Common genetic variants associated with lipid profiles in a Chinese pediatric population

Genome-wide association (GWA) studies have identified many candidate genes that are associated with blood lipid and lipoprotein concentrations. In this study, we want to know whether the results from European for lipid-related single-nucleotide polymorphisms (SNPs) are generalizable to Chinese children. We genotyped seven SNPs in Chinese school-age children (n = 3,503) and assessed the associations of these SNPs with lipids profiles and dyslipidemia. After false discovery rate correction, of the seven SNPs, six (rs2144300, p ~ 9.30 × 10^?3; rs1260333, p ~ 6.20 × 10^?11; rs1260326, p ~ 8.73 × 10^?11; rs10105606, p ~ 0.010; rs1748195, p ~ 0.016 and rs964184, p ~ 2.33 × 10^?13) showed strong association with triglycerides. Three SNPs (rs1260333, p ~ 3.30 × 10^?3; rs1260326, p ~ 4.39 × 10^?3 and rs2954029, p ~ 6.36 × 10^?4) showed strong association with total cholesterol. Two SNPs (rs10105606, p ~ 6.66 × 10^?4 and rs1748195, p ~ 2.55 × 10^?3) showed strong association with high density lipoprotein cholesterol. Four SNPs (rs1260333, p ~ 0.017; rs1260326, p ~ 0.013; rs2954029, p ~ 1.09 × 10^?3 and rs964184, p ~ 5.51 × 10^?3) showed strong association with low density lipoprotein cholesterol. There were significant associations between rs1260333 (OR is 0.82, 95 % CI 0.74–0.92, p ~ 3.96 × 10^?4), rs1260326 (OR is 0.82, 95 % CI 0.74–0.92, p ~ 5.31 × 10^?4), and rs964184 (OR is 1.36, 95 % CI 1.20–1.55, p ~ 1.89 × 10^?6) and dyslipidemia. These SNPs generated strong combined effects on lipid profiles and dyslipidemia. Our study demonstrates that SNPs associated with lipids from European GWA studies also play roles in Chinese children, which broadened the understanding of lipids metabolism.     

Gene-environment interactions and obesity traits among postmenopausal African-American and Hispanic women in the Women’s Health Initiative SHARe Study

Genome-wide association studies (GWAS) of obesity measures have identified associations with single nucleotide polymorphisms (SNPs). However, no large-scale evaluation of gene-environment interactions has been performed. We conducted a search of gene-environment (G × E) interactions in post-menopausal African-American and Hispanic women from the Women’s Health Initiative SNP Health Association Resource GWAS study. Single SNP linear regression on body mass index (BMI) and waist-to-hip circumference ratio (WHR) adjusted for multidimensional-scaling-derived axes of ancestry and age was run in race-stratified data with 871,512 SNPs available from African-Americans (N = 8,203) and 786,776 SNPs from Hispanics (N = 3,484). Tests of G × E interaction at all SNPs for recreational physical activity (m h/week), dietary energy intake (kcal/day), alcohol intake (categorical), cigarette smoking years, and cigarette smoking (ever vs. never) were run in African-Americans and Hispanics adjusted for ancestry and age at interview, followed by meta-analysis of G × E interaction terms. The strongest evidence for concordant G × E interactions in African-Americans and Hispanics was for smoking and marker rs10133840 (Q statistic P = 0.70, beta = ?0.01, P = 3.81 × 10^?7) with BMI as the outcome. The strongest evidence for G × E interaction within a cohort was in African-Americans with WHR as outcome for dietary energy intake and rs9557704 (SNP × kcal = ?0.04, P = 2.17 × 10^?7). No results exceeded the Bonferroni-corrected statistical significance threshold.     

Identification of genetic variation that determines human trehalase activity and its association with type 2 diabetes

A prior linkage scan in Pima Indians identified a putative locus for type two diabetes (T2D) and body mass index (BMI) on chromosome 11q23-25. Association mapping across this region identified single nucleotide polymorphisms (SNPs) in the trehalase gene (TREH) that were associated with T2D. To assess the putative connection between trehalase activity and T2D, we performed a linkage study for trehalase activity in 570 Pima Indians who had measures of trehalase activity. Strong evidence of linkage of plasma trehalase activity (LOD = 7.0) was observed in the TREH locus. Four tag SNPs in TREH were genotyped in these subjects and plasma trehalase activity was highly associated with three SNPs: rs2276064, rs117619140 and rs558907 (p = 2.2 × 10^?11–1.4 × 10^?23), and the fourth SNP, rs10790256, was associated conditionally on these three (p = 2.9 × 10^?7). Together, the four tag SNPs explained 51 % of the variance in plasma trehalase activity and 79 % of the variance attributed to the linked locus. These four tag SNPs were further genotyped in 828 subjects used for association mapping of T2D, and rs558907 was associated with T2D (odds ratio (OR) 1.94, p = 0.002). To assess replication of the T2D association, all four tag SNPs were additionally genotyped in two non-overlapping samples of Native Americans. Rs558907 was reproducibly associated with T2D in 2,942 full-heritage Pima Indians (OR 1.27 p = 0.03) and 3,897 “mixed” heritage Native Americans (OR 1.21, p = 0.03), and the strongest evidence for association came from combining all samples (OR 1.27 p = 1.6 × 10^?4, n = 7,667). However, among 320 longitudinally studied subjects, measures of trehalase activity from a non-diabetic exam did not predict those who would eventually develop diabetes versus those who would remain non-diabetic (hazard ratio 0.94 per SD of trehalase activity, p = 0.29). We conclude that variants in TREH control trehalase activity, and although one of these variants is also reproducibly associated with T2D, it is likely that the effect of the SNP on risk of T2D occurs by a mechanism different than affecting trehalase activity. Alternatively, TREH variants may be tagging a nearby T2D locus.     

A meta-analysis of two genome-wide association studies to identify novel loci for maximum number of alcoholic drinks

Maximum number of alcoholic drinks consumed in a 24-h period (maxdrinks) is a heritable (>50 %) trait and is strongly correlated with vulnerability to excessive alcohol consumption and subsequent alcohol dependence (AD). Several genome-wide association studies (GWAS) have studied alcohol dependence, but few have concentrated on excessive alcohol consumption. We performed two GWAS using maxdrinks as an excessive alcohol consumption phenotype: one in 118 extended families (N = 2,322) selected from the Collaborative Study on the Genetics of Alcoholism (COGA), and the other in a case–control sample (N = 2,593) derived from the Study of Addiction: Genes and Environment (SAGE). The strongest association in the COGA families was detected with rs9523562 (p = 2.1 × 10^?6) located in an intergenic region on chromosome 13q31.1; the strongest association in the SAGE dataset was with rs67666182 (p = 7.1 × 10^?7), located in an intergenic region on chromosome 8. We also performed a meta-analysis with these two GWAS and demonstrated evidence of association in both datasets for the LMO1 (p = 7.2 × 10^?7) and PLCL1 genes (p = 4.1 × 10^?6) with maxdrinks. A variant in AUTS2 and variants in INADL, C15orf32 and HIP1 that were associated with measures of alcohol consumption in a meta-analysis of GWAS studies and a GWAS of alcohol consumption factor score also showed nominal association in the current meta-analysis. The present study has identified several loci that warrant further examination in independent samples. Among the top SNPs in each of the dataset (p ≤ 10^?4) far more showed the same direction of effect in the other dataset than would be expected by chance (p = 2 × 10^?3, 3 × 10^?6), suggesting that there are true signals among these top SNPs, even though no SNP reached genome-wide levels of significance.     

Male-specific genetic effect on hypertension and metabolic disorders

Genetic risk factors for hypertension may have age or gender specificity and pleiotropic effects. This study aims to measure the risk of genetic and non-genetic factors in the occurrence of hypertension and related diseases, with consideration of potential confounding factors and age-gender stratification. A discovery set of 352,228 genotyped plus 1.8 million imputed single-nucleotide polymorphisms were analyzed for 2,886 hypertensive cases and 3,440 healthy controls obtained from two community-based cohorts in Korea, and selected gene variants were replicated in the Health Examinee cohort (665 cases and 1,285 controls). Genome-wide association analyses were conducted in 12 groups stratified by age and gender after adjusting for potential covariates under three genetic models. Age, rural area residence, body mass index, family history of hypertension, male gender, current alcohol drinking status, and current smoking status were significantly associated with hypertension (P = 4 × 10^?151 to 0.011). Five gene variants, rs11066280 (C12orf51), rs12229654 and rs3782889 (MYL2), rs2072134 (OAS3), rs2093395 (TREML2), and rs17249754 (ATP2B1), were found to be associated with hypertension mostly in men (P = 4.76 × 10^?14 to 4.46 × 10^?7 in the joint analysis); three SNPs (rs11066280, rs12229654, and rs3782889) remained significant after Bonferroni correction in an independent population. Three gene variants, rs12229654, rs17249754, and rs11066280, were significantly associated with metabolic disorders such as hyperlipidemia and diabetes (P = 0.00071 to 0.0097, respectively). Careful consideration of the potential confounding effects in future genome-wide association studies is necessary to uncover the genetic underpinnings of complex diseases.     

BET1L and TNRC6B associate with uterine fibroid risk among European Americans

Uterine fibroid (UFs) affect 77 % of women by menopause and account for $9.4 billion in healthcare costs each year. Although UFs are heritable, genetic risk is poorly understood. The first genome-wide association study (GWAS) of UFs was recently performed in a Japanese population, with reported genome-wide significance for single nucleotide polymorphisms (SNPs) across three chromosomal regions. We tested these SNPs for association with UFs in US cohorts. Women were enrolled in the Right from the Start (RFTS) cohort and the BioVU DNA repository. UF status in both cohorts was determined by pelvic imaging. We tested 65 candidate and haplotype-tagging SNPs for association with UFs presence using logistic regression in RFTS and the top three GWAS-associated SNPs in BioVU. We also combined association results from both cohorts using meta-analysis. 1,086 European American (EA) cases and 1,549 controls were examined. Two SNP associations replicated [blocked early in transport 1 homolog (BET1L) rs2280543, RFTS–BioVU meta-odds ratio (OR) = 0.67 95 % confidence interval (CI) 0.38–0.96, Q = 0.70, I = 0, p = 6.9 × 10^?3; trinucleotide repeat containing 6B (TNRC6B) rs12484776, RFTS–BioVU meta-OR = 1.21, 95 % CI 1.07–1.35, Q = 0.24, I = 28.37, p = 8.7 × 10^?3). Meta-analyses combining evidence from RFTS, BioVU, and prior GWAS showed little heterogeneity in effect sizes across studies, with meta-p values between 7.45 × 10^?8 and 3.89 × 10^?9, which were stronger than prior GWAS and supported associations observed for all previously identified loci. These data suggest common variants increase risk for UF in both EA and Japanese populations. However, further research is needed to assess the role of these genes across other racial groups.     

Genome-wide association study in Han Chinese identifies three novel loci for human height

Human height is a complex genetic trait with high heritability but discovery efforts in Asian populations are limited. We carried out a meta-analysis of genome-wide association studies (GWAS) for height in 6,534 subjects with in silico replication of 1,881 subjects in Han Chinese. We identified three novel loci reaching the genome-wide significance threshold (P < 5 × 10^?8), which mapped in or near ZNF638 (rs12612930, P = 2.02 × 10^?10), MAML2 (rs11021504, P = 7.81 × 10^?9), and C18orf12 (rs11082671, P = 1.87 × 10^?8). We also confirmed two loci previously reported in European populations including CS (rs3816804, P = 2.63 × 10^?9) and CYP19A1 (rs3751599, P = 4.80 × 10^?10). In addition, we provided evidence supporting 35 SNPs identified by previous GWAS (P < 0.05). Our study provides new insights into the genetic determination of biological regulation of human height.     

Replication of genomewide association studies on age at menarche in the Korean population

Early menarche is associated with adverse health outcomes, including breast cancer, endometrial cancer, obesity, type 2 diabetes, and cardiovascular disease. Recently, a genomewide association study (GWAS) of age at menarche (AAM) in 104,533 individuals of European ancestry was reported by the ReproGen consortium. They identified 42 loci known and novel loci that were linked to age at menarche. Because age at menarche varies between ethnic groups, we decided to investigate if these results would be replicated in the Korean population. To this end, we examined the association of the SNPs reported in the ReproGen GWAS with AAM in 3,194 individuals from the Korean Genome and Epidemiology Study (KoGES) cohort. Genotype data for total 17 SNPs (6 genotyped SNPs and 11 imputed SNPs) were available for the association analysis using linear regression analysis for age at menarche with controlling current age, waist-to-hip ratio, and body mass index as the covariates. We found replication of the ReproGen study in two SNPs; one SNP (rs466639) in the retinoic acid receptor gamma gene (RXRG), showing a significant association with early menarche (beta = ?0.224 ± 0.065, p value = 5.2 × 10^?4, Bonferroni-corrected p value = 0.009), and the other (rs10899489), in GRB2 (growth factor receptor bound protein 2)-associated binding protein 2 (GAB2), linked to late menarche (beta = 0.140 ± 0.047, p value = 2.8 × 10^?3, Bonferroni-corrected p value = 0.049). This result possibly suggests that genetic factors governing AAM in the Korean population would be distinct from those in the Europeans, implying roles of modulating or interacting factors in determining AAM, including environmental factors such as nutritional status.     

Association study of common variations of FBN1 gene and essential hypertension in Han Chinese population

Fibrillin-1 (FBN1) was reported to have impact on the physiological arterial stiffness and vascular remodeling with hypertension of recent years. In the previous study we reported the association of four functional single nucleotide polymorphisms (SNPs) of FBN1 gene and hypertension. Here, we further investigate the association of four tagging SNPs (tagSNPs) which covered remain genetic variation blocks of FBN1 gene with hypertension, blood pressure and efficacy of antihypertensive in a South Han Chinese population. A case–control study including 2,012 hypertension cases and 2,116 controls age- and sex-matched controls was conducted from a community-based population and four candidate tagSNPs of the FBN1 gene were genotyped. Association analysis by multiple logistic regression was conducted for allele, genotype and haplotype and hypertension, blood pressure trait and control status with antihypertensive. General linear model was applied to compare blood pressure levels between genotypes. The association of rs17361868 and hypertension was statistically significant and that was further observed in female, ≥55 years, non-smoking and non-drinking populations (P < 0.05). Significant association of rs668842, rs11635140 and hypertension were observed in <55 years population as well as the later in female and non-smoking populations respectively. Haplotype G-T constructed of rs668842 and rs11635140 was significantly associated with hypertension comparing to reference haplotype A-C (P = 0.022). Normally distributed square root of TGF-β1 (pg/ml) of hypertension cases (148.56 ± 66.46) was significantly higher than that of control (128.52 ± 65.11), P = 0.008. Furthermore, TGF-β1 was significantly correlated with SBP (r = 0.135, P = 0.018) and DBP (r = 0.154, P = 0.007) respectively whereas no statistical difference of blood pressure or TGF-β1 was observed between genotypes. Remarkably, rs17361868 were significantly associated with the status of blood pressure in the patients taking three of the antihypertensive drugs, Zhen Ju Jiang Ya tablets, Jiang Ya tablet and compound reserpine (P < 0.05). The present study provides further association evidence of FBN1 gene polymorphisms and hypertension, antihypertensive efficacy. Further replication of these results via association or prospective studies conducted in other populations is warranted.     

Association of 20 potential ATP2B1-interacting genes with blood pressure in Koreans

Plasma membrane calcium-transporting ATPase 1 (ATP2B1) is associated significantly with blood pressure in Caucasians and Asians. ATP2B1 regulates calcium homeostasis and belongs to the P-type calcium pump family; several studies have identified diverse proteins that bind to ATP2B1. We hypothesized that ATP2B1 regulates blood pressure through ATP2B1-interacting genes. To this end, 20 potential ATP2B1-interacting genes were selected, 197 SNPs of which were analyzed for their association of systolic and diastolic blood pressure. These 20 genes were categorized into 2 groups: ATP2B1-binding genes and ATP2B1-cleaving calpain family members. Three ATP2B1-binding genes (CALM1, NOS1, and PDLIM1) were associated with blood pressure, and a SNP in CALM1 (rs2401887) generated the strongest association signal (beta=?3.60 ±0.92, p=8.9×10^?5 for systolic blood pressure and beta=?1.40 ±0.62, p=0.02 for diastolic blood pressure). Of the calpain family members, 3 genes (CAPN6, CAPN9, and CAPN10) were associated with blood pressure, and the CAPN10 SNP rs4676348 yielded the strongest association signal (beta=?0.88 ±0.27, p=0.001 for systolic blood pressure and beta=?0.58 ±0.18, p=0.015 for diastolic blood pressure). Further, the interaction of CALM1 to ATP2B1 was examined using the blood pressure of individuals who carried both variants of CALM1 and ATP2B1 genes. Similarly the interaction of CAPN10 to ATP2B1 was also examined. The CALM1 variant (rs2401887) and CAPN10 variants (rs4676348) appear to decrease blood pressure further in addition to the decrease by the variant (rs17249754) of ATP2B1, which suggests that ATP2B1 might regulate blood pressure through the ATP2B1-interacting genes CALM1 and CAPN10.     

Genetic variants in the JAK1 gene confer higher risk of Behcet’s disease with ocular involvement in Han Chinese

Recent surveys have identified SLC22A4, SLC22A5, RUNX1, JAK1 as susceptibility genes for various immune-related diseases. An association study was performed in 738 Behcet’s patients with ocular involvement and 1,873 controls using the iPLEX system method. The first-stage study for 30 SNPs showed that SNPs rs2780815, rs310241, rs3790532 in JAK1 were associated with Behcet’s disease in Han Chinese (Pc_{(Bonferroni correction)} = 0.022–7.7 × 10^?3). The G allele and AA genotype of SNP rs2834643 in RUNX1 (Pc = 0.041–1.75 × 10^?3), but none of the other SNPs, were associated with Behcet’s disease. Haplotype analysis for the SLC22A4, SLC22A5 genes showed an increased tendency for AGTCTGCCGC frequency in patients compared with controls; however, the significance was lost after Bonferroni correction (P = 0.004, Pc > 0.05). Subsequently, we further replicated the significantly associated SNPs using another independent cohort. Replication and combining studies showed that three SNPs rs2780815, rs310241, rs3790532 in JAK1, but not SNP rs2834643 in RUNX1, were consistently associated with Behcet’s disease (replication: Pc = 0.012–9.60 × 10^?4; combining: Pc = 0.030–1.90 × 10^?4). SNPs rs2780815, rs310241, rs3790532 were estimated to confer a population attributable risk of 35.0, 28.0, 27.0 %, respectively. We found a strong association between HLA-B51 with Behcet’s disease in Chinese Han population (P = 1.35 × 10^?73; OR = 5.15; 95 % CI 4.28–6.19). GMDR analysis showed that no gene–gene interaction was detectable between JAK1 and HLA-B51. Logistic analysis indicated that the JAK1 gene was an independent risk factor for Behcet’s disease (P > 0.05). Real-time PCR analysis showed that no difference on the expression of JAK1 in PBMCs or LPS-stimulated PBMCs between individuals with the different rs1762780815 genotypes studied (P > 0.05). In conclusion, this study suggests that JAK1, but not SLC22A4, SLC22A5 and RUNX1, contributes to the genetic susceptibility to Behcet’s disease with ocular involvement.     

Chromosome 9p21 rs10757278 polymorphism is associated with the risk of metabolic syndrome

Metabolic syndrome (MetS) is a common multifactorial disorder that involves abdominal obesity, dyslipidemia, hypertension, and hyperglycemia. Genome-wide association studies have identified a major risk locus for coronary artery disease and myocardial infarction on chromosome 9p21. Here, we examined the frequency of single nucleotide polymorphisms (SNPs) on chromosome 9p21 in a sample of Turkish patients with MetS and further investigated the correlation between regional SNPs, haplotypes, and MetS. The real-time polymerase chain reaction (RT-PCR) was used to analyze 4 SNPs (rs10757274 A/G, rs2383207 A/G, rs10757278 A/G, rs1333049 C/G) in 291 MetS patients and 247 controls. Analysis of 4 SNPs revealed a significant difference in the genotype distribution for rs2383207, rs10757278, and rs1333049 between MetS patients and controls (p = 0.041, p = 0.005, p = 0.023, respectively) but not for rs10757274 (p = 0.211). MetS and control allelic frequencies for rs2383207, rs10757278, and rs1333049 were statistically different (p < 0.05). The rs2383207 AG variant, was identified as a MetS risk factor (p = 0.012, OR = 33.271; 95 % CI: 2.193–504.805) and the AA haplotype in block 1 and the GC, AG haplotypes in block 2 were associated with MetS (χ ² = 3.875, p = 0.049; χ ² = 9.334, p = 0.0022; χ ² = 9.134, p = 0.0025, respectively). In this study, we found that chromosome 9p21 SNP rs10757278 and related haplotypes correlate with MetS risk. This is the first report showing an association between a 9p21 variant and MetS and suggests that rs10757278 polymorphism may confer increased risk for disease.     

Linkage analysis for plasma amyloid beta levels in persons with hypertension implicates Aβ-40 levels to presenilin 2

Plasma concentrations of Aβ40 and Aβ42 rise with age and are increased in people with mutations that cause early-onset Alzheimer’s disease (AD). Amyloid beta (Aβ) plasma levels were successfully used as an (endo)phenotype for gene discovery using a linkage approach in families with dominant forms of disease. Here, we searched for loci involved in Aβ plasma levels in a series of non-demented patients with hypertension in the Erasmus Rucphen Family study. Aβ40 and Aβ42 levels were determined in 125 subjects with severe hypertension. All patients were genotyped with a 6,000 single nucleotide polymorphisms (SNPs) illumina array designed for linkage analysis. We conducted linkage analysis of plasma Aβ levels. None of the linkage analyses yielded genome-wide significant logarithm of odds (LOD) score over 3.3, but there was suggestive evidence for linkage (LOD?>?1.9) for two regions: 1q41 (LOD?=?2.07) and 11q14.3 (LOD?=?2.97), both for Aβ40. These regions were followed up with association analysis in the study subjects and in 320 subjects from a population-based cohort. For the Aβ40 region on chromosome 1, association of several SNPs was observed at the presenilin 2 gene (PSEN2) (p?=?2.58?×?10^?4 for rs6703170). On chromosome 11q14-21, we found some association (p?=?3.1?×?10^?3 for rs2514299). This linkage study of plasma concentrations of Aβ40 and Aβ42 yielded two suggestive regions, of which one points toward a known locus for familial AD.     

Identification of BACH2 as a susceptibility gene for Graves’ disease in the Chinese Han population based on a three-stage genome-wide association study

The BACH2 gene regulates B cell differentiation and function and has been reported to be a shared susceptibility gene for several autoimmune diseases. Our previous genome-wide association study (GWAS) indicated that several single nucleotide polymorphisms (SNPs) in the BACH2 gene are associated with Graves’ disease (GD) in the Chinese Han population; however, the association did not achieve genome-wide significance levels. Recently, this association of BACH2 with GD was confirmed in Caucasians in the UK population, but fine mapping in this region has not yet been reported. Here, we provide a refined analysis of a 331-kb region in the BACH2 gene, which harbors 359 SNPs, using GWAS data from 1,442 GD patients and 1,468 controls. The SNPs rs2474619 and rs9344996 were implied as the independent variants associated with GD by forward and two-locus logistic regression analysis. We genotyped eight out of 10 tagSNPs with P < 1 × 10^?3 in 3,508 GD patients and 3,209 controls, the results also showed that rs2474619 was independently associated with GD in the combined population from GWAS and the second stage (P = 1.81 × 10^?5). The rs2474619 and rs9344996 were further genotyped in the third stage cohorts, and rs2474619 showed evidence of association with GD at genome-wide significance levels in the combined population (P = 3.28 × 10^?8, odds ratio = 1.13). The association of rs9344996 with GD can be explained by its linkage to rs2474619 in the combined population. Our study clearly demonstrated that BACH2 is a susceptibility gene for GD in the Chinese Han population and further supported rs2474619, in intron 2 of BACH2, is the best association signal with GD. However, the mechanism by which BACH2 confers increased risk of GD requires further study.     

Polymorphic variants in tenascin-C (TNC) are associated with atherosclerosis and coronary artery disease

Tenascin-C (TNC) is an extracellular matrix protein implicated in biological processes important for atherosclerotic plaque development and progression, including smooth muscle cell migration and proliferation. Previously, we observed differential expression of TNC in atherosclerotic aortas compared with healthy aortas. The goal of this study was to investigate whether common genetic variation within TNC is associated with risk of atherosclerosis and coronary artery disease (CAD) in three independent datasets. We genotyped 35 single nucleotide polymorphisms (SNPs), including 21 haplotype tagging SNPs, in two of these datasets: human aorta tissue samples (n?=?205) and the CATHGEN cardiovascular study (n?=?1,325). Eleven of these 35 SNPs were then genotyped in a third dataset, the GENECARD family study of early-onset CAD (n?=?879 families). Three SNPs representing a block of linkage disequilibrium, rs3789875, rs12347433, and rs4552883, were significantly associated with atherosclerosis in multiple datasets and demonstrated consistent, but suggestive, genetic effects in all analyses. In combined analysis rs3789875 and rs12347433 were statistically significant after Bonferroni correction for 35 comparisons, p?=?2?×?10^?6 and 5?×?10^?6, respectively. The SNP rs12347433 is a synonymous coding SNP and may be biologically relevant to the mechanism by which tenascin-C influences the pathophysiology of CAD and atherosclerosis. This is the first report of genetic association between polymorphisms in TNC and atherosclerosis or CAD.     

NOS2A, TLR4, and IFNGR1 interactions influence pulmonary tuberculosis susceptibility in African-Americans

Tuberculosis (TB) has substantial mortality worldwide with 5–10% of those exposed progressing to active TB disease. Studies in mice and humans indicate that the inducible nitric oxide synthase (iNOS) molecule plays an important role in immune response to TB. A mixed case–control association study of individuals with TB, relatives, or close contact controls was performed in 726 individuals (279 case and 166 control African-Americans; 198 case and 123 control Caucasians). Thirty-nine single nucleotide polymorphisms (SNPs) were selected from the NOS2A gene for single SNP, haplotype, and multilocus interaction analyses with other typed candidate genes using generalized estimating equations. In African-Americans, ten NOS2A SNPs were associated with TB. The strongest associations were observed at rs2274894 (odds ratio (OR) = 1.84, 95% confidence interval (CI) [1.23–2.77], p = 0.003) and rs7215373 (OR = 1.67, 95% CI [1.17–2.37], p = 0.004), both of which passed a false discovery rate correction for multiple comparisons (q* = 0.20). The strongest gene–gene interactions were observed between NOS2A rs2248814 and IFNGR1 rs1327474 (p = 0.0004) and NOS2A rs944722 and IFNGR1 rs1327474 (p = 0.0006). Three other SNPs in NOS2A interacted with TLR4 rs5030729 and five other NOS2A SNPs interacted with IFNGR1 rs1327474. No significant associations were observed in Caucasians. These results suggest that NOS2A variants may contribute to TB susceptibility, particularly in individuals of African descent, and may act synergistically with SNPs in TLR4 and IFNGR1.     

Genetic susceptibility to obesity and diet intakes: association and interaction analyses in the Malmö Diet and Cancer Study

Gene–environment interactions need to be studied to better understand the obesity. We aimed at determining whether genetic susceptibility to obesity associates with diet intake levels and whether diet intakes modify the genetic susceptibility. In 29,480 subjects of the population-based Malmö Diet and Cancer Study (MDCS), we first assessed association between 16 genome-wide association studies identified obesity-related single-nucleotide polymorphisms (SNPs) with body mass index (BMI) and associated traits. We then conducted association analyses between a genetic risk score (GRS) comprising of 13 replicated SNPs and the individual SNPs, and relative dietary intakes of fat, carbohydrates, protein, fiber and total energy intake, as well as interaction analyses on BMI and associated traits among 26,107 nondiabetic MDCS participants. GRS associated strongly with increased BMI (P = 3.6 × 10^?34), fat mass (P = 6.3 × 10^?28) and fat-free mass (P = 1.3 × 10^?24). Higher GRS associated with lower total energy intake (P = 0.001) and higher intake of fiber (P = 2.3 × 10^?4). No significant interactions were observed between GRS and the studied dietary intakes on BMI or related traits. Of the individual SNPs, after correcting for multiple comparisons, NEGR1 rs2815752 associated with diet intakes and BDNF rs4923461 showed interaction with protein intake on BMI. In conclusion, our study does not provide evidence for a major role for macronutrient-, fiber- or total energy intake levels in modifying genetic susceptibility to obesity measured as GRS. However, our data suggest that the number of risk alleles as well as some of the individual obesity loci may have a role in regulation of food and energy intake and that some individual loci may interact with diet.     

Linkage disequilibrium pattern and age-at-diagnosis are critical for replicating genetic associations across ethnic groups in leprosy

One of the persistent challenges of genetic association studies is the replication of genetic marker-disease associations across ethnic groups. Here, we conducted high-density association mapping of PARK2/PACRG SNPs with leprosy and identified 69 SNPs significantly associated with leprosy in 198 single-case Vietnamese leprosy families. A total of 56 associated SNPs localized to the overlapping promoter regions of PARK2/PACRG. For this region, multivariate analysis identified four SNPs belonging to two major SNP bins (rs1333955, rs7744433) and two single SNP bins (rs2023004, rs6936895) that capture the combined statistical evidence (P = 1.1 × 10^?5) for association among Vietnamese patients. Next, we enrolled a case–control sample of 364 leprosy cases and 370 controls from Northern India. We genotyped all subjects for 149 SNPs that capture >80 % of the genetic variation in the Vietnamese sample and found 24 SNPs significantly associated with leprosy. Multivariate analysis identified three SNPs (rs1333955, rs9356058 and rs2023004) that capture the association with leprosy (P < 10^?8). Hence, two SNPs (rs1333955 and rs2023004) were replicated by multivariate analysis between both ethnic groups. Marked differences in the linkage disequilibrium pattern explained some of the differences in univariate analysis between the two ethnic groups. In addition, the strength of association for two promoter region SNP bins was significantly stronger among young leprosy patients in the Vietnamese sample. The same trend was observed in the Indian sample, but due to the higher age-at-diagnosis of the patients the age effect was less pronounced.     

Association of three single nucleotide polymorphisms at the SIX1-SIX6 locus with primary open angle glaucoma in the Chinese population

This study investigated the genetic association of three single nucleotide polymorphisms(SNPs; rs10483727, rs33912345, and rs146737847) at the SIX1-SIX6 locus with primary open angle glaucoma(POAG) in the Chinese population. A total of 866 subjects with POAG(685 high-tension glaucoma(HTG) and 181 normal-tension glaucoma(NTG)) and 266 control individuals were included. Significant genetic association was identified for rs10483727 in HTG(P=0.02; odds ratio(OR)=1.31), NTG(P=7.41×10~(-6); OR=2.71), and POAG(i.e., HTG and NTG combined; P=0.001; OR=1.44). rs33912345 was also significantly associated with HTG(P=0.008; OR=1.36), NTG(P=2.72×10~(-6); OR=2.27), and POAG(P=3.84×10~(-4); OR=1.49). The rare SIX6 mutation, rs146737847, was not found in the subjects enrolled in this study. Stratification by patient age identified that both rs10483727 and rs33912345 were significantly associated with NTG in patients aged above 40 years(P=2.08×10~(-5); OR=2.28), whereas in patients aged between 20–40 years, rs33912345 was significantly associated with NTG(P=0.017; OR=2.06). In HTG, the genetic associations for both rs10483727 and rs33912345 were significant in patients aged between 20–40 years(P=0.006; OR=1.56) but not in those aged above 40 years(P=0.118, OR=1.21 and P=0.042, OR=1.29, respectively). This study replicated the association of POAG with two SNPs at the SIX1-SIX6 locus and demonstrated that SNPs, rs10483727 and rs33912345, are significantly associated with POAG, especially with NTG in patients aged above 40 years.     

Genome-wide association study identified the human leukocyte antigen region as a novel locus for plasma beta-2 microglobulin

Beta-2 microglobulin (B2M) is a component of the major histocompatibility complex (MHC) class I molecule and has been studied as a biomarker of kidney function, cardiovascular diseases and mortality. Little is known about the genes influencing its levels directly or through glomerular filtration rate (GFR). We conducted a genome-wide association study of plasma B2M levels in 6738 European Americans from the Atherosclerosis Risk in Communities study to identify novel loci for B2M and assessed its association with known estimated GFR (eGFR) loci. We identified 2 genome-wide significant loci. One was in the human leukocyte antigen (HLA) region on chromosome 6 (lowest p value = 1.8 × 10^?23 for rs9264638). At this locus, 6 index SNPs accounted for 3.2 % of log(B2M) variance, and their association with B2M could largely be explained by imputed classical alleles of the MHC class I genes: HLA-A, HLA-B, or HLA-C. The index SNPs at this locus were not associated with eGFR based on serum creatinine (eGFRcr). The other locus of B2M was on chromosome 12 (rs3184504 at SH2B3, beta = 0.02, p value = 3.1 × 10^?8), which was previously implicated as an eGFR locus. In conclusion, although B2M is known to be a component of MHC class I molecule, the association between HLA class I alleles and plasma B2M levels in a community-based population is novel. The identification of the two novel loci for B2M extends our understanding of its metabolism and informs its use as a kidney filtration biomarker.