Associations Between the Serum Metabolome and All-Cause Mortality Among African Americans in the Atherosclerosis Risk in Communities (ARIC) Study

Early and accurate identification of people at high risk of premature death may assist in the targeting of preventive therapies in order to improve overall health. To identify novel biomarkers for all-cause mortality, we performed untargeted metabolomics in the Atherosclerosis Risk in Communities (ARIC) Study. We included 1,887 eligible ARIC African Americans, and 671 deaths occurred during a median follow-up period of 22.5 years (1987–2011). Chromatography and mass spectroscopy identified and quantitated 204 serum metabolites, and Cox proportional hazards models were used to analyze the longitudinal associations with all-cause and cardiovascular mortality. Nine metabolites, including cotinine, mannose, glycocholate, pregnendiol disulfate, α-hydroxyisovalerate, N-acetylalanine, andro-steroid monosulfate 2, uridine, and γ-glutamyl-leucine, showed independent associations with all-cause mortality, with an average risk change of 18% per standard-deviation increase in metabolite level (P < 1.23 × 10−4). A metabolite risk score, created on the basis of the weighted levels of the identified metabolites, improved the predictive ability of all-cause mortality over traditional risk factors (bias-corrected Harrell's C statistic 0.752 vs. 0.730). Mannose and glycocholate were associated with cardiovascular mortality (P < 1.23 × 10−4), but predictive ability was not improved beyond the traditional risk factors. This metabolomic analysis revealed potential novel biomarkers for all-cause mortality beyond the traditional risk factors

The use of measured genotype information in the analysis of quantitative phenotypes in man.

We have begun a measured genotype approach to the genetic analysis of lipid and lipoprotein variability. This approach enables one to simultaneously estimate the frequencies and effects of alleles at specific loci along with the residual polygenetic variance component. In this study we consider the contribution of three common alleles at the locus coding for apolipoprotein E to interindividual variation of total cholesterol, betalipoprotein, and triglyceride levels. A sample of 102 nuclear families consisting of 434 individuals was studied. The frequencies of the ε2, ε3, and ε4 alleles in this sample are 0·137,0·740, and 0·123, respectively. In separate analyses of cholesterol and betalipoprotein levels, a complete model that includes the effects of the six apo E genotypes, unmeasured polygenes, and individual specific environmental effects fits these data significantly better than a reduced model that does not include the effects of the apo E polymorphism or a reduced model that does not include the effects of polygenes. On the average the ε2 allele lowers total cholesterol and betalipoprotein levels by 0·425 mmol/l and 0·811 units, respectively. The ε4 allele is associated with an average increase of these phenotypes by 0·255 mmol/l and 0·628 units, respectively. Simultaneous estimates of the interindividual variability of total cholesterol levels attributable to the apo E polymorphism and to residual polygenic effects are 8% and 56%, respectively. For betalipoprotein levels, we simultaneously estimate these values to be 7% and 42%, respectively. A reduced model including the effects of polygenes but not the effects of the apo E polymorphism fitted the triglyceride data as well as the complete model. The estimate of the fraction of interindividual variability associated with polygenetic effects was 26.5%. We review our present understanding of the genetic architecture underlying variability of cholesterol levels in the population at large and infer that the majority of the genetic variability may be accounted for by polymorphic gene loci with moderate effects on cholesterol levels.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65212/1/j.1469-1809.1987.tb00874.x.pd

Contrasting multi-site genotypic distributions among discordant quantitative phenotypes: the APOA1/C3/A4/A5 gene cluster and cardiovascular disease risk factors

Most tests of association between DNA sequence variation and quantitative phenotypes in samples of randomly chosen individuals rely on specification of genotypic strata followed by comparison of phenotypes across these strata. This strategy often succeeds when phenotypic differences are caused by one or two single nucleotide polymorphisms (SNPs) among the surveyed markers. However, when multiple-SNP haplotypes account for observed phenotypic variation, identification of the best partitioning requires examination of an inordinate number of SNP combinations. An alternative approach is to rank individuals by their phenotypic measures and ask whether attributes of the genotypic variation show a non-random distribution along this phenotypic ranking. One simple version of this strategy selects the top and bottom tails of the distribution, and then tests whether genotypes from these two samples are drawn from a single population. This framework does not require the recovery of phased haplotypes and allows contrasts between large numbers of sites at once. We use a method based on this approach to identify associations between plasma triglyceride level, a risk factor for cardiovascular disease, and multi-site genotypes located in the APOA1/C3/A4/A5 cluster of apolipoprotein genes in unrelated individuals (1,071 African-American females, 780 African-American males, 1,036 European-American females, and 930 European-American males) sampled from four US cities as part of the Coronary Artery Risk Development in Young Adults (CARDIA) study. Method performance is investigated using simulations that model genealogical variation and different genetic architectures. Results indicate that this multi-site test can identify genotype-phenotype associations with reasonable power, including those generated by some simple epistatic models. Genet. Epidemiol . 2006. © 2006 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55790/1/20163_ftp.pd

Linkage Analysis of Plasma ApoE in Three Ethnic Groups: Multiple Genes with Context-Dependent Effects

We performed variance component-based linkage analysis in four samples (two of non-Hispanic European-Americans from Rochester, MN; African-Americans from Jackson, MS; and Mexican-Americans from Starr County, TX) to identify chromosomal regions containing genes influencing plasma apolipoprotein E (apoE) levels. The APOE gene region on chromosome (chr) 19 was identified with a LOD ≥ 2.00 in both samples from Rochester and the sample from Jackson. Adjustment of apoE levels for differences among means of genotypes defined by the APOE ε2/3/4 alleles reduced evidence of linkage, indicating that the APOE gene was responsible for the majority of the linkage signal. In stratified linkage analyses, there was a LOD of 1.70 in the Starr County sibships with average total cholesterol (TC) above the median level for all sibships in that population. Adjustment for APOE genotype did not remove this LOD score, suggesting a second gene in this region may influence apoE variation. Evidence of linkage ( LOD = 3.32) on chr 17 was observed in the Starr County sibships with average TC below the median. Inter-individual variation in plasma apoE level may be influenced by variations in the structural gene, and at least one other gene whose effects differ among populations and are dependent on the influence of unmeasured genetic and environmental factors indexed by correlated measures of lipid metabolism.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66071/1/j.1469-1809.2004.00148.x.pd

A genetic variant on chromosome 9p21 and incident heart failure in the ARIC study

Recent studies showed that polymorphisms on chromosome 9p21 are associated with coronary heart disease (CHD), but few studies examined the association with heart failure (HF), stroke, or other subclinical atherosclerotic diseases. We tested the association of chromosome 9p21 polymorphisms with non-coronary atherosclerotic diseases

Pharmacogenetic Association of NOS3 Variants with Cardiovascular Disease in Patients with Hypertension: The GenHAT Study

Nitric oxide synthase 3 (NOS3) catalyzes production of NO in the endothelium and may play a role in cardiovascular disease (CVD). We assessed the pharmacogenetic associations of three NOS3 polymorphisms and three antihypertensive drugs with CVD outcomes. Hypertensive subjects (n = 30,280) from a multi-center, double-blind clinical trial were randomized to chlorthalidone, amlodipine, or lisinopril treatment (mean follow up, 4.9 years). Outcomes included coronary heart disease (CHD: fatal CHD and nonfatal myocardial infarction); stroke; heart failure (fatal, requiring hospitalization, or outpatient treatment); all-cause mortality; and end-stage renal disease (ESRD). Main effects of NOS3 variants on outcome and genotype-treatment interactions were tested. For NOS3 −690 C>T (rs3918226), a higher hazard ratio (HR) was found in minor allele carriers for CHD (CC = 1.00, CT+TT = 1.12 (95% confidence interval (CI) = 1.00–1.26), P = 0.048). For NOS3 −922 A>G (rs1800779), a higher HR was found in minor allele carriers for heart failure (AA = 1.00, AG+GG = 1.10 (CI = 1.00–1.21), P = 0.046). Significant pharmacogenetic findings were observed for stroke and all-cause mortality. For −690 C>T, a lower HR was observed for stroke in minor allele carriers when treated with amlodipine versus lisinopril (CC = 0.85 (CI = 0.73–0.99), CT+TT = 0.49 (CI = 0.31–0.80), P = 0.04). For glu298asp G>T (rs1799983), a lower HR was observed for all-cause mortality in minor allele carriers when treated with amlodipine versus lisinopril (GG = 1.01 (CI = 0.91–1.13), GT+TT = 0.85 (CI = 0.75–0.97), P = 0.04). We observed significant associations with NOS3 variants and CHD and heart failure and significant pharmacogenetic effects for stroke and all cause mortality. This suggests that NOS3 variants may potentially provide useful clinical information with respect to treatment decisions in the future

TCF7L2 single nucleotide polymorphisms, cardiovascular disease and all-cause mortality: the Atherosclerosis Risk in Communities (ARIC) study

We hypothesize that transcription factor 7-like 2 (TCF7L2) single nucleotide polymorphisms (SNPs) are associated with cardiovascular disease (CVD) and that the associations differ in diabetic and non-diabetic participants

Influence of single nucleotide polymorphisms in factor VIII and von Willebrand factor genes on plasma factor VIII activity: the ARIC Study

Factor VIII (FVIII) functions as a cofactor for factor IXa in the contact coagulation pathway and circulates in a protective complex with von Willebrand factor (VWF). Plasma FVIII activity is strongly influenced by environmental and genetic factors through VWF-dependent and independent mechanisms. Single nucleotide polymorphisms (SNPs) of the coding and promoter sequence in the FVIII gene have been extensively studied for effects on FVIII synthesis, secretion, and activity, but impacts of non–disease-causing intronic SNPs remain largely unknown. We analyzed FVIII SNPs and FVIII activity in 10 434 healthy Americans of European (EA) or African (AA) descent in the Atherosclerosis Risk in Communities (ARIC) study. Among covariates, age, race, diabetes, and ABO contributed 2.2%, 3.5%, 4%, and 10.7% to FVIII intersubject variation, respectively. Four intronic FVIII SNPs associated with FVIII activity and 8 with FVIII-VWF ratio in a sex- and race-dependent manner. The FVIII haplotypes AT and GCTTTT also associated with FVIII activity. Seven VWF SNPs were associated with FVIII activity in EA subjects, but no FVIII SNPs were associated with VWF Ag. These data demonstrate that intronic SNPs could directly or indirectly influence intersubject variation of FVIII activity. Further investigation may reveal novel mechanisms of regulating FVIII expression and activity

Association of rs780094 in \u3ci\u3eGCKR\u3c/i\u3e with Metabolic Traits and Incident Diabetes and Cardiovascular Disease: The ARIC Study

Objective: The minor T-allele of rs780094 in the glucokinase regulator gene (GCKR) associates with a number of metabolic traits including higher triglyceride levels and improved glycemic regulation in study populations of mostly European ancestry. Using data from the Atherosclerosis Risk in Communities (ARIC) Study, we sought to replicate these findings, examine them in a large population-based sample of African American study participants, and to investigate independent associations with other metabolic traits in order to determine if variation in GKCR contributes to their observed clustering. In addition, we examined the association of rs780094 with incident diabetes, coronary heart disease (CHD), and stroke over up mean follow-up times of 8, 15, and 15 years, respectively. Research Design and Methods: Race-stratified analyses were conducted among 10,929 white and 3,960 black participants aged 45–64 at baseline assuming an additive genetic model and using linear and logistic regression and Cox proportional hazards models. Results: Previous findings replicated among white participants in multivariable adjusted models: the T-allele of rs780094 was associated with lower fasting glucose (p = 10-7) and insulin levels (p = 10-6), lower insulin resistance (HOMA-IR, p=10-9), less prevalent diabetes (p = 10-6), and higher CRP (p = 10-8), 2-h postprandial glucose (OGTT, p = 10-6), and triglyceride levels (p = 10-31). Moreover, the T-allele was independently associated with higher HDL cholesterol levels (p = 0.022), metabolic syndrome prevalence (p = 0.043), and lower beta-cell function measured as HOMA-B (p = 0.011). Among black participants, the T-allele was associated only with higher triglyceride levels (p = 0.004) and lower insulin levels (p = 0.002) and HOMA-IR (p = 0.013). Prospectively, the T-allele was associated with reduced incidence of diabetes (p = 10-4) among white participants, but not with incidence of CHD or stroke. Conclusions: Our findings indicate rs780094 has independent associations with multiple metabolic traits as well as incident diabetes, but not incident CHD or stroke. The magnitude of association between the SNP and most traits was of lower magnitude among African American compared to white participants

Role of BMI in the Association of the TCF7L2 rs7903146 Variant with Coronary Heart Disease: The Atherosclerosis Risk in Communities (ARIC) Study

We examined the association of variation in the type 2 diabetes risk-conferring TCF7L2 gene with the risk of incident coronary heart disease (CHD) among the lean, overweight, and obese members of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Cox proportional hazard regression analyses were performed using a general model, with the major homozygote as the reference category. For 9,865 whites, a significant increase in the risk of CHD was seen only among lean ( BMI < 25 kg/m2) individuals homozygous for the T allele of the TCF7L2 rs7903146 gene risk variant (hazard ratio 1.42; 95% CI 1.03,1.97; P = .01). No association was found among 3,631 blacks, regardless of BMI status. An attenuated hazard ratio was observed among the nondiabetic ARIC cohort members. This study suggests that body mass modifies the association of the TCF7L2 rs7903146 T allele with CHD risk