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1.  A Genome-Wide Association Study of Chronic Otitis Media with Effusion and Recurrent Otitis Media Identifies a Novel Susceptibility Locus on Chromosome 2 
Chronic otitis media with effusion (COME) and recurrent otitis media (ROM) have been shown to be heritable, but candidate gene and linkage studies to date have been equivocal. Our aim was to identify genetic susceptibility factors using a genome-wide association study (GWAS). We genotyped 602 subjects from 143 families with 373 COME/ROM subjects using the Illumina Human CNV370-Duo DNA Bead Chip (324,748 SNPs). We carried out the GWAS scan and imputed SNPs at the regions with the most significant associations. Replication genotyping in an independent family-based sample was conducted for 53 SNPs: the 41 most significant SNPs with P < 10−4 and 12 imputed SNPs with P < 10−4 on chromosome 15 (near the strongest signal). We replicated the association of rs10497394 (GWAS discovery P = 1.30 × 10−5) on chromosome 2 in the independent otitis media population (P = 4.7 × 10−5; meta-analysis P = 1.52 × 10−8). Three additional SNPs had replication P values < 0.10. Two were on chromosome 15q26.1 including rs1110060, the strongest association with COME/ROM in the primary GWAS (P = 3.4 ×10−7) in KIF7 intron 7 (P = 0.072), and rs10775247, a non-synonymous SNP in TICRR exon 2 (P = 0.075). The third SNP rs386057 was on chromosome 5 in TPPP intron 1 (P = 0.045). We have performed the first GWAS of COME/ROM and have identified a SNP rs10497394 on chromosome 2 is significantly associated with COME/ROM susceptibility. This SNP is within a 537 kb intergenic region, bordered by CDCA7 and SP3. The genomic and functional significance of this newly identified locus in COME/ROM pathogenesis requires additional investigation.
PMCID: PMC3825021  PMID: 23974705
otitis media; genetics; genome; susceptibility; locus
2.  Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm 
Gretarsdottir, Solveig | Baas, Annette F | Thorleifsson, Gudmar | Holm, Hilma | den Heijer, Martin | de Vries, Jean-Paul P M | Kranendonk, Steef E | Zeebregts, Clark J A M | van Sterkenburg, Steven M | Geelkerken, Robert H | van Rij, Andre M | Williams, Michael J A | Boll, Albert P M | Kostic, Jelena P | Jonasdottir, Adalbjorg | Jonasdottir, Aslaug | Walters, G Bragi | Masson, Gisli | Sulem, Patrick | Saemundsdottir, Jona | Mouy, Magali | Magnusson, Kristinn P | Tromp, Gerard | Elmore, James R | Sakalihasan, Natzi | Limet, Raymond | Defraigne, Jean-Olivier | Ferrell, Robert E | Ronkainen, Antti | Ruigrok, Ynte M | Wijmenga, Cisca | Grobbee, Diederick E | Shah, Svati H | Granger, Christopher B | Quyyumi, Arshed A | Vaccarino, Viola | Patel, Riyaz S | Zafari, A Maziar | Levey, Allan I | Austin, Harland | Girelli, Domenico | Pignatti, Pier Franco | Olivieri, Oliviero | Martinelli, Nicola | Malerba, Giovanni | Trabetti, Elisabetta | Becker, Lewis C | Becker, Diane M | Reilly, Muredach P | Rader, Daniel J | Mueller, Thomas | Dieplinger, Benjamin | Haltmayer, Meinhard | Urbonavicius, Sigitas | Lindblad, Bengt | Gottsäter, Anders | Gaetani, Eleonora | Pola, Roberto | Wells, Philip | Rodger, Marc | Forgie, Melissa | Langlois, Nicole | Corral, Javier | Vicente, Vicente | Fontcuberta, Jordi | España, Francisco | Grarup, Niels | Jørgensen, Torben | Witte, Daniel R | Hansen, Torben | Pedersen, Oluf | Aben, Katja K | de Graaf, Jacqueline | Holewijn, Suzanne | Folkersen, Lasse | Franco-Cereceda, Anders | Eriksson, Per | Collier, David A | Stefansson, Hreinn | Steinthorsdottir, Valgerdur | Rafnar, Thorunn | Valdimarsson, Einar M | Magnadottir, Hulda B | Sveinbjornsdottir, Sigurlaug | Olafsson, Isleifur | Magnusson, Magnus Karl | Palmason, Robert | Haraldsdottir, Vilhelmina | Andersen, Karl | Onundarson, Pall T | Thorgeirsson, Gudmundur | Kiemeney, Lambertus A | Powell, Janet T | Carey, David J | Kuivaniemi, Helena | Lindholt, Jes S | Jones, Gregory T | Kong, Augustine | Blankensteijn, Jan D | Matthiasson, Stefan E | Thorsteinsdottir, Unnur | Stefansson, Kari
Nature genetics  2010;42(8):692-697.
We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 × 10−10. In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 × 10−5), peripheral arterial disease (OR = 1.14, P = 3.9 × 10−5) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases—that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.
PMCID: PMC4157066  PMID: 20622881
3.  The AVPR1A Gene and Substance Use Disorders: Association, Replication, and Functional Evidence 
Biological psychiatry  2011;70(6):519-527.
The liability to addiction has been shown to be highly genetically correlated across drug classes, suggesting nondrug-specific mechanisms.
In 757 subjects, we performed association analysis between 1536 single nucleotide polymorphisms (SNPs) in 106 candidate genes and a drug use disorder diagnosis (DUD).
Associations (p ≤ .0008) were detected with three SNPs in the arginine vasopressin 1A receptor gene, AVPR1A, with a gene-wise p value of 3 × 10−5. Bioinformatic evidence points to a role for rs11174811 (microRNA binding site disruption) in AVPR1A function. Based on literature implicating AVPR1A in social bonding, we tested spousal satisfaction as a mediator of the association of rs11174811 with the DUD. Spousal satisfaction was significantly associated with DUD in males (p <.0001). The functional AVPR1A SNP, rs11174811, was associated with spousal satisfaction in males (p = .007). Spousal satisfaction was a significant mediator of the relationship between rs11174811 and DUD. We also present replication of the association in males between rs11174811 and substance use in one clinically ascertained (n = 1399) and one epidemiologic sample (n = 2231). The direction of the association is consistent across the clinically-ascertained samples but reversed in the epidemiologic sample. Lastly, we found a significant impact of rs11174811 genotype on AVPR1A expression in a postmortem brain sample.
The findings of this study call for expansion of research into the role of the arginine vasopressin and other neuropeptide system variation in DUD liability.
PMCID: PMC4083653  PMID: 21514569
Addiction; alcoholism; gene systems; genetic association; social relationships; vasopressin
4.  Polymorphic variation in the dopamine D4 receptor predicts delay discounting as a function of childhood socioeconomic status: evidence for differential susceptibility 
Inconsistent or null findings among studies associating behaviors on the externalizing spectrum—addictions, impulsivity, risk-taking, novelty-seeking traits—with presence of the 7-repeat allele of a common length polymorphism in the gene encoding the dopamine D4 receptor (DRD4) may stem from individuals’ variable exposures to prominent environmental moderators (gene × environment interaction). Here, we report that relative preference for immediate, smaller rewards over larger rewards delayed in time (delay discounting), a behavioral endophenotype of impulsive decision-making, varied by interaction of DRD4 genotype with childhood socioeconomic status (SES) among 546 mid-life community volunteers. Independent of age, sex, adulthood SES and IQ, participants who were both raised in families of distinctly low SES (low parental education and occupational grade) and carried the DRD4 7-repeat allele discounted future rewards more steeply than like-reared counterparts of alternate DRD4 genotype. In the absence of childhood socioeconomic disadvantage, however, participants carrying the 7-repeat allele discounted future rewards less steeply. This bidirectional association of DRD4 genotype with temporal discounting, conditioned by participants’ early life circumstances, accords with a recently proposed developmental model of gene × environment interaction (‘differential susceptibility’) that posits genetically modulated sensitivity to both adverse and salubrious environmental influences.
PMCID: PMC3682430  PMID: 22345368
gene–environment interaction; differential susceptibility; delay discounting; DRD4; childhood socioeconomic status; impulsivity
5.  Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment 
Neuropsychopharmacology  2013;38(6):985-995.
Depression has been associated with inflammation, and inflammation may both influence and interact with growth factors such as brain-derived neurotrophic factor (BDNF). Both the functional Val66Met BDNF polymorphism (rs6265) and BDNF levels have been associated with depression. It is thus plausible that decreased BDNF could mediate and/or moderate cytokine-induced depression. We therefore prospectively employed the Beck Depression Inventory-II (BDI-II), the Hospital Anxiety and Depression Scale (HADS), and the Montgomery–Asberg Depression Rating Scale (MADRS) in 124 initially euthymic patients during treatment with interferon-alpha (IFN-α), assessing serum BDNF and rs6265. Using mixed-effect repeated measures, lower pretreatment BDNF was associated with higher depression symptoms during IFN-α treatment (F144,17.2=6.8; P<0.0001). However, although the Met allele was associated with lower BDNF levels (F1,83.0=5.0; P=0.03), it was only associated with increased MADRS scores (F4,8.9=20.3; P<0.001), and not the BDI-II or HADS. An exploratory comparison of individual BDI-II items indicated that the Met allele was associated with suicidal ideation, sadness, and worthlessness, but not neurovegetative symptoms. Conversely, the serotonin transporter promoter polymorphism (5-HTTLPR) short allele was associated with neurovegetative symptoms such as insomnia, poor appetite and fatigue, but not sadness, worthlessness, or suicidal ideation. IFN-α therapy further lowered BDNF serum levels (F4,37.7=5.0; P=0.003), but this decrease occurred regardless of depression development. The findings thus do not support the hypothesis that decreasing BDNF is the primary pathway by which IFN-α worsens depression. Nonetheless, the results support the hypothesis that BDNF levels influence resiliency against developing inflammatory cytokine-associated depression, and specifically to a subset of symptoms distinct from those influenced by 5-HTTLPR.
PMCID: PMC3629388  PMID: 23303061
Depression; Unipolar; Bipolar; Mood; Anxiety; Stress Disorders; Neuropharmacology; Neuropsychoimmunology; Pharmacogenetics; Pharmacogenomics; cytokine; inflammation; growth factor; major depression; pharmacogenetic; psychoneuroimmunology
6.  Mannose binding lectin genotypes are not associated with increased risk of unexplained recurrent pregnancy loss 
Immune response to infections has been associated with recurrent pregnancy loss (RPL). Low plasma mannose binding lectin (MBL) levels, an innate immunity factor in infections, has been related to RPL. In this study, we tested the hypothesis that MBL genotypes that are known to cause reduced plasma MBL levels are significantly more frequent among women experiencing unexplained RPL.
This study included 219 Caucasian women diagnosed with unexplained RPL and 236 control women. All participants were genotyped for two promoter (−550 C > G and −221 G > C) and three missense (R52C, G54D and G57E) mutations in exon 1. These mutations are known to be associated with variations in plasma MBL levels. Genotype frequencies were estimated by gene counting and were compared to the expectation of Hardy-Weinberg equilibrium by chi-squared (X2) analysis and Fisher’s exact test. Allele and genotype frequencies were compared in cases and controls using X2 contingency table analysis.
There was no difference in demographics between cases and controls. The number of miscarriages in the participants with RPL ranged from 2 to 10 spontaneous abortions (SAB’s) per participant. Populations genotyped were in Hardy-Weinberg equilibrium. There was no association between a history of RPL and multi-SNP genotypes at the MBL locus. In unexplained RPL, the number of SAB’s and live birth rates were unaffected by MBL genotype. There was no association between MBL genotype and the risk of unexplained RPL. The occurrence of live birth was not associated with MBL genotype.
Genotypes known to cause low MBL plasma levels are not associated with an increased risk of unexplained RPL.
PMCID: PMC3663970  PMID: 23563916
Recurrent pregnancy loss; Mannose binding lectin; Genotyping; Spontaneous abortion
7.  Racial Variation in Toll-like Receptor Variants Among Women With Pelvic Inflammatory Disease 
The Journal of Infectious Diseases  2012;207(6):940-946.
Background. Racial disparities exist in gynecological diseases. Variations in Toll-like receptor (TLR) genes may alter signaling following microbial recognition.
Methods. We explored genotypic differences in 6 functional variants in 4 TLR genes (TLR1, TLR2, TLR4, TLR6) and the adaptor molecule TIRAP between 205 African American women and 51 white women with clinically suspected pelvic inflammatory disease (PID). A permutated P < .007 was used to assess significance. Associations between race and endometritis and/or upper genital tract infection (UGTI) were explored. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).
Results. The TT genotype for TLR1 rs5743618, the GG genotype for TLR1 rs4833095, the CC genotype for TLR2 rs3804099, the TLR6 rs5743810 T allele, and the CC genotype for TIRAP rs8177374 significantly differed between races (P < .007). African American race was associated with endometritis and/or UGTI (OR, 4.2 [95% CI, 2.0–8.7]; P = .01). Among African Americans, the TLR6 rs5743810 T allele significantly decreased endometritis and/or UGTI (OR, 0.4 [95% CI, .2–.9]; P = .04). Additionally, rs5743618, rs4833095, and rs8177374 increased endometritis and/or UGTI, albeit not significantly.
Conclusions. Among women with PID, TLR variants that increase inflammation are associated with African American race and may mediate the relationship between race and endometritis and/or UGTI.
PMCID: PMC3571443  PMID: 23255565
Chlamydia trachomatis; Neisseria gonorrhoeae; inflammation; pelvic inflammatory disease; race; Toll-like receptors
8.  The Brain-Derived Neurotrophic Factor Val66Met Polymorphism Moderates an Effect of Physical Activity on Working Memory Performance 
Psychological science  2013;24(9):1770-1779.
Physical activity enhances cognitive performance, yet individual variability in its effectiveness limits its widespread therapeutic application. Genetic differences might be one source of this variation. For example, carriers of the methionine-specifying (Met) allele of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have reduced secretion of BDNF and poorer memory, yet physical activity increases BDNF levels. To determine whether the BDNF polymorphism moderated an association of physical activity with cognitive functioning among 1,032 midlife volunteers (mean age = 44.59 years), we evaluated participants’ performance on a battery of tests assessing memory, learning, and executive processes, and evaluated their physical activity with the Paffenbarger Physical Activity Questionnaire. BDNF genotype interacted robustly with physical activity to affect working memory, but not other areas of cognitive functioning. In particular, greater levels of physical activity offset a deleterious effect of the Met allele on working memory performance. These findings suggest that physical activity can modulate domain-specific genetic (BDNF) effects on cognition.
PMCID: PMC3947596  PMID: 23907543
BDNF; physical activity; working memory; executive function; genetics; visual memory; episodic memory
9.  Melanopsin Gene Variations Interact With Season to Predict Sleep Onset and Chronotype 
Chronobiology international  2012;29(8):1036-1047.
The human melanopsin gene has been reported to mediate risk for seasonal affective disorder (SAD), which is hypothesized to be caused by decreased photic input during winter when light levels fall below threshold, resulting in differences in circadian phase and/or sleep. However, it is unclear if melanopsin increases risk of SAD by causing differences in sleep or circadian phase, or if those differences are symptoms of the mood disorder. To determine if melanopsin sequence variations are associated with differences in sleep-wake behavior among those not suffering from a mood disorder, the authors tested associations between melanopsin gene polymorphisms and self-reported sleep timing (sleep onset and wake time) in a community sample (N = 234) of non-Hispanic Caucasian participants (age 30–54 yrs) with no history of psychological, neurological, or sleep disorders. The authors also tested the effect of melanopsin variations on differences in preferred sleep and activity timing (i.e., chronotype), which may reflect differences in circadian phase, sleep homeostasis, or both. Daylength on the day of assessment was measured and included in analyses. DNA samples were genotyped for melanopsin gene polymorphisms using fluorescence polarization. P10L genotype interacted with daylength to predict self-reported sleep onset (interaction p < .05). Specifically, sleep onset among those with the TT genotype was later in the day when individuals were assessed on longer days and earlier in the day on shorter days, whereas individuals in the other genotype groups (i.e., CC and CT) did not show this interaction effect. P10L genotype also interacted in an analogous way with daylength to predict self-reported morningness (interaction p < .05). These results suggest that the P10L TT genotype interacts with daylength to predispose individuals to vary in sleep onset and chronotype as a function of daylength, whereas other genotypes at P10L do not seem to have effects that vary by daylength. A better understanding of how melanopsin confers heightened responsivity to daylength may improve our understanding of a broad range of behavioral responses to light (i.e., circadian, sleep, mood) as well as the etiology of disorders with seasonal patterns of recurrence or exacerbation.
PMCID: PMC3724237  PMID: 22881342
Chronotype; Genetics; Melanopsin; Seasonal affective disorder; Sleep
10.  Renal Function and Genetic Polymorphisms in Pediatric Heart Transplant Recipients 
Common genetic variations influence rejection, infection, drug metabolism, and side effect profiles after pediatric heart transplantation. Reports in adults suggest that genetic background may influence post-transplant renal function. In this multicenter study we investigated the association of genetic polymorphisms (GP) in a panel of candidate genes on renal function in 453 pediatric heart transplant recipients.
We performed genotyping for functional GPs in 19 candidate genes. Renal function was determined annually after transplantation by calculation of glomerular filtration rate (eGFR). Mixed effects and Cox proportional hazard models were used to assess recipient characteristics and the effect of GPs on longitudinal eGFR and time to eGFR <60 mL/min/1.73m2.
Mean age at transplantation was 6.2 ± 6.1 years and mean follow-up was 5.1 ± 2.5 years. Older age at transplant and black race were independently associated with post-transplant renal dysfunction. In univariate analyses, FASL (C-843T) T allele (p=0.014) and HO-1 (A326G) G allele (p=0.0017) were associated with decreased renal function. After adjusting for age and race, these associations were attenuated [FASL (p=0.075), HO-1 (p=0.053)]. We found no associations of other GPs, including GPs in TGFβ1, CYP3A5, ABCB1, and ACE, with post-transplant renal function.
In this multicenter, large sample of pediatric heart transplant recipients we found no strong associations between GPs in 19 candidate genes and post-transplant renal function. Our findings contradict reported associations of CYP3A5 and TGFβ1 with renal function and suggest that genotyping for these GPs will not facilitate individualized immunosuppression for the purpose of protecting renal function after pediatric heart transplantation.
PMCID: PMC3428223  PMID: 22789135
American journal of hypertension  2009;22(3):288-293.
Sodium lithium countertransport (SLC) activity, an intermediate phenotype of essential hypertension, has been linked to a region of baboon chromosome 5, homologous to human chromosome 4p. Human SLC34A2, located at chromosome 4p15.1-p15.3, is a positional candidate gene for SLC. The specific aim of this study was to identify genetic variants of the SLC34A2 gene in both baboon and human, and to examine the relationship of these polymorphisms with SLC activity and blood pressure.
Single nucleotide polymorphism (SNP) was identified by sequencing the SLC34A2 gene in 24 baboon founders and 94 unrelated individuals. All tag SNPs in SLC34A2 were genotyped in 1856 individuals from 252 pedigrees of mixed European ancestry. Three SNPs in baboon were genotyped in 634 baboons comprising 11 pedigrees.
In human, one SNP (rs12501856) was found to be significantly associated with SLC individually, though it did not pass multiple testing correction; however haplotype 2 containing allele C of SNP rs12501856 showed strong evidence of association with SLC (p=0.0037) after multiple comparison adjustment. This haplotype was also marginally associated with diastolic blood pressure and systolic blood pressure. This finding was confirmed in baboons, where a highly significant association was detected between SLC and baboon SNP Asn136Asn (p=0.0001). However, the associated SNP did not account for the linkage signal on baboon chromosome 5.
Consistent results in two different species imply that SLC34A2 is associated with SLC activity and blood pressure.
PMCID: PMC2652891  PMID: 19119262
12.  Genetic Analysis of Vertebral Trabecular Bone Density and Cross-Sectional Area in Older Men 
Vertebral bone mineral density (BMD) and cross-sectional area (CSA) are important determinants of vertebral bone strength. Little is known about the specific genetic variants that influence these phenotypes in humans. We investigated the potential genetic variants associated with vertebral trabecular volumetric BMD (vBMD) and CSA measured by quantitative computed tomography (QCT). We initially tested for association between these phenotypes and 4608 tagging and potentially functional single nucleotide polymorphisms (SNPs) in 383 candidate genes in 862 community-dwelling Caucasian men aged ≥65 years in the Osteoporotic Fractures in Men Study (MrOS). The most promising SNP associations (P<0.01) were then validated by genotyping an additional 1,156 randomly sampled men from the same cohort. We identified 11 SNPs in 10 genes (TGFBR3, SOST, KL, CALCR, LEP, CSF1R, PTN, GNRH2, FGFR2, MEPE) that were consistently associated with trabecular vBMD and 5 SNPs in 5 genes (CYP11B1, DVL2, DLX5, WNT4, PAX7) that were consistently associated with CSA in both samples (p<0.005). None of the SNPs associated with trabecular vBMD were associated with CSA. Our findings raise the possibility that at least some of the loci for vertebral trabecular BMD and bone size may be distinct.
PMCID: PMC3691107  PMID: 21153022
Osteoporosis; Genetics; BMD; men; QCT; Polymorphism
13.  Racial Disparities and Sex-Based Outcomes Differences after Severe Injury 
Controversy exists regarding mechanisms responsible for sex based outcome differences post-injury. X-chromosome linked immune response pathway polymorphisms represent a potential mechanism resulting in sex based outcome differences post-injury. The prevalences of these variants are known to differ across race. We sought to characterize racial differences and the strength of any sex based dimorphism post-injury.
Study Design
A retrospective analysis was performed using data derived from the National Trauma Data Bank (NTDB 7.1, 2002–2006). Blunt injured adult (>15yr) patients, surviving > 24hrs, with an injury severity score (ISS) >16 were analyzed (n=244,371). Patients were stratified by race (Caucasian, Black, Hispanic, Asian) and multivariable regression analysis was used to characterize the risk of mortality and the strength of protection associated with sex (Female vs. Male).
When stratified by race, multivariable models demonstrated Caucasian females had an 8.5% lower adjusted risk of mortality (OR 0.91, 95%CI 0.88–0.95, p < 0.001) relative to Caucasian males, with no significant association found for Hispanics or Blacks. An exaggerated survival benefit was afforded to Asian females relative to Asian males, having over a 40% lower adjusted risk of mortality (OR 0.59, 95%CI 0.44–78, p < 0.001). Asian males had over a 75% higher adjusted risk of mortality relative to non-Asian males (OR 1.77, 95%CI 1.5–2.0, p<0.001), while no significant difference in the mortality risk was found for Asian females relative to non-Asian females.
These results suggest that Asian race is associated with sex based outcome differences which are exaggerated, resulting due to worse outcome for Asian males. These racial disparities suggest a negative male X-chromosome linked effect as the mechanism responsible for these sex based outcome differences.
PMCID: PMC3360838  PMID: 22521668
14.  Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment 
Secondary lymphedema is a frequent complication of breast cancer associated with surgery, chemotherapy, or radiation following breast cancer treatment. The potential contribution of genetic susceptibility to risk of developing secondary lymphedema following surgical trauma, radiation, and other tissue insults has not been studied.
Experimental Design
To determine if women with breast cancer and secondary lymphedema had mutations in candidate lymphedema genes, we undertook a case - control study of 188 women diagnosed with breast cancer recruited from the University of Pittsburgh Breast Cancer Program ( between 2000–2010.
Candidate lymphedema genes, GJC2 (encoding connexin 47 [Cx47]), FOXC2, HGF, MET, and FLT4 (encoding VEGFR3), were sequenced for mutation. Bioinformatics analysis and in vitro functional assays were used to confirm significance of novel mutations.
Cx47 mutations were identified in individuals having secondary lymphedema following breast cancer treatment but not in breast cancer controls or normal women without breast cancer. These novel mutations are dysfunctional as assessed through in vitro assays and bioinformatics analysis, and provide evidence that altered gap junction function leads to lymphedema.
Our findings challenge the view that secondary lymphedema is solely due to mechanical trauma and support the hypothesis that genetic susceptibility is an important risk factor for secondary lymphedema. A priori recognition of genetic risk 1) raises the potential for early detection and intervention for a high risk group, and 2) allows the possibility of altering surgical approach and/or chemo- and radiation therapy, or direct medical treatment of secondary lymphedema with novel connexin modifying drugs.
Translational Relevance
Secondary lymphedema is a frequent and serious chronic complication of breast cancer treatment. Our finding of four independent mutations in Cx47, including one shared mutation previously reported in primary lymphedema, not only supports these mutations as a genetic risk to the development of secondary lymphedema but raises the likelihood that other genes may contribute to such a genetic risk to secondary lymphedema as well.
PMCID: PMC3625665  PMID: 22351697
The Journal of infectious diseases  2009;200(4):629-637.
Severe malarial anemia (SMA) resulting from Plasmodium falciparum infections is one of the leading causes of childhood mortality in sub-Saharan Africa. The innate immune mediator, macrophage migration inhibitory factor (MIF) plays a critical role in the pathogenesis of SMA.
To investigate the influence of MIF genetic variation on susceptibility to SMA, haplotypes of the MIF-173(G/C) and -794CATT5–8 polymorphisms were examined in a cohort of Kenyan children.
A statistically significant relationship between increasing frequencies of longer CATT repeats at -794 and increasing malarial anemia severity was observed. In addition, there was a strong association between lower MIF concentrations and longer CATT repeats. Multivariate logistic regression analyses demonstrated that the MIF-794CATT6/-173G (6G) haplotype was associated with protection against SMA while carriers of 7C or 8C haplotypes had increased risk of developing SMA. Furthermore, carriers of the 7C or 8C haplotypes had reduced plasma MIF levels during acute disease.
The findings demonstrate that variation in the MIF promoter influences susceptibility to SMA and peripheral MIF production. However, the MIF-173 and -794 polymorphisms appear to have both independent, as well as interactive effects on different measures of disease severity, suggesting a complex role for MIF in malarial pathogenesis.
PMCID: PMC3607439  PMID: 19591577
Plasmodium falciparum; severe malaria; anemia; Macrophage migration inhibitory factor (MIF); promoter polymorphisms
16.  Variants in Toll-like Receptor 1 and 4 Genes Are Associated With Chlamydia trachomatis Among Women With Pelvic Inflammatory Disease 
The Journal of Infectious Diseases  2012;205(4):603-609.
Background. Toll-like receptors (TLRs) are involved in the innate immune response. We examined whether TLR variants are associated with Chlamydia trachomatis infection among women with pelvic inflammatory disease (PID).
Methods. We tested whether 18 tagging single nucleotide polymorphisms (tagSNPs) assayed in 4 TLR genes (TLR1, TLR2, TLR4, TLR6) and 2 adaptor molecules (TIRAP, MyD88) were associated with C. trachomatis among 205 African American women with clinically suspected PID from the PID Evaluation and Clinical Health Study. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). An empirical P value of <.004 was considered significant.
Results. Women with PID who carried the TLR4 rs1927911 CC genotype had significantly increased odds of C. trachomatis (OR, 3.7; 95% CI, 1.6–8.8; P = .002). The TLR1 rs5743618TT genotype was also associated with C. trachomatis (OR, 2.8; 95% CI, 1.3–6.2; P = .008).
Conclusions. Among African American women with PID, variants in the TLR1 and TLR4 genes, which may increase signaling, were associated with increased C. trachomatis infection.
PMCID: PMC3266128  PMID: 22238472
17.  Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype 
Background Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case–control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking.
Methods To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, ‘Y402H’) with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26 494 individuals, including 14 174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene–smoking interaction; and 16 published studies from non-European ancestry.
Results In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10–2.45; P = 1.1 x 10−161]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies.
Conclusion The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.
PMCID: PMC3304526  PMID: 22253316
Age-related macular degeneration (AMD); Complement factor H gene; meta-ananlysis
18.  TOMM40 poly-T repeat lengths, age of onset and psychosis risk in Alzheimer disease 
Neurobiology of aging  2011;32(12):2328.e1-2328.e9.
Apolipoprotein E (APOE) ε4 alleles increase the risk for late-onset Alzheimer disease (LOAD) and decrease the age of onset. Recently, sequencing the APOE region in a small sample of LOAD subjects identified a variable length poly-T repeat sequence in the nearby gene, TOMM40, which may affect age of onset. We genotyped the TOMM40 poly-T repeat using a novel statistical approach to refine the identification of allele length in 892 LOAD subjects and evaluated its effects on age of onset. Because psychosis in LOAD is a heritable phenotype which has shown conflicting associations with APOE genotype, we also evaluated the association of poly-T repeat length with psychosis. Poly-T repeat lengths had a trimodal distribution which differed between APOE genotype groups. After accounting for APOE ε4 there was no association of poly-T repeat length with age of onset. Neither APOE ε4 nor poly-T repeat length was associated with psychosis. Our findings do not support the association of poly-T repeat length with age of onset in LOAD. The clinical implications of this repeat length polymorphism remain to be elucidated.
PMCID: PMC3192304  PMID: 21820212
Apolipoprotein E (APOE) ε4; late-onset Alzheimer disease (LOAD); psychosis; TOMM40; variable length poly-T repeat sequence
19.  Multi-institutional prostate cancer study of genetic susceptibility in populations of African descent 
Carcinogenesis  2011;32(9):1361-1365.
Prostate cancer disparities have been reported in men of African descent who show the highest incidence, mortality, compared with other ethnic groups. Few studies have explored the genetic and environmental factors for prostate cancer in men of African ancestry. The glutathione-S-transferases family conjugates carcinogens before their excretion and is expressed in prostate tissue. This study addressed the role of GSTM1 and GSTT1 deletions on prostate cancer risk in populations of African descent. This multi-institutional case–control study gathered data from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database, the African-Caribbean Cancer Consortium (AC3) and Men of African Descent and Carcinoma of the Prostate Consortium (MADCaP). The analysis included 10 studies (1715 cases and 2363 controls), five in African-Americans, three in African-Caribbean and two in African men. Both the GSTM1 and the GSTT1 deletions showed significant inverse associations with prostate cancer [odds ratio (OR): 0.90, 95% confidence interval (CI) 0.83–0.97 and OR 0.88, 95% CI: 0.82–0.96, respectively]. The association was restricted to Caribbean and African populations. A significant positive association was observed between GSTM1 deletion and prostate cancer in smokers in African-American studies (OR: 1.28, 95% CI: 1.01–1.56), whereas a reduced risk was observed in never-smokers (OR: 0.66, 95% CI: 0.46–0.95). The risk of prostate cancer increased across quartiles of pack-years among subjects carrying the deletion of GSTM1 but not among subjects carrying a functional GSTM1. Gene–environment interaction between smoking and GSTM1 may be involved in the etiology of prostate cancer in populations of African descent.
PMCID: PMC3165127  PMID: 21705483
20.  Alcohol dependence, disinhibited behavior and variation in the prodynorphin gene 
Biological psychology  2011;88(1):51-56.
The results of the current analyses present preliminary evidence of an association between putatively functional variation in the prodynorphin (PDYN) gene and a dimensional measure of disinhibited behavior. A 68 bp sequence in the core promoter region of the PDYN gene was genotyped in a community sample of 1021 adults aged 30–54. Participants were interviewed for lifetime history of DSM-IV alcohol dependence and completed two self-report measures of sensation seeking and impulsiveness. Fifteen percent (n=151) of the sample met DSM-IV criteria for alcohol dependence and while results did not support an association between the PDYN polymorphism and the diagnosis of alcohol dependence, we did observe an association between the “low” expressing L allele of the PDYN gene and a preference for engaging in disinhibited behavior. Additionally, people who had both a history of alcohol dependence and higher scores on this Disinhibited Behavior scale were most likely to carry an L allele. These results indicate that variation in the PDYN gene is associated with a dimensional trait or intermediate phenotype that reflects a preference for heavy drinking and engaging in related risky behaviors (e.g., drug use, sexual activity).
PMCID: PMC3171516  PMID: 21736916
21.  Multilocus Genetic Profile for Dopamine Signaling Predicts Ventral Striatum Reactivity 
Neuropsychopharmacology  2011;36(9):1940-1947.
Research integrating neuroimaging and molecular genetics has yielded important insights into how variability in brain chemistry predicts individual differences in brain function, behavior and related risk for psychopathology. However, existing studies have been limited by their focus on the independent effects of single polymorphisms with modest impact on brain chemistry. Here, we explored the effects of five functional polymorphisms affecting dopamine (DA) signaling on reward-related ventral striatum (VS) reactivity, measured with BOLD fMRI, in a sample of 69 Caucasians. We also compiled individual multilocus genetic profile scores reflecting the additive effects of alleles conferring relatively increased DA signaling across the five polymorphic loci: DAT1 9-repeat, DRD4 7-repeat, DRD2 -141C Del, DRD2 Taq1A C (A2), and COMT 158Met. These multilocus DA profile scores accounted for 10.9% of the inter-individual variability in reward-related VS reactivity. In contrast, none of the individual polymorphisms accounted for significant variability. Our results show that biologically informed multilocus genetic profiles have unique promise as indices of variability in brain chemistry that may yield advances in mapping individual differences in behaviorally relevant brain function. In turn, such genetic profiles may fuel gene–environment interactions research establishing trajectories of risk for psychopathology.
PMCID: PMC3154113  PMID: 21593733
genetic profile; dopamine; ventral striatum; reward; fMRI; dopamine; neurogenetics; neurotransmitters; biological psychiatry; genetic profile; ventral striatum; reward; fMRI
22.  Polymorphic variation in choline transporter gene (CHT1) is associated with early, subclinical measures of carotid atherosclerosis in humans 
Atherosclerosis is a heritable trait with little known about specific genetic influences on preclinical measures of plaque formation. Based on relations of parasympathetic-cholinergic function to atherosclerosis and to a choline transporter gene [CHT1 (G/T)] polymorphism, we investigated whether the same allelic variant predicts variation in carotid intima-media thickness (IMT) and plaque formation. Carotid IMT and plaque occurrence as well as genotyping for the CHT1 (G/T) variant were measured in a sample (N = 264) of generally healthy adults (age 30–55) of European ancestry. CHT1 GG homozygotes had greater IMT (P < 0.005) and plaque occurrence (P < 0.020) than T allele carriers. This is the first study showing polymorphic variation in the CHT1 gene to predict early, subclinical measures of carotid atherosclerosis which may aid in understanding cholinergic-vagal processes potentially underlying atherosclerotic risk.
PMCID: PMC3403193  PMID: 21337021
Atherosclerosis; Intima-media thickness; Plaque; Cholinergic function; Choline transport; Acetylcholine
23.  Variants of the Adenosine A2A Receptor Gene Are Protective against Proliferative Diabetic Retinopathy in Patients with Type 1 Diabetes 
Ophthalmic Research  2010;46(1):1-8.
The adenosine A2A receptor (ADORA2A) may ameliorate deleterious physiologic effects associated with tissue injury in individuals with diabetes. We explored associations between variants of the ADORA2A gene and proliferative diabetic retinopathy (PDR) in a cohort of patients with type 1 diabetes (T1D).
The participants were from the Pittsburgh Epidemiology of Diabetes Complications prospective study of childhood-onset T1D. Stereoscopic photographs of the retinal fundus taken at baseline, then biennially, for 10 years were used to define PDR according to the modified Airlie House system. Two tagging single nucleotide polymorphisms (tSNPs; rs2236624-C/T and rs4822489-G/T) in the ADORA2A gene were selected using the HapMap (haplotype map) reference database.
A significant association was observed between SNP rs2236624 and PDR in the recessive genetic model. Participants homozygous for the T allele displayed a decreased risk of developing prevalent PDR (odds ratio, OR = 0.36; p = 0.04) and incident PDR (hazard ratio = 0.156; p = 0.009), and for all cases of PDR combined (OR = 0.23; p = 0.001). The protective effect of T allele homozygosity remained after adjusting for covariates. Similarly, for SNP rs4822489, an association between PDR and T allele homozygosity was observed following covariate adjustment (OR = 0.55; 95% CI: 0.31–0.92; p = 0.04).
Genetic variants of ADORA2A offer statistically significant protection against PDR development in patients with T1D.
PMCID: PMC2997447  PMID: 21088442
Diabetes; Diabetic retinopathy; Single nucleotide polymorphism; Adenosine receptor
24.  PER2 rs2304672 Polymorphism Moderates Circadian-Relevant Reward Circuitry Activity in Adolescents 
Biological Psychiatry  2011;71(5):451-457.
Reward behavior in animals is influenced by circadian genes, including clock-pathway genes such as Period2 (PER2). Several forms of psychiatric illness are associated with both altered reward function and disturbances in circadian function. The PER2 single nucleotide polymorphism (SNP) rs2304672 has been associated with psychiatric illnesses involving reward dysfunction. Associations among circadian genes, function in neural reward circuits, and circadian-influenced behavior have not yet been studied in humans, however.
90 healthy adolescents underwent functional magnetic resonance imaging during a guessing task with monetary reward, genotyping for two PER2 SNPs (rs2304672, rs2304674), and actigraphy to measure sleep in their home environments. Weekend sleep midpoint, a behavioral index of circadian function, was derived from actigraphy. Puberty was measured by physical exam.
The rs2304672 SNP predicted blood oxygenation level-dependent response to monetary reward as constrained by sleep midpoint. Later sleep midpoint was associated with reduced activity in a key component of reward circuitry, medial prefrontal cortex (mPFC; Brodmann area 9/10/32), to reward outcome (pcorrected < .05). G allele carriers showed reduced activity in mPFC relative to CC homozygotes.
Our findings are the first to indicate that circadian genes have a significant impact upon circadian-relevant reward circuitry in humans. These findings have the potential to elucidate gene-brain-behavior relationships underlying reward processing and psychopathology.
PMCID: PMC3323120  PMID: 22137505
Brain function; circadian function; clock-pathway genes; development; reward; PER2
25.  No association of psychosis in Alzheimer disease with neurodegenerative pathway genes 
Neurobiology of aging  2010;32(3):555.e9-555.e11.
Psychotic symptoms occur in approximately 40% of subjects with Alzheimer disease (AD with Psychosis, AD+P) and identify a subgroup with more rapid cognitive decline. We evaluated in 867 AD subjects the association of AD+P with genes which may modify the pathologic process via effects on the accumulation of amyloid beta (Aβ) protein and/or hyperphosphorylated microtubule-associated protein tau (MAPT): amyloid precursor protein (APP), beta-site amyloid precursor protein cleaving enzyme (BACE1), sortilin-related receptor (SORL1), and MAPT. Each gene was thoroughly interrogated with tag SNPs, and gene-based tests were used to enhance power. We found no association of these genes with AD+P.
PMCID: PMC3065549  PMID: 21093110
Alzheimer's disease; psychosis; amyloid precursor protein (APP); beta-site amyloid precursor protein cleaving enzyme (BACE1); sortilin-related receptor (SORL1); microtubule-associated protein tau (MAPT); and Apolipoprotein E e4 (APOE e4)

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