A correction to: Bonnie R Joubert, Ethan M Lange, Nora Franceschini, Victor Mwapasa, Kari E North, Steven R Meshnick andthe NIAID Center for HIV/AIDS Vaccine Immunology. A whole genome association study of mother-to-child transmission of HIV in Malawi. Genome Medicine 2010, 2:17.
To determine whether genetic variants associated with glucose homeostasis are associated with gestational diabetes (GDM).
We genotyped 899 self-identified Caucasian women and 386 self-identified African-American women in the Pregnancy, Infection and Nutrition (PIN) Studies cohorts for 36 single-nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2DM) and/or glucose homeostasis in European populations.
GDM was diagnosed in 56 of 899 (6.2%) Caucasian and 24 of 386 (6.2%) African-American women. Among Caucasian women, GDM was associated with carriage of TCF7L2 rs7901695, MTNR1B rs10830963 and GCKR rs780094 alleles associated with T2DM and fasting glucose in non-pregnant populations. Among African-American participants, we found an increased risk among TSPAN8 rs7961581 C allele homozygotes and reduced risk among carriers of the JAZF1 rs864745 T allele.
We found several SNPs that are associated with GDM risk in the PIN cohorts. Maternal genotyping may identify women at risk for impaired gestational glucose tolerance.
diabetes; gestational diabetes; genetics; single nucleotide polymorphisms
Evidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18–100 years, from multiple U.S. studies in the Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18–25 years), adulthood (ages 26–49 years), middle-age adulthood (ages 50–69 years), and older adulthood (ages ≥70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m2, respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data.
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10−15) and HLA-B (rs2922994, P=2.43 × 10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
Marginal zone lymphoma (MZL) is a common subtype of B-cell non-Hodgkin lymphoma. Here the authors carry out a two-stage genome-wide association study in over 8,000 Europeans and identify two new MZL risk loci at chromosome 6p, implicating the major histocompatibility complex in the disease for the first time.
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
Coronary heart disease (CHD) is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of published variants in CHD loci with incident CHD, attempted to fine map these loci, and characterize novel variants influencing CHD risk in African Americans.
Methods and Results
Up to 8,201 African Americans (including 546 first CHD events) were genotyped using the MetaboChip array in the Atherosclerosis Risk in Communities (ARIC) study and Women's Health Initiative (WHI). We tested associations using Cox proportional hazard models in sex- and study-stratified analyses and combined results using meta-analysis. Among 44 validated CHD loci available in the array, we replicated and fine-mapped the SORT1 locus, and showed same direction of effects as reported in studies of individuals of European ancestry for SNPs in 22 additional published loci. We also identified a SNP achieving array wide significance (MYC: rs2070583, allele frequency 0.02, P = 8.1×10−8), but the association did not replicate in an additional 8,059 African Americans (577 events) from the WHI, HealthABC and GeneSTAR studies, and in a meta-analysis of 5 cohort studies of European ancestry (24,024 individuals including 1,570 cases of MI and 2,406 cases of CHD) from the CHARGE Consortium.
Our findings suggest that some CHD loci previously identified in individuals of European ancestry may be relevant to incident CHD in African Americans.
Background & Aims
Metabolic syndrome (MetS), characterized by abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, and insulin resistance is a major public health concern in the United States. Omega-3 fatty acids have been relatively well studied in relation to many individual cardiovascular risk factors; however, their effects on MetS are not well established.
We conducted a cross-sectional study consisting of 4,941 participants from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study to assess the relation of dietary omega-3 fatty acids with the prevalence of MetS. Omega-3 intake was assessed using a food frequency questionnaire and we used generalized estimating equations to estimate adjusted odds ratios for prevalent MetS.
Our study population had a mean age (SD) of 52.1 (13.9) years and 45.9% were men. The mean (SD) of dietary omega-3 fatty acids was 0.25g/day (0.27). From the lowest to the highest quintile of dietary omega-3 fatty acids, multivariable adjusted ORs (95% CI) for MetS were 1.00 (ref), 0.90 (0.72–1.13), 1.03 (0.82–1.28), 0.94 (0.74–1.18), and 0.99 (0.77–1.25), respectively. In a secondary analysis, neither fish consumption nor dietary alpha-linolenic acid was associated with MetS.
Our findings do not support an association between dietary omega-3 fatty acids and MetS in a large US population.
Omega-3 fatty acids; fish; dietary alpha-linolenic acid (ALA); metabolic syndrome
Genome-wide association studies (GWAS) have identified many variants that influence high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and/or triglycerides. However, environmental modifiers, such as smoking, of these known genotype–phenotype associations are just recently emerging in the literature. We have tested for interactions between smoking and 49 GWAS-identified variants in over 41,000 racially/ethnically diverse samples with lipid levels from the Population Architecture Using Genomics and Epidemiology (PAGE) study. Despite their biological plausibility, we were unable to detect significant SNP × smoking interactions.
Blood pressure (BP) is a complex trait, with a heritability of 30 to 40%. Several genome wide associated BP loci explain only a small fraction of the phenotypic variation. Family studies can provide an important tool for gene discovery by utilizing trait and genetic transmission information among relative-pairs. We have previously described a quantitative trait locus at chromosome 17q25.3 influencing systolic BP in American Indians of the Strong Heart Family Study (SHFS). This locus has been reported to associate with variation in BP traits in family studies of Europeans, African Americans and Hispanics.
To follow-up persuasive linkage findings at this locus, we performed comprehensive genotyping in the 1-LOD unit support interval region surrounding this QTL using a multi-step strategy. We first genotyped 1,334 single nucleotide polymorphisms (SNPs) in 928 individuals from families that showed evidence of linkage for BP. We then genotyped a second panel of 306 SNPs in all SHFS participants (N = 3,807) for genes that displayed the strongest evidence of association in the region, and, in a third step, included additional genotyping to better cover the genes of interest and to interrogate plausible candidate genes in the region.
Three genes had multiple SNPs marginally associated with systolic BP (TBC1D16, HRNBP3 and AZI1). In BQTN analysis, used to estimate the posterior probability that any variant in each gene had an effect on the phenotype, AZI1 showed the most prominent findings (posterior probability of 0.66). Importantly, upon correction for multiple testing, none of our study findings could be distinguished from chance.
Our findings demonstrate the difficulty of follow-up studies of linkage studies for complex traits, particularly in the context of low powered studies and rare variants underlying linkage peaks.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2261-14-158) contains supplementary material, which is available to authorized users.
Summary: Although the 1000 Genomes haplotypes are the most commonly used reference panel for imputation, medical sequencing projects are generating large alternate sets of sequenced samples. Imputation in African Americans using 3384 haplotypes from the Exome Sequencing Project, compared with 2184 haplotypes from 1000 Genomes Project, increased effective sample size by 8.3–11.4% for coding variants with minor allele frequency <1%. No loss of imputation quality was observed using a panel built from phenotypic extremes. We recommend using haplotypes from Exome Sequencing Project alone or concatenation of the two panels over quality score-based post-imputation selection or IMPUTE2’s two-panel combination.
Supplementary data are available at Bioinformatics online.
Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P < 5.0 × 10−8) near FTO (P = 3.72 × 10−23), TMEM18 (P = 3.24 × 10−17), MC4R (P = 4.41 × 10−17), TNNI3K (P = 4.32 × 10−11), SEC16B (P = 6.24 × 10−9), GNPDA2 (P = 1.11 × 10−8) and POMC (P = 4.94 × 10−8) as well as a potential secondary signal at the POMC locus (rs2118404, P = 2.4 × 10−5 after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 18–90) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P < 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different ages.
Common obesity risk variants have been associated with macronutrient intake; however, these associations' generalizability across populations has not been demonstrated. We investigated the associations between 6 obesity risk variants in (or near) the NEGR1, TMEM18, BDNF, FTO, MC4R, and KCTD15 genes and macronutrient intake (carbohydrate, protein, ethanol, and fat) in 3 Population Architecture using Genomics and Epidemiology (PAGE) studies: the Multiethnic Cohort Study (1993–2006) (n = 19,529), the Atherosclerosis Risk in Communities Study (1987–1989) (n = 11,114), and the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) Study, which accesses data from the Third National Health and Nutrition Examination Survey (1991–1994) (n = 6,347). We used linear regression, with adjustment for age, sex, and ethnicity, to estimate the associations between obesity risk genotypes and macronutrient intake. A fixed-effects meta-analysis model showed that the FTO rs8050136 A allele (n = 36,973) was positively associated with percentage of calories derived from fat (βmeta = 0.2244 (standard error, 0.0548); P = 4 × 10−5) and inversely associated with percentage of calories derived from carbohydrate (βmeta = −0.2796 (standard error, 0.0709); P = 8 × 10−5). In the Multiethnic Cohort Study, percentage of calories from fat assessed at baseline was a partial mediator of the rs8050136 effect on body mass index (weight (kg)/height (m)2) obtained at 10 years of follow-up (mediation of effect = 0.0823 kg/m2, 95% confidence interval: 0.0559, 0.1128). Our data provide additional evidence that the association of FTO with obesity is partially mediated by dietary intake.
energy intake; fat mass and obesity-associated (FTO) gene; obesity; percent calories from fat; race/ethnicity
Numerous common genetic variants that influence plasma high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) distributions have been identified via genome-wide association studies (GWAS). However, whether or not these associations are age dependent has largely been overlooked. We conducted an association study and meta-analysis in more than 22,000 European Americans between 49 previously identified GWAS variants and the three lipid traits, stratified by age (males: <50 or ≥50 years of age; females: pre- or post-menopausal). For each variant, a test of heterogeneity was performed between the two age strata and significant Phet values were used as evidence of age-specific genetic effects. We identified seven associations in females and eight in males that displayed suggestive heterogeneity by age (Phet<0.05). The association between rs174547 (FADS1) and LDL-C in males displayed the most evidence for heterogeneity between age groups (Phet=1.74E-03, I2=89.8), with a significant association in older males (P=1.39E-06) but not younger males (P=0.99). However, none of the suggestive modifying effects survived adjustment for multiple testing, highlighting the challenges of identifying modifiers of modest SNP-trait associations despite large sample sizes.
PAGE; modifier; age; lipids; genetic association
Background & aims
Previous studies have suggested that cocoa products, which are rich sources of flavonoids, may lower blood pressure, serum cholesterol, fasting blood glucose and improve endothelial function. However, it is unclear whether consumption of cocoa products including chocolate influences the risk of metabolic syndrome (MetS).
In a cross-sectional design, we sought to examine the association between chocolate consumption and the prevalence of MetS.
We studied 4098 participants from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study aged 25–93 years. Chocolate consumption was assessed using a semi-quantitative food-frequency questionnaire. MetS was defined using the NCEP III criteria. Generalized estimating equations were used to estimate prevalence odds ratios of MetS according to frequency of chocolate intake.
Of the 4098 participants (mean age 51.7 y) included in the analyses, 2206 (53.8%) were female. The prevalence of metabolic syndrome in our population was 30.2%. Compared with those who did not consume any chocolate, multivariate adjusted odds ratios (95% CI) for MetS were 1.26 (0.94, 1.69), 1.15 (0.85, 1.55), and 0.99 (0.66, 1.51) among women who reported chocolate consumption of 1–3 times/ month, 1–4 times/week, and 5+ times/week, respectively. Corresponding values for men were: 1.13 (0.82, 1.57), 1.02 (0.74, 1.39), and 1.21 (0.79, 1.85).
These data do not support an association between chocolate intake and the prevalence of MetS in US adult men and women.
Chocolate; Metabolic syndrome; Cardiovascular disease risk
Heavy alcohol consumption increases risk of developing squamous cell carcinoma of the head and neck (SCCHN). Alcohol metabolism to cytotoxic and mutagenic intermediates acetaldehyde and reactive oxygen species is critical for alcohol-drinking-associated carcinogenesis. We hypothesized that polymorphisms in alcohol metabolism-related and antioxidant genes influence SCCHN survival.
Interview and genotyping data (64 polymorphisms in 12 genes) were obtained from 1227 white and African-American cases from the Carolina Head and Neck Cancer Epidemiology study, a population-based case–control study of SCCHN conducted in North Carolina from 2002 to 2006. Vital status, date and cause of death through 2009 were obtained from the National Death Index. Kaplan–Meier log-rank tests and adjusted hazard ratios were calculated to identify alleles associated with survival.
Most tested SNPs were not associated with survival, with the exception of the minor alleles of rs3813865 and rs8192772 in CYP2E1. These were associated with poorer cancer-specific survival (HRrs3813865, 95%CI = 2.00, 1.33–3.01; HRrs8192772, 95%CI = 1.62, 1.17–2.23). Hazard ratios for 8 additional SNPs in CYP2E1, GPx2, SOD1, and SOD2, though not statistically significant, were suggestive of differences in allele hazards for all-cause and/or cancer death. No consistent associations with survival were found for SNPs in ADH1B, ADH1C, ADH4, ADH7, ALDH2, GPx2, GPx4, and CAT.
We identified some polymorphisms in alcohol and oxidative stress metabolism genes that influence survival in subjects with SCCHN. Previously unreported associations of SNPs in CYP2E1 warrant further investigation.
Head and neck neoplasms/epidemiology; Genes; Survival; Alcohol drinking/metabolism; Oxidative stress
Obesity is of global health concern. There are well-described inverse relationships between female pubertal timing and obesity. Recent genome-wide association studies of age at menarche identified several obesity-related variants. Using data from the ReproGen Consortium, we employed meta-analytical techniques to estimate the associations of 95 a priori and recently identified obesity-related (body mass index (weight (kg)/height (m)2), waist circumference, and waist:hip ratio) single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970–2010), in order to estimate associations between genetic variants associated with central or overall adiposity and pubertal timing in girls. Investigators in each study performed a separate analysis of associations between the selected SNPs and age at menarche (ages 9–17 years) using linear regression models and adjusting for birth year, site (as appropriate), and population stratification. Heterogeneity of effect-measure estimates was investigated using meta-regression. Six novel associations of body mass index loci with age at menarche were identified, and 11 adiposity loci previously reported to be associated with age at menarche were confirmed, but none of the central adiposity variants individually showed significant associations. These findings suggest complex genetic relationships between menarche and overall obesity, and to a lesser extent central obesity, in normal processes of growth and development.
adiposity; body mass index; genetic association studies; menarche; obesity; waist circumference; waist:hip ratio; women's health
OBJECTIVE—Although variants in the transcription factor 7-like 2 (TCF7L2) gene are consistently associated with type 2 diabetes, large population-based studies of African Americans are lacking. Moreover, few studies have investigated the effects of TCF7L2 on type 2 diabetes in the context of metabolic risk factors of type 2 diabetes.
RESEARCH DESIGN AND METHODS—We investigated the association between the TCF7L2 rs7903146 polymorphism and type 2 diabetes in 2,727 African American and 9,302 Caucasian participants without diabetes who were inducted into the Atherosclerosis Risk in Communities study in 1987–1989 and followed for 9 years.
RESULTS—A total of 485 and 923 cases of type 2 diabetes were identified in African Americans and Caucasians, respectively. Compared with homozygous CC individuals, heterozygous CT and homozygous TT individuals had higher cumulative incidence of type 2 diabetes over 9 years of follow-up: 11.3% (95% CI 10.2–12.4) vs. 21.1% (20.8–21.4) and 27.9% (19.3–36.5) in African Americans, respectively, and 9.7% (8.8–10.6) vs. 11.3% (10.2–12.4) and 13.6% (11.1–16.1), respectively, in Caucasians. Individuals with the risk allele had the highest hazards of diabetes if they were obese and had low HDL cholesterol, followed by individuals with any one and none of the traits.
CONCLUSIONS—Our study provides the first significant evidence of association between the TCF7L2 rs7903146 polymorphism and type 2 diabetes risk in a large African American population and also demonstrates that the diabetes risk conveyed by the rs7903146 risk allele is substantially increased in the context of some metabolic risk factors for type 2 diabetes. Our study findings need to be replicated in other large, population-based studies.
Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 × 10-7). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 × 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
The association of body mass index (BMI) with blood pressure may be stronger in Asian than non-Asian populations, however, longitudinal studies with direct comparisons between ethnicities are lacking. We compared the relationship of BMI with incident hypertension over approximately 9.5 years of follow-up in young (24-39 years) and middle-aged (45-64 years) Chinese Asians (n=5354), American Blacks (n=6076) and American Whites (n=13451). We estimated risk differences using logistic regression models and calculated adjusted incidences and incidence differences. To facilitate comparisons across ethnicities, standardized estimates were calculated using mean covariate values for age, sex, smoking, education and field center, and included the quadratic terms for BMI and age. Weighted least-squares regression models with were constructed to summarize ethnic-specific incidence differences across BMI. Wald statistics and p-values were calculated based on chi-square distributions. The association of BMI with the incidence difference for hypertension was steeper in Chinese (p<0.05) than in American populations during young and middle-adulthood. For example, at a BMI of 25 vs 21 kg/m2 the adjusted incidence differences per 1000 persons (95% CI) in young adults with a BMI of 25 vs those with a BMI of 21 was 83 (36-130) for Chinese, 50 (26-74) for Blacks and 30 (12-48) for Whites; among middle-aged adults it was 137 (77-198) for Chinese, 49 (9-88) for Blacks and 54 (38-69) for Whites. Whether hypertension carries the same level of risk of stroke or cardiovascular disease across national or ethnic groups remains uncertain.
blood pressure; multi-ethnic; obesity; African American; cardiovascular disease
Background: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.
Objective: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.
Design: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10−6 were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.
Results: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10−8) and lower fat (β ± SE: −0.21 ± 0.04%; P = 1.57 × 10−9) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)–increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10−10), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10−7).
Conclusion: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
A number of genetic variants have been discovered by recent genome-wide association studies for their associations with clinical coronary heart disease (CHD). However, it is unclear whether these variants are also associated with the development of CHD as measured by subclinical atherosclerosis phenotypes, ankle brachial index (ABI), carotid artery intima-media thickness (cIMT) and carotid plaque.
Ten CHD risk single nucleotide polymorphisms (SNPs) were genotyped in individuals of European American (EA), African American (AA), American Indian (AI), and Mexican American (MA) ancestry in the Population Architecture using Genomics and Epidemiology (PAGE) study. In each individual study, we performed linear or logistic regression to examine population-specific associations between SNPs and ABI, common and internal cIMT, and plaque. The results from individual studies were meta-analyzed using a fixed effect inverse variance weighted model.
None of the ten SNPs was significantly associated with ABI and common or internal cIMT, after Bonferroni correction. In the sample of 13,337 EA, 3,809 AA, and 5,353 AI individuals with carotid plaque measurement, the GCKR SNP rs780094 was significantly associated with the presence of plaque in AI only (OR = 1.32, 95% confidence interval: 1.17, 1.49, P = 1.08 × 10−5), but not in the other populations (P = 0.90 in EA and P = 0.99 in AA). A 9p21 region SNP, rs1333049, was nominally associated with plaque in EA (OR = 1.07, P = 0.02) and in AI (OR = 1.10, P = 0.05).
We identified a significant association between rs780094 and plaque in AI populations, which needs to be replicated in future studies. There was little evidence that the index CHD risk variants identified through genome-wide association studies in EA influence the development of CHD through subclinical atherosclerosis as assessed by cIMT and ABI across ancestries.
ankle brachial index; carotid artery intima-media thickness; carotid plaque; coronary heart disease; genetic association study; multiethnic populations; subclinical atherosclerosis
In order to identify regulatory genes, we determined the heritability of gene transcripts, performed linkage analysis to identify quantitative trait loci (QTLs), and evaluated the evidence for shared genetic effects among transcripts with co-localized QTLs in non-diseased participants from 14 CEPH (Centre d'Etude du Polymorphisme Humain) Utah families. Seventy-six percent of transcripts had a significant heritability and 54% of them had LOD score ≥ 1.8. Bivariate genetic analysis of 15 transcripts that had co-localized QTLs on 4q28.2-q31.1 identified significant genetic correlation among some transcripts although no improvement in the magnitude of LOD scores in this region was noted. Similar results were found in analysis of 12 transcripts, that had co-localized QTLs in the 13q34 region. Principal-component analyses did not improve the ability to identify chromosomal regions of co-localized gene expressions.
Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to hepatic inflammation to cirrhosis. We sought to identify common genetic variants contributing to NAFLD, using CT measured fatty liver (FL), and alanine aminotransferase levels (ALT), as a biochemical marker of hepatic inflammation.
We employed a correlated meta-analysis (CMA) to test whether combining FL and ALT genomewide association (GWA) results, using ~2.5 million imputed SNPs, could enhance ability to detect variants influencing both traits.
Variants of the ERLIN1-CHUK-CWF19L1 gene cluster were associated with concomitant variation of FL and ALT. Nine variants (rs2862954, rs1408579, rs10883451, rs11597086, rs11591741, rs17729876, rs17668255, rs17668357, rs12784396) displayed genomewide significant associations at loci concomitantly influencing FL and ALT (2.47×10−9≤CMA-p≤4.29×10−10) as compared with the suggestive significance of marginal tests (4.11×10−5≤GWA-p≤2.34×10−6). For example, the missense variant in ERLIN1-rs2862954 was genomewide significant (CMA-p=4.88×10−10) for the combination of FL and ALT, while the respective univariate associations were suggestive (FL:p=5.74×10−6, ALT:p=3.71×10−6). Further we investigated whether the concomitant associations were driven mainly by ALT levels. When we adjusted FL by ALT, the correlated associations diminished but did not vanish (CMA-p≤3.3×10−7). Our findings suggest ERLIN1-CHUK-CWF19L1 variants are associated with early stage of FL accumulation (measured by CT) to hepatic inflammation (ALT levels), and the association enhances when accounting for the correlations between their scans.
CMA approach enhanced the ability to identify novel variants of the ERLIN1-CHUK-CWF19L1 influencing both simple steatosis and hepatic steatosis with inflammation, which suggest that this gene cluster may regulate the susceptibility of NAFLD in a wide spectrum of disease.
A loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008–2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 × 10−67, P = 3.98 × 10−5, P = 6.97 × 10−9, and P = 5.33 × 10−4 in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 × 10−10, P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 × 10−80) and a 1.75-fold increase in the odds of gout (P = 1.09 × 10−12). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.
ABCG2 protein, human; genetic association studies; gout; meta-analysis; polymorphism, single nucleotide; urate transporter; uric acid