Systemic issues can adversely affect the diagnostic process. Many system-related barriers can be masked by ‘resilient’ actions of frontline providers (ie, actions supporting the safe delivery of care in the presence of pressures that the system cannot readily adapt to). We explored system barriers and resilient actions of primary care providers (PCPs) in the diagnostic evaluation of cancer.
We conducted a secondary data analysis of interviews of PCPs involved in diagnostic evaluation of 29 lung and colorectal cancer cases. Cases covered a range of diagnostic timeliness and were analyzed to identify barriers for rapid diagnostic evaluation, and PCPs’ actions involving elements of resilience addressing those barriers. We rated these actions according to whether they were usual or extraordinary for typical PCP work.
Resilient actions and associated barriers were found in 59% of the cases, in all ranges of timeliness, with 40% involving actions rated as beyond typical. Most of the barriers were related to access to specialty services and coordination with patients. Many of the resilient actions involved using additional communication channels to solicit cooperation from other participants in the diagnostic process.
Diagnostic evaluation of cancer involves several resilient actions by PCPs targeted at system deficiencies. PCPs’ actions can sometimes mitigate system barriers to diagnosis, and thereby impact the sensitivity of ‘downstream’ measures (eg, delays) in detecting barriers. While resilient actions might enable providers to mitigate system deficiencies in the short run, they can be resource intensive and potentially unsustainable. They complement, rather than substitute for, structural remedies to improve system performance. Measures to detect and fix system performance issues targeted by these resilient actions could facilitate diagnostic safety.
patient safety; systems resilience; quality and safety measurements; test results; care delays
Electronic health record (EHR)-based alerts can facilitate transmission of test results to healthcare providers, helping ensure timely and appropriate follow-up. However, failure to follow-up on abnormal test results (missed test results) persists in EHR-enabled healthcare settings. We aimed to identify contextual factors associated with facility-level variation in missed test results within the Veterans Affairs (VA) health system.
Design, setting and participants
Based on a previous survey, we categorised VA facilities according to primary care providers’ (PCPs’) perceptions of low (n=20) versus high (n=20) risk of missed test results. We interviewed facility representatives to collect data on several contextual factors derived from a sociotechnical conceptual model of safe and effective EHR use. We compared these factors between facilities categorised as low and high perceived risk, adjusting for structural characteristics.
Facilities with low perceived risk were significantly more likely to use specific strategies to prevent alerts from being lost to follow-up (p=0.0114). Qualitative analysis identified three high-risk scenarios for missed test results: alerts on tests ordered by trainees, alerts ‘handed off’ to another covering clinician (surrogate clinician), and alerts on patients not assigned in the EHR to a PCP. Test result management policies and procedures to address these high-risk situations varied considerably across facilities.
Our study identified several scenarios that pose a higher risk for missed test results in EHR-based healthcare systems. In addition to implementing provider-level strategies to prevent missed test results, healthcare organisations should consider implementing monitoring systems to track missed test results.
Elecronic Health Records; Missed Test Results; Patient Follow-up; Social-Technical Model; Patient Safety; Diagnostic Errors
Objective and methods
The association of 17 candidate single nucleotide polymorphisms (SNPs) in IL10 and other immune response genes (CRP, TLR4, IL6, IL1B, IL8, TNF, RNASEL) and genes related to obesity (PPARG, TCF7L2, ADIPOQ, LEP) with colorectal cancer was investigated. Haplotype tagging SNPs were chosen for IL10, CRP, and TLR4. Incident colorectal cancer cases (n = 208) and matched controls (n = 381) were identified between baseline in 1989 and 2003 among participants in the CLUE II cohort. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression.
Compared with the AA genotype at the candidate IL10-1082 locus (rs1800896), carrying one (OR, 0.79; 95% CI, 0.53–1.18) or two (OR, 0.58; 95% CI, 0.35–0.95) G alleles, a known higher producer of the anti-inflammatory cytokine IL-10, was associated with lower risk of colorectal cancer (ptrend = 0.03). Statistically significant associations with colorectal cancer were observed for three tagSNPs in IL10 (rs1800890, rs3024496, rs3024498) and one common haplotype, but these associations were due to high linkage disequilibrium with IL10-1082. Two CRP haplotypes (global p = 0.04) and TLR4 tagSNPs (rs7873784, rs11536891), but not TLR4 haplotypes, were associated with colorectal cancer.
Our study suggests that polymorphisms in IL10, and also possibly in CRP and other genes related to immune response or obesity may be associated with colorectal cancer.
Inflammation; Obesity; Colorectal cancer; Genetic epidemiology; Prospective study
A recent Institute of Medicine report called for attention to safety issues related to electronic health records (EHRs). We analyzed EHR-related safety concerns reported within a large, integrated healthcare system.
The Informatics Patient Safety Office of the Veterans Health Administration (VA) maintains a non-punitive, voluntary reporting system to collect and investigate EHR-related safety concerns (ie, adverse events, potential events, and near misses). We analyzed completed investigations using an eight-dimension sociotechnical conceptual model that accounted for both technical and non-technical dimensions of safety. Using the framework analysis approach to qualitative data, we identified emergent and recurring safety concerns common to multiple reports.
We extracted 100 consecutive, unique, closed investigations between August 2009 and May 2013 from 344 reported incidents. Seventy-four involved unsafe technology and 25 involved unsafe use of technology. A majority (70%) involved two or more model dimensions. Most often, non-technical dimensions such as workflow, policies, and personnel interacted in a complex fashion with technical dimensions such as software/hardware, content, and user interface to produce safety concerns. Most (94%) safety concerns related to either unmet data-display needs in the EHR (ie, displayed information available to the end user failed to reduce uncertainty or led to increased potential for patient harm), software upgrades or modifications, data transmission between components of the EHR, or ‘hidden dependencies’ within the EHR.
EHR-related safety concerns involving both unsafe technology and unsafe use of technology persist long after ‘go-live’ and despite the sophisticated EHR infrastructure represented in our data source. Currently, few healthcare institutions have reporting and analysis capabilities similar to the VA.
Because EHR-related safety concerns have complex sociotechnical origins, institutions with long-standing as well as recent EHR implementations should build a robust infrastructure to monitor and learn from them.
Electronic Health Records; sociotechnical; reporting systems; medical errors; human factors; patients safety
The hypothesis that germ-line polymorphisms in DNA repair genes influence cancer risk has previously been tested primarily on a cancer site-specific basis. The purpose of this study was to test the hypothesis that DNA repair gene allelic variants contribute to globally elevated cancer risk by measuring associations with risk of all cancers that occurred within a population-based cohort. In the CLUE II cohort study established in 1989 in Washington County, MD, this study was comprised of all 3619 cancer cases ascertained through 2007 compared with a sample of 2296 with no cancer. Associations were measured between 759 DNA repair gene single nucleotide polymorphisms (SNPs) and risk of all cancers. A SNP in O6-methylguanine-DNA methyltransferase, MGMT, (rs2296675) was significantly associated with overall cancer risk [per minor allele odds ratio (OR) 1.30, 95% confidence interval (CI) 1.19–1.43 and P-value: 4.1 × 10−8]. The association between rs2296675 and cancer risk was stronger among those aged ≤54 years old than those who were ≥55 years at baseline (P-for-interaction = 0.021). OR were in the direction of increased risk for all 15 categories of malignancies studied (P < 0.0001), ranging from 1.22 (P = 0.42) for ovarian cancer to 2.01 (P = 0.008) for urinary tract cancers; the smallest P-value was for breast cancer (OR 1.45, P = 0.0002). The results indicate that the minor allele of MGMT SNP rs2296675, a common genetic marker with 37% carriers, was significantly associated with increased risk of cancer across multiple tissues. Replication is needed to more definitively determine the scientific and public health significance of this observed association.
Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR.
Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula.
The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4×10−5) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5×10−4) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5×10−4) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome.
The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN.
A personal history of basal cell carcinoma (BCC) is associated with increased risk of other malignancies, but the reason is unknown. The hedgehog pathway is critical to the etiology of BCC, and is also believed to contribute to susceptibility to other cancers. This study tested the hypothesis that hedgehog pathway and pathway-related gene variants contribute to the increased risk of subsequent cancers among those with a history of BCC.
The study was nested within the ongoing CLUE II cohort study, established in 1989 in Washington County, Maryland, USA. The study consisted of a cancer-free control group (n=2,296) compared to three different groups of cancer cases ascertained through 2007, those diagnosed with: 1) Other (non-BCC) cancer only (n=2,349); 2) BCC only (n=534); and 3) BCC plus other cancer (n=446). The frequencies of variant alleles were compared among these four groups for 20 single nucleotide polymorphisms (SNPs) in 6 hedgehog pathway genes (SHH, IHH, PTCH2, SMO, GLI1, SUFU), and also 22 SNPs in VDR and 8 SNPs in FAS, which have cross-talk with the hedgehog pathway.
Comparing those with both BCC and other cancer versus those with no cancer, no significant associations were observed for any of the hedgehog pathway SNPs, or for the FAS SNPs. One VDR SNP was nominally significantly associated with the BCC cancer-prone phenotype, rs11574085 [per minor allele odds ratio (OR) 1.38, 95% confidence interval (CI) 1.05–1.82; p-value=0.02].
The hedgehog pathway gene SNPs studied, along with the VDR and FAS SNPs studied, are not strongly associated with the BCC cancer-prone phenotype.
skin cancer; genetics; polymorphisms; hedgehog; vitamin D receptor; fas
For unknown reasons, non-melanoma skin cancer (NMSC) is associated with increased risk of other malignancies. Focusing solely on DNA repair or DNA repair-related genes, this study tested the hypothesis that DNA repair gene variants contribute to the increased cancer risk associated with a personal history of NMSC. From the parent CLUE II cohort study, established in 1989 in Washington County, MD, the study consisted of a cancer-free control group (n 5 2296) compared with three mutually exclusive groups of cancer cases ascertained through 2007: (i) Other (non-NMSC) cancer only (n 5 2349); (ii) NMSC only (n 5 694) and (iii) NMSC plus other cancer (n 5 577). The frequency of minor alleles in 759 DNA repair gene single nucleotide polymorphisms (SNPs) was compared in these four groups. Comparing those with both NMSC and other cancer versus those with no cancer, 10 SNPs had allelic trend P-values <0.01. The two top-ranked SNPs were both within the thymine DNA glycosylase gene (TDG). One was a non-synonymous coding SNP (rs2888805) [per allele odds ratio (OR) 1.40, 95% confidence interval (CI) 1.16–1.70; P-value 5 0.0006] and the other was an intronic SNP in high linkage disequilibrium with rs2888805 (rs4135150). None of the associations had a P-value <6.6310−5, the threshold for statistical significance after correcting for multiple comparisons. The results pinpoint DNA repair genes most likely to contribute to the NMSC cancer-prone phenotype. A promising lead is genetic variants in TDG, important not only in base excision repair but also in regulating the epigenome and gene expression, which may contribute to the NMSC-associated increase in overall cancer risk.
Hepatitis B viral infection remains a serious global health problem despite the availability of a highly effective vaccine. Approximately 5% of HBV-infected adults develop chronic hepatitis B, which may result in liver cirrhosis or hepatocellular carcinoma. Variants of interleukin-10 (IL10) have been previously associated with chronic hepatitis B infection and progression to hepatocellular carcinoma. Single nucleotide polymorphisms (SNPs, n = 42) from the IL10, IL19, and IL20 gene regions were examined for an association with HBV infection outcome, either chronic or recovered, in a nested case-control study of African Americans and European Americans. Among African Americans, three nominally statistically significant SNP associations in IL10, two in IL20, and one haplotype association were observed with different HBV infection outcomes (P = 0.005–0.04). The SNP, rs1518108, in IL20 nominally deviated significantly from Hardy-Weinberg equilibrium in African Americans, with a large excess of heterozygotes in chronic HBV-infected cases (P = 0.0006), which suggests a strong genetic effect. Among European Americans, a nominally statistically significant SNP association in IL20, as well as an IL20 haplotype were associated with HBV recovery (P = 0.01–0.04). These results suggest that IL10 and IL20 gene variants influence HBV infection outcome and encourage the pursuit of further studies of these cytokines in HBV pathogenesis.
Interleukin-10; Inflammation; African American; Immunogenetics; Hepatitis b; HIV co-infection
Failure to notify patients of test results is common even when electronic health records (EHRs) are used to report results to practitioners. We sought to understand the broad range of social and technical factors that affect test result management in an integrated EHR-based health system.
Between June and November 2010, we conducted a cross-sectional, web-based survey of all primary care practitioners (PCPs) within the Department of Veterans Affairs nationwide. Survey development was guided by a socio-technical model describing multiple inter-related dimensions of EHR use.
Of 5001 PCPs invited, 2590 (51.8%) responded. 55.5% believed that the EHRs did not have convenient features for notifying patients of test results. Over a third (37.9%) reported having staff support needed for notifying patients of test results. Many relied on the patient's next visit to notify them for normal (46.1%) and abnormal results (20.1%). Only 45.7% reported receiving adequate training on using the EHR notification system and 35.1% reported having an assigned contact for technical assistance with the EHR; most received help from colleagues (60.4%). A majority (85.6%) stayed after hours or came in on weekends to address notifications; less than a third reported receiving protected time (30.1%). PCPs strongly endorsed several new features to improve test result management, including better tracking and visualization of result notifications.
Despite an advanced EHR, both social and technical challenges exist in ensuring notification of test results to practitioners and patients. Current EHR technology requires significant improvement in order to avoid similar challenges elsewhere.
missed test results; medical errors; diagnostic errors; lack of follow-up; health information technology; electronic health records
Nucleotide excision repair (NER) is responsible for protecting DNA in skin cells against ultraviolet radiation-induced damage. Using a candidate pathway approach, a matched case-control study nested within a prospective, community-based cohort was carried out to test the hypothesis that single nucleotide polymorphisms (SNPs) in NER genes are associated with susceptibility to non-melanoma skin cancer (NMSC). Histologically-confirmed cases of NMSC (n=900) were matched to controls (n=900) on age, gender, and skin type. Associations were measured between NMSC and 221 SNPs in 26 NER genes. Using the additive model, two tightly linked functional SNPs in ERCC6 were significantly associated with increased risk of NMSC: rs2228527 (odds ratio (OR) 1.57, 95% confidence interval (CI) 1.20 – 2.05), and rs2228529 (OR 1.57, 95% CI 1.20 – 2.05). These associations were confined to basal cell carcinoma of the skin (BCC) (rs2228529, OR 1.78, 95% CI 1.30 – 2.44; rs2228527 OR 1.78, 95% CI 1.31 – 2.43). These hypothesis-generating findings suggest functional variants in ERCC6 may be associated with an increased risk of NMSC that may be specific to BCC.
Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals.
A genomewide scan comprising more than 5,500 autosomal single nucleotide polymorphism markers (average spacing of 0.6 cM) was performed on 1,235 nuclear and extended pedigrees (3,972 diabetic participants) ascertained for DN from African-American (AA), American-Indian (AI), European-American (EA) and Mexican-American (MA) populations.
Strong evidence for linkage to DN was detected on chromosome 6p (p = 8.0 × 10−5, LOD = 3.09) in EA families as well as suggestive evidence for linkage to chromosome 7p in AI families. Regions on chromosomes 3p in AA, 7q in EA, 16q in AA and 22q in MA displayed suggestive evidence of linkage for urine ACR. The linkage peak on chromosome 22q overlaps the MYH9/APOL1 gene region, previously implicated in AA diabetic and nondiabetic nephropathies.
These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN.
Albuminuria; Diabetes mellitus; Renal failure; End-stage renal disease; Linkage; Allelic association
Cytomegalovirus (CMV) retinitis is a common opportunistic infection among patients with AIDS and still causes visual morbidity despite the wide spread usage of highly active antiretroviral therapy (HAART). The ubiquitous CMV pathogen contains a human interleukin-10 (IL-10) homolog in its genome and utilizes it to evade host immune reactions through an IL-10 receptor mediated immune-suppression pathway.
Effects of IL-10R1, IL-10 and previously described AIDS restriction gene variants are investigated on the development of CMV retinitis in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) cohort (n=1284).
In Europen Americans (n=750), a haplotype carrying an amino acid changing variation in the cytoplasmic domain (S420L) of IL-10R1 can be protective (OR = 0.14, CI: 0.02–0.94, P = 0.04) against, whereas another haplotype carrying an amino acid changing variation in the extracellular domain (I224V) of IL-10R1 can be more susceptible (OR = 6.21, CI: 1.22–31.54, P = 0.03) to CMV retinitis. In African Americans (n=534), potential effects of IL-10 variants are observed.
Host genetics may have a role in the occurrence of CMV retinitis in patients infected with HIV.
AIDS; CMV retinitis; HIV-1; host genetics; interleukin-10 receptor
We attempted to refine the understanding of an association of Y-chromosomal haplogroup I (hg-I) with enhanced AIDS progression that had been previously reported. First, we compared the progression phenotype between hg-I and its phylogenetically closest haplogroup J (hg-J). Then, we took a candidate gene approach resequencing DDX3Y, a crucial autoimmunity gene, in hg-I and other common European Y- chromosome haplogroups looking for functional variants. We extended the genetic analyses to CD24L4 and compared and contrasted the roles of disease based selection, demographic history, and population structure shaping the contemporary genetic landscape of hg-I chromosomes. Our results confirmed and refined the AIDS progression signal to hg-I, though no gene variant was identified that can explain the disease association. Molecular evolutionary and genetic analyses of the examined loci suggested a unique evolutionary history in hg-I, probably shaped by complex interactions of selection, demographic history, and high geographical differentiation leading to the formation of distinct hg-I subhaplogroups that today are associated with HIV/AIDS onset. Clearly, further studies on Y chromosome candidate loci sequencing to discover functional variants and discern the roles of evolutionary factors are warranted.
AIDS progression; CD24L4; DDX3Y; population growth; population structure; selection; Y chromosome
Chronic intra-prostatic inflammation and obesity are thought to influence prostate carcinogenesis. Thus, variants in genes in these pathways could be associated with prostate cancer risk.
We genotyped 17 common single nucleotide polymorphisms (SNPs) in RNASEL, TLR4, IL1B, IL6, IL8, IL10, TNF, CRP, ADIPOQ, LEP, PPARG, and TCF7L2 in 258 white prostate cancer cases and 258 matched controls nested in CLUE II. Single-locus analyses were conducted using conditional logistic regression. TagSNPs were selected in IL10, CRP, and TLR4 and haplotype analyses were done.
The A allele of IL10 -1082G>A (rs1800896), known to result in lower levels of this anti-inflammatory cytokine, was positively associated with risk (AG vs. GG, OR=1.69, 95% CI: 1.10–2.60; AA vs. GG, OR=1.81, 95% CI: 1.11–2.96; Ptrend=0.02). Associations of IL10 haplotypes with prostate cancer were explained by high linkage disequilibrium between two tagSNPs (rs1800890 and rs3024496) and -1082G>A. A TLR4 candidate SNP (rs4986790; AG/GG vs. AA, OR=0.60, 95% CI: 0.33–1.08; Ptrend=0.09), known to have decreased expression and be associated with lower circulating levels of inflammatory mediators, and tagSNP (rs10116253; CC vs. TT, OR=3.05, 95% CI: 1.11–8.41), but not haplotypes, were associated with risk. None of the other candidate SNPs or haplotypes was statistically significantly associated with risk.
Our prospective study suggests that genetic variation in IL10 and possibly TLR4 is associated with prostate cancer risk. Although none of the SNPs in the obesity genes tested was associated, this does not rule out a complex role of obesity and its metabolic consequences in prostate cancer etiology.
prostate cancer; single nucleotide polymorphism; inflammation; obesity
Candidate gene association studies (CGAS) are a useful epidemiologic approach to drawing inferences about relations between genes and disease, especially when experimental data support the involvement of specific biochemical pathways. The value of CGAS is apparent when allele frequencies are low, effect sizes are small, or the study population is limited or unique. CGAS is also valuable for validating previous reports of genetic associations with disease in different populations. Despite the many advantages, the information generated from CGAS is sometimes compromised because of either inefficient study design or suboptimal analytical approaches. Here the authors discuss issues related to the study design and statistical analyses of CGAS that can help to optimize their usefulness and information content. These issues include judicious hypothesis-driven selection of biochemical pathways, genes, and single nucleotide polymorphisms, as well as appropriate quality control and analytical procedures for measuring main effects and for evaluating environmental exposure modifications and interactions. A study design algorithm using the example of DNA repair genes and cancer is presented for purposes of illustration.
cancer; data analysis; DNA repair; genetic epidemiology; genome-wide association study; haplotypes; polymorphism, single nucleotide; research design
Africa is the source of all modern humans, but characterization of genetic variation and of relationships among populations across the continent has been enigmatic. We studied 121 African populations, four African American populations, and 60 non-African populations for patterns of variation at 1327 nuclear microsatellite and insertion/deletion markers. We identified 14 ancestral population clusters in Africa that correlate with self-described ethnicity and shared cultural and/or linguistic properties. We observed high levels of mixed ancestry in most populations, reflecting historical migration events across the continent. Our data also provide evidence for shared ancestry among geographically diverse hunter-gatherer populations (Khoesan speakers and Pygmies). The ancestry of African Americans is predominantly from Niger-Kordofanian (~71%), European (~13%), and other African (~8%) populations, although admixture levels varied considerably among individuals. This study helps tease apart the complex evolutionary history of Africans and African Americans, aiding both anthropological and genetic epidemiologic studies.
The host genetic basis of differential outcomes in HIV infection, progression, viral load set point and highly active retroviral therapy (HAART) responses was examined for the common Y haplogroups in European Americans and African Americans. Accelerated progression to acquired immune deficiency syndrome (AIDS) and related death in European Americans among Y chromosome haplogroup I (Y-I) subjects was discovered. Additionally, Y-I haplogroup subjects on HAART took a longer time to HIV-1 viral suppression and were more likely to fail HAART. Both the accelerated progression and longer time to viral suppression results observed in haplogroup Y-I were significant after false-discovery-rate corrections. A higher frequency of AIDS-defining illnesses was also observed in haplogroup Y-I. These effects were independent of the previously identified autosomal AIDS restriction genes. When the Y-I haplogroup subjects were further subdivided into six I subhaplogroups, no one subhaplogroup accounted for the effects on HIV progression, viral load or HAART response. Adjustment of the analyses for population stratification found significant and concordant haplogroup Y-I results. The Y chromosome haplogroup analyses of HIV infection and progression in African Americans were not significant. Our results suggest that one or more loci on the Y chromosome found on haplogroup Y-I have an effect on AIDS progression and treatment responses in European Americans.
Increasing evidence supports a role for cell-mediated immunity in the pathogenesis of cardiovascular disease. Single nucleotide polymorphisms (SNPs) in JAK3, STAT4, and STAT6 of the Janus kinase–signal transducer and activator of transcription (Jak-Stat) signal transduction pathway were examined for association with time to new cardiovascular events in incident dialysis patients from the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease study.
Prospective cohort study.
Setting & Participants
764 White (n=518) and Black (n=246) participants from 79 dialysis centers.
SNPs in JAK3, STAT4, and STAT6 selectedusing a pairwise approach to identify a maximally informative set of tag SNPs for populations of European and African descent.
Outcomes and Measurements
Cox proportional hazards models were used to estimate unadjusted and multivariable adjusted hazard ratios (HR) for incident cardiovascular disease events after dialysis initiation associated with each race-specific SNP.
Two European tag SNPs (rs3212780 and rs3213409) were associated with new cardiovascular disease events in White patients in JAK3, with unadjusted HR 1.92 (p<0.001) and 1.82 (p=0.07), respectively. One dual-tag SNP (rs3212752) in JAK3 was associated with new cardiovascular events in White patients with unadjusted HR 2.09 (p<0.001) and in Black patients with HR 2.07 (p=0.007). SNP rs3213409 codes for a valine to isoleucine change at amino acid 722, a potentially functional mutation. SNPs in STAT4 and STAT6 were not associated with cardiovascular events after the initiation of dialysis.
This study does not provide direct evidence for the mechanism of increased risk. Replication in independent cohorts is necessary.
Genetic polymorphisms in the Jak-Stat signaling pathway are associated with an increased risk of new cardiovascular events in incident dialysis patients.
dialysis; cardiovascular diseases; inflammation; genes
The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of African ancestry has been largely unexplained. To identify genetic variants predisposing to idiopathic and HIV-1–associated focal segmental glomerulosclerosis (FSGS), we carried out an admixture-mapping linkage-disequilibrium genome scan on 190 African American individuals with FSGS and 222 controls. We identified a chromosome 22 region with a genome-wide logarithm of the odds (lod) score of 9.2 and a peak lod of 12.4 centered on MYH9, a functional candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and haplotypes were recessively associated with FSGS, most strongly a haplotype spanning exons 14 through 23 (OR = 5.0, 95% CI = 3.5–7.1; P = 4 × 10−23, n = 852). This association extended to hypertensive ESKD (OR = 2.2, 95% CI = 1.5–3.4; n = 433), but not type 2 diabetic ESKD (n = 476). Genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESKD among African Americans.
Detecting recent selected ‘genomic footprints’ applies directly to the discovery of disease genes and in the imputation of the formative events that molded modern population genetic structure. The imprints of historic selection/adaptation episodes left in human and animal genomes allow one to interpret modern and ancestral gene origins and modifications. Current approaches to reveal selected regions applied in genome-wide selection scans (GWSSs) fall into eight principal categories: (I) phylogenetic footprinting, (II) detecting increased rates of functional mutations, (III) evaluating divergence versus polymorphism, (IV) detecting extended segments of linkage disequilibrium, (V) evaluating local reduction in genetic variation, (VI) detecting changes in the shape of the frequency distribution (spectrum) of genetic variation, (VII) assessing differentiating between populations (FST), and (VIII) detecting excess or decrease in admixture contribution from one population. Here, we review and compare these approaches using available human genome-wide datasets to provide independent verification (or not) of regions found by different methods and using different populations. The lessons learned from GWSSs will be applied to identify genome signatures of historic selective pressures on genes and gene regions in other species with emerging genome sequences. This would offer considerable potential for genome annotation in functional, developmental and evolutionary contexts.
genomes; genome-wide selection scans; whole genome sequences; candidate genes; human populations; vertebrate species
Rare mutations in nephrosis 2 (NPHS2), encoding podocin, are found in patients with familial and sporadic steroid resistant nephrotic syndrome and focal segmental glomerular sclerosis. The objective of this study was to assess the contribution of the commonly reported functional podocin polymorphism R229Q to kidney disease in the population-at-large and to replicate a prior study of an association of R229Q and albuminuria in the general population.
Large sample of the Atherosclerosis Risk in Communities (ARIC) Study, a population-based prospective study.
Setting and Participants
4424 white and 3746 black middle-aged adults
Genotype at the R229Q polymorphism in podocin
Urinary albumin-to-creatinine ratio (ACR) and decreased estimated glomerular filtration rate (eGFR) as measures of kidney damage/dysfunction
Crude and multivariable adjusted linear and logistic regression models
The R229Q allele frequency was 3.7% in 4424 white and 0.6% in 3746 black individuals. No significant association of R229Q with increased ACR or decreased eGFR was observed (adjusted odds ratio of ACR ≥30 mg/g in RQ/QQ vs. RR carriers 1.18 (95% CI 0.76–1.84; adjusted odds ratio of eGFR <60 ml/min/1.73m2 in RQ/QQ vs. RR carriers 1.18 (95% CI 0.76–1.83). As expected, the established kidney disease risk factors hypertension and diabetes mellitus were strongly associated with measures of kidney damage/dysfunction, but the R229Q polymorphism was not associated with a further increase of kidney disease measures.
Single measurement of ACR, sample of all ARIC participants
No significant association of the relatively rare R229Q variant and ACR or eGFR was found in either white or back individuals. The phenotypic effect of a variant such as R229Q would have to be of great magnitude in order to meaningfully contribute to the risk of kidney disease on a population level. The importance of such variants in the general population as well as replication studies can best be evaluated in large community-based studies that allow for accounting of established disease risk factors.
NPHS2; podocin; albuminuria; association study; functional variant; population-based sample
Apolipoprotein E polymorphisms (APOE) have been associated with lowered glomerular filtration rate (GFR) and chronic kidney disease (CKD) with e2 allele conferring risk and e4 providing protection. However, few data are available in non-European ethnic groups or in a population-based cohort.
The authors analyzed 5,583 individuals from the Third National Health and Nutrition Examination Survey (NHANES III) to determine association with estimated GFR by the Modification of Diet in Renal Disease (MDRD) equation and low-GFR cases. Low-GFR cases were defined as GFR <75 ml/min/1.73 m2; additionally, GFR was analyzed continuously.
In univariate analysis, the e4 allele was negatively associated with low-GFR cases in non-Hispanic whites, odds ratio (OR): 0.76, 95% confidence interval (CI): 0.60, 0.97. In whites, there was a significant association between increasing APOE score (indicating greater number of e2 alleles) and higher prevalence of low-GFR cases (OR: 1.21, 95%CI: 1.01, 1.45). Analysis of continuous GFR in whites found the e4 allele was associated with higher levels of continuous GFR (β-coefficient: 2.57 ml/min/1.73 m2, 95%CI: 0.005, 5.14); in non-Hispanic blacks the e2 allele was associated with lower levels of continuous GFR (β-coefficient: -3.73 ml/min/1.73 m2, 95%CI: -6.61, -0.84). APOE e2 and e4 alleles were rare and not associated with low-GFR cases or continuous GFR in Mexican Americans.
In conclusion, the authors observed a weak association between the APOE e4 allele and low-GFR cases and continuous GFR in non-Hispanic whites, and the APOE e2 allele and continuous GFR in non-Hispanic blacks, but found no association with either measure of kidney function in Mexican Americans. Larger studies including multiethnic groups are needed to determine the significance of this association.
End stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans. This led to the hypothesis that susceptibility alleles for ESRD have a higher frequency in West African than European gene pool. We performed a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and demonstrated a highly significant association between excess African ancestry and non-diabetic ESRD (LOD 5.70) but not diabetic ESRD (LOD 0.47) on chromosome 22q12. Each copy of the European ancestral allele conferred a relative risk of 0.50 (95% credible interval 0.39 – 0.63) compared to African ancestry. Multiple common SNPs (allele frequency ranging from 0.2 to 0.6) in the gene that encodes non-muscle myosin heavy chain type II isoform A (MYH9) were associated with 2-4 times greater risk of non-diabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans.
Understanding structure and function of human genome requires knowledge of genomes of our closest living relatives, the primates. Nucleotide insertions and deletions (indels) play a significant role in differentiation that underlies phenotypic differences between humans and chimpanzees. In this study, we evaluated distribution, evolutionary history, and function of indels found by comparing syntenic regions of the human and chimpanzee genomes.
Specifically, we identified 6,279 indels of 10 bp or greater in a ~33 Mb alignment between human and chimpanzee chromosome 22. After the exclusion of those in repetitive DNA, 1,429 or 23% of indels still remained. This group was characterized according to the local or genome-wide repetitive nature, size, location relative to genes, and other genomic features. We defined three major classes of these indels, using local structure analysis: (i) those indels found uniquely without additional copies of indel sequence in the surrounding (10 Kb) region, (ii) those with at least one exact copy found nearby, and (iii) those with similar but not identical copies found locally. Among these classes, we encountered a high number of exactly repeated indel sequences, most likely due to recent duplications. Many of these indels (683 of 1,429) were in proximity of known human genes. Coding sequences and splice sites contained significantly fewer of these indels than expected from random expectations, suggesting that selection is a factor in limiting their persistence. A subset of indels from coding regions was experimentally validated and their impacts were predicted based on direct sequencing in several human populations as well as chimpanzees, bonobos, gorillas, and two subspecies of orangutans.
Our analysis demonstrates that while indels are distributed essentially randomly in intergenic and intronic genomic regions, they are significantly under-represented in coding sequences. There are substantial differences in representation of indel classes among genomic elements, most likely caused by differences in their evolutionary histories. Using local sequence context, we predicted origins and phylogenetic relationships of gene-impacting indels in primate species. These results suggest that genome plasticity is a major force behind speciation events separating the great ape lineages.