undertaken in high- and middle-income countries. For women, 11 studies showed a statistically significant association (an association unlikely to have occurred by chance) between IPV and subsequent depressive symptoms. In a meta-analysis of six studies, experience of IPV nearly doubled the risk of women subsequently reporting depressive symptoms. In addition, there was evidence of an association in the reverse direction. In a meta-analysis of four studies, depressive symptoms nearly doubled the risk of women subsequently experiencing IPV. IPV was also associated with subsequent suicide attempts among women. For men, there was some evidence from two studies that IPV was associated with depressive symptoms but no evidence for an association between IPV and subsequent suicide attempt or between depressive symptoms and subsequent IPV.
What Do These Findings Mean?
These findings suggest that women who are exposed to IPV are at increased risk of subsequent depression and that women who are depressed are more likely to be at risk of IPV. They also provide evidence of an association between IPV and subsequent suicide attempt for women. The study provides little evidence for similar relationships among men, but additional studies are needed to confirm this finding. Moreover, the accuracy of these findings is likely to be affected by several limitations of the study. For example, few of the included studies controlled for other factors that might have affected both exposure to IPV and depressive symptoms, and none of the studies considered the effect of emotional violence on depressive symptoms and suicide attempts. Nevertheless, these findings have two important implications. First, they suggest that preventing violence against women has the potential to reduce the global burden of disease related to depression and suicide. Second, they suggest that clinicians should pay attention to past experiences of violence and the risk of future violence when treating women who present with symptoms of depression.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001439.
This study is further discussed in a PLOS Medicine Perspective by Alexander Tsai
The US National Institute of Mental Health provides information on all aspects of depression and of suicide and suicide prevention (in English and Spanish)
The UK National Health Service Choices website provides detailed information about depression, including personal stories about depression, and information on suicide and its prevention; it has a webpage about domestic violence, which includes descriptions of personal experiences
The World Health Organization provides information on depression, on the global burden of suicide and on suicide prevention, and on intimate partner violence (some information in several languages)
MedlinePlus provides links to other resources about depression, suicide, and domestic violence (in English and Spanish)
The charity Healthtalkonline has personal stories about depression and about dealing with suicide
doi:10.1371/journal.pmed.1001439
PMCID: PMC3646718  PMID: 23671407
21.  The Impact of Newly Identified Loci on Coronary Heart Disease, Stroke and Total Mortality in the MORGAM Prospective Cohorts 
Genetic epidemiology  2009;33(3):237-246.
Recently, genome wide association studies (GWAS) have identified a number of single nucleotide polymorphisms (SNPs) as being associated with coronary heart disease (CHD). We estimated the effect of these SNPs on incident CHD, stroke and total mortality in the prospective cohorts of the MORGAM Project. We studied cohorts from Finland, Sweden, France and Northern Ireland (total N = 33,282, including 1,436 incident CHD events and 571 incident stroke events). The lead SNPs at seven loci identified thus far and additional SNPs (in total 42) were genotyped using a case-cohort design. We estimated the effect of the SNPs on disease history at baseline, disease events during follow-up and classic risk factors. Multiple testing was taken into account using false discovery rate (FDR) analysis. SNP rs1333049 on chromosome 9p21.3 was associated with both CHD and stroke (HR = 1.20, 95% CI 1.08–1.34 for incident CHD events and 1.15, 0.99–1.34 for incident stroke). SNP rs11670734 (19q12) was associated with total mortality and stroke. SNP rs2146807 (10q11.21) showed some association with the fatality of acute coronary event. SNP rs2943634 (2q36.3) was associated with high density lipoprotein (HDL) cholesterol and SNPs rs599839, rs4970834 (1p13.3) and rs17228212 (15q22.23) were associated with non-HDL cholesterol. SNPs rs2943634 (2q36.3) and rs12525353 (6q25.1) were associated with blood pressure. These findings underline the need for replication studies in prospective settings and confirm the candidacy of several SNPs that may play a role in the etiology of cardiovascular disease.
doi:10.1002/gepi.20374
PMCID: PMC2696097  PMID: 18979498
cardiovascular disease; genes; risk factors
22.  Independent Associations of Fasting Insulin, Glucose, and Glycated Haemoglobin with Stroke and Coronary Heart Disease in Older Women 
PLoS Medicine  2007;4(8):e263.
Background
Evidence suggests that variations in fasting glucose and insulin amongst those without frank type 2 diabetes mellitus are important determinants of cardiovascular disease. However, the relative importance of variations in fasting insulin, glucose, and glycated haemoglobin as risk factors for cardiovascular disease in women without diabetes is unclear. Our aim was to determine the independent associations of fasting insulin, glucose, and glycated haemoglobin with coronary heart disease and stroke in older women.
Methods and Findings
We undertook a prospective cohort study of 3,246 British women aged 60–79 y, all of whom were free of baseline coronary heart disease, stroke, and diabetes, and all of whom had fasting glucose levels below 7 mmol/l. Fasting insulin and homeostasis model assessment for insulin sensitivity (HOMA-S) were linearly associated with a combined outcome of coronary heart disease or stroke (n = 219 events), but there was no association of fasting glucose or glycated haemoglobin with these outcomes. Results were similar for coronary heart disease and stroke as separate outcomes. The age, life-course socioeconomic position, smoking, and physical activity adjusted hazard ratio for a combined outcome of incident coronary heart disease or stroke per one standard deviation of fasting insulin was 1.14 (95% CI 1.02–1.33). Additional adjustment for other components of metabolic syndrome, low-density lipoprotein cholesterol, fasting glucose, and glycated haemoglobin had little effect on this result.
Conclusions
Our findings suggest that in women in the 60–79 y age range, insulin resistance, rather than insulin secretion or chronic hyperglycaemia, is a more important risk factor for coronary heart disease and stroke. Below currently used thresholds of fasting glucose for defining diabetes, neither fasting glucose nor glycated haemoglobin are associated with cardiovascular disease.
From a prospective study of women aged 60-79 years, Debbie Lawlor and colleagues conclude that insulin resistance is an important risk factor for coronary heart disease and stroke.
Editors' Summary
Background.
Narrowing of the vessels that take blood to the heart and brain is a common form of cardiovascular disease—i.e., a disorder of the heart and blood vessels. It is a major cause of illness and death. By starving the heart and brain of oxygen, this condition causes coronary heart disease (CHD; heart problems such as angina and heart attacks) and strokes. A major risk factor for CHD and strokes is diabetes, a common chronic disease characterized by high levels of sugar (glucose) in the blood. In people who don't have diabetes, the hormone insulin controls blood-sugar levels. Insulin, which is released by the pancreas after eating, “instructs” insulin-responsive muscle and fat cells to absorb the glucose (released from food) from the bloodstream. In the very early stages of type 2 diabetes (the commonest type of diabetes, also called “adult onset” or “noninsulin-dependent” diabetes”), muscle and fat cells become unresponsive to insulin, so blood-sugar levels increase. This is called “insulin resistance.” The pancreas responds by making more insulin. As a result, people with insulin resistance have high blood levels of both insulin (hyperinsulinemia) and glucose (hyperglycemia). Eventually, the insulin-producing cells in the pancreas start to malfunction, insulin secretion decreases, and type 2 diabetes is the result.
Why Was This Study Done?
It is not yet clear whether it is insulin resistance or reduced insulin secretion that is responsible for the association between diabetes and cardiovascular disease. Physicians would like to know this information to help them to prevent CHD and strokes in their patients. There is evidence that variations in fasting glucose levels (blood glucose measured more than 8 h after eating), which provide an indication of how well pancreatic cells are producing insulin, and in fasting insulin levels, which provide an indication of insulin resistance, determine cardiovascular disease risk among people without type 2 diabetes, but the relative importance of these risk factors is unclear. In this study, the researchers have investigated whether markers of insulin resistance (fasting hyperinsulinemia) and of altered insulin secretion (fasting hyperglycemia, and increased glycated hemoglobin, which indicates how much sugar has been in the blood over the past few months) are associated with CHD and strokes in elderly women without diabetes. Their aim is to gain new insights into how diabetes affects cardiovascular disease risk.
What Did the Researchers Do and Find?
The researchers measured glucose, insulin, and glycated hemoglobulin in fasting blood samples taken from about 3,000 women aged 60–79 y when they enrolled in the British Women's Heart and Health Study. None of the women had CHD at enrollment, none had had a stroke, none had diagnosed diabetes, and all had a fasting blood glucose below 7 mmol/l (a higher reading indicates diabetes). After monitoring the women for nearly 5 y for CHD and strokes, the researchers looked for statistical associations between the occurrence of cardiovascular disease and markers of insulin resistance and reduced insulin secretion. They found that fasting insulin levels, but not fasting glucose or glycated hemoglobin levels, were associated with CHD and stroke, even after allowing for other factors that affect cardiovascular disease risk such as smoking and physical activity. In other words, raised fasting insulin levels increased the women's risk of developing cardiovascular disease.
What Do These Findings Mean?
These results indicate that in elderly women without diabetes, fasting insulin (a marker of insulin resistance) is a better predictor of future cardiovascular disease risk than fasting glucose or glycated hemoglobin (markers of reduced insulin secretion). This suggests that insulin resistance might be the main mechanism linking type 2 diabetes to CHD and stroke in elderly women. (Elderly women are known to run a high risk of developing these conditions, but they have been relatively neglected in previous studies of the risk factors for cardiovascular disease.) However, because relatively few women developed CHD during the study and even fewer had a stroke, this conclusion needs confirming in larger studies, preferably ones that include more rigorous tests of insulin resistance and secretion and also include women from more ethnic backgrounds than this study did. If the association between fasting insulin levels and cardiovascular disease risk is confirmed, therapeutic interventions or lifestyle interventions (for example, increased physical activity or weight loss) that prevent or reverse insulin resistance might reduce cardiovascular disease risk better than interventions that prevent chronic hyperglycemia.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040263.
MedlinePlus encyclopedia page on coronary heart disease, stroke, and diabetes (in English and Spanish)
Information for patients and caregivers from the US National Diabetes Information Clearinghouse on diabetes, including information on insulin resistance and on diabetes, heart disease, and stroke
Information on the British Women's Heart and Health Study
doi:10.1371/journal.pmed.0040263
PMCID: PMC1952205  PMID: 17760500
23.  Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1 Interacting Genes 
Cancer research  2011;71(17):5792-5805.
Inherited BRCA1 mutations confer elevated breast cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, TOPBP1 and time to breast and ovarian cancer diagnosis. False Discovery Rate (FDR) adjusted p-value for overall association of haplotypes (pFDR) with breast cancer were identified at ATM (pFDR =0.029), BRCC45 (pFDR=0.0.19), BRIP1 (pFDR =0.008), CTIP (pFDR =0.017), MERIT40 (pFDR =0.019), NBS1 (pFDR=0.003), RAD50 (pFDR=0.014), and TOPBP1 (pFDR =0.011) and were associated with breast cancer risk. Haplotypes at ABRA1 (pFDR=0.007), BRCC45 (pFDR=0.016 and pFDR=0.005 in two haplotype blocks) and RAP80 (pFDR<0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.
doi:10.1158/0008-5472.CAN-11-0773
PMCID: PMC3170727  PMID: 21799032
24.  Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1 Interacting Genes 
Cancer research  2011;71(17):5792-5805.
Inherited BRCA1 mutations confer elevated breast cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, TOPBP1 and time to breast and ovarian cancer diagnosis. False Discovery Rate (FDR) adjusted p-value for overall association of haplotypes (pFDR) with breast cancer were identified at ATM (pFDR =0.029), BRCC45 (pFDR=0.0.19), BRIP1 (pFDR =0.008), CTIP (pFDR =0.017), MERIT40 (pFDR =0.019), NBS1 (pFDR=0.003), RAD50 (pFDR=0.014), and TOPBP1 (pFDR =0.011) and were associated with breast cancer risk. Haplotypes at ABRA1 (pFDR=0.007), BRCC45 (pFDR=0.016 and pFDR=0.005 in two haplotype blocks) and RAP80 (pFDR<0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.
doi:10.1158/0008-5472.CAN-11-0773
PMCID: PMC3170727  PMID: 21799032
25.  Selectivity in Genetic Association with Sub-classified Migraine in Women 
PLoS Genetics  2014;10(5):e1004366.
Migraine can be sub-classified not only according to presence of migraine aura (MA) or absence of migraine aura (MO), but also by additional features accompanying migraine attacks, e.g. photophobia, phonophobia, nausea, etc. all of which are formally recognized by the International Classification of Headache Disorders. It remains unclear how aura status and the other migraine features may be related to underlying migraine pathophysiology. Recent genome-wide association studies (GWAS) have identified 12 independent loci at which single nucleotide polymorphisms (SNPs) are associated with migraine. Using a likelihood framework, we explored the selective association of these SNPs with migraine, sub-classified according to aura status and the other features in a large population-based cohort of women including 3,003 active migraineurs and 18,108 free of migraine. Five loci met stringent significance for association with migraine, among which four were selective for sub-classified migraine, including rs11172113 (LRP1) for MO. The number of loci associated with migraine increased to 11 at suggestive significance thresholds, including five additional selective associations for MO but none for MA. No two SNPs showed similar patterns of selective association with migraine characteristics. At one extreme, SNPs rs6790925 (near TGFBR2) and rs2274316 (MEF2D) were not associated with migraine overall, MA, or MO but were selective for migraine sub-classified by the presence of one or more of the additional migraine features. In contrast, SNP rs7577262 (TRPM8) was associated with migraine overall and showed little or no selectivity for any of the migraine characteristics. The results emphasize the multivalent nature of migraine pathophysiology and suggest that a complete understanding of the genetic influence on migraine may benefit from analyses that stratify migraine according to both aura status and the additional diagnostic features used for clinical characterization of migraine.
Author Summary
Migraine is among the most common and debilitating neurological disorders. Diagnostic criteria for migraine recognize a variety of symptoms including a primary dichotomous classification for the presence or absence of aura, typically a visual disturbance phenomenon, as well as others such as sensitivity to light or sound, and nausea, etc. We explored whether any of 12 recently discovered genetic variants associated with common migraine might have selective association for migraine sub-classified by aura status or nine additional migraine features in a population of middle-aged women including 3,003 migraineurs and 18,180 non-migraineurs. Five of the 12 genetic variants met the most stringent significance criterion for association with migraine, among which four had selective association with sub-classified migraine, including one that was selective for migraine without aura. At suggestive significance, all of the remaining genetic variants were selective for sub-classifications of migraine although no two variants showed the same pattern of selectivity. The selectivity patterns suggest very different contributions to migraine pathophysiology among the 12 loci and their implicated genes. Further, the results suggest that future discovery efforts for new migraine susceptibility loci would benefit by considering associations with sub-classified migraine toward the ultimate goals of more specific diagnosis and personalized treatment.
doi:10.1371/journal.pgen.1004366
PMCID: PMC4031047  PMID: 24852292

Results 1-25 (665914)