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There has been great interest in genetic risk prediction using risk scores in recent years, however, the utility of scores developed in European populations and later applied to non-European populations has not been successful. The goal of this study was to create a methylation risk score (MRS) for metabolic syndrome (MetS), demonstrating the utility of MRS across race groups using cross-sectional data from the Hypertension Genetic Epidemiology Network (HyperGEN, N = 614 African Americans (AA)) and the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, N = 995 European Americans (EA)). To demonstrate this, we first selected cytosine-guanine dinucleotides (CpG) sites measured on Illumina Methyl450 arrays previously reported to be significantly associated with MetS and/or component conditions in more than one race/ethnic group (CPT1A cg00574958, PHOSPHO1 cg02650017, ABCG1 cg06500161, SREBF1 cg11024682, SOCS3 cg18181703, TXNIP cg19693031). Second, we calculated the parameter estimates for the 6 CpGs in the HyperGEN data (AA) and used the beta estimates as weights to construct a MRS in HyperGEN (AA), which was validated in GOLDN (EA). We performed association analyses using logistic mixed models to test the association between the MRS and MetS, adjusting for covariates. Results showed the MRS was significantly associated with MetS in both populations. In summary, a MRS for MetS was a strong predictor for the condition across two race groups, suggesting MRS may be useful to examine metabolic disease risk or related complications across race/ethnic groups.

Background: Hypertensive African Americans have a ~50% response rate to thiazide diuretic treatment. This contributes to a high prevalence of uncontrolled high blood pressure. Here, we examined the role of the mitochondrial genome on thiazide diuretic treatment response in hypertensive African Americans enrolled in a clinical trial. Methods: Participants from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT, n= 4279) were genotyped using the Illumina Infinium Multi-Ethnic Beadchip. Haplotype groups were called using HaploGrep. We used a linear regression analysis to examine the association between mitochondrial haplogroups (L, M, and N) and changes in blood pressure and fasting glucose over six months and two years, respectively. Results: The analysis revealed a null association between mitochondrial haplogroups M and N versus L for each of the outcomes. In subgroup analysis, the L subclades L1, L2, and L3/L4 (versus L0) were each inversely associated with fasting glucose response (p < 0.05). Conclusions: This discovery analysis suggests the mitochondrial genome has a small effect on fasting glucose response, but not that of blood pressure, to thiazide diuretic treatment in African Americans.

Background: Hypertensive African Americans have a ~50% response rate to thiazide diuretic treatment. This contributes to a high prevalence of uncontrolled high blood pressure. Here, we examined the role of the mitochondrial genome on thiazide diuretic treatment response in hypertensive African Americans enrolled in a clinical trial. Methods: Participants from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT, n= 4279) were genotyped using the Illumina Infinium Multi-Ethnic Beadchip. Haplotype groups were called using HaploGrep. We used a linear regression analysis to examine the association between mitochondrial haplogroups (L, M, and N) and changes in blood pressure and fasting glucose over six months and two years, respectively. Results: The analysis revealed a null association between mitochondrial haplogroups M and N versus L for each of the outcomes. In subgroup analysis, the L subclades L1, L2, and L3/L4 (versus L0) were each inversely associated with fasting glucose response (p < 0.05). Conclusions: This discovery analysis suggests the mitochondrial genome has a small effect on fasting glucose response, but not that of blood pressure, to thiazide diuretic treatment in African Americans.

Abstract Chronic kidney disease (CKD) impacts about 1 in 7 adults in the United States, but African Americans (AAs) carry a disproportionately higher burden of disease. Epigenetic modifications, such as DNA methylation at cytosine-phosphate-guanine (CpG) sites, have been linked to kidney function and may have clinical utility in predicting the risk of CKD. Given the dynamic relationship between the epigenome, environment, and disease, AAs may be especially sensitive to environment-driven methylation alterations. Moreover, risk models incorporating CpG methylation have been shown to predict disease across multiple racial groups. In this study, we developed a methylation risk score (MRS) for CKD in cohorts of AAs. We selected nine CpG sites that were previously reported to be associated with estimated glomerular filtration rate (eGFR) in epigenome-wide association studies to construct a MRS in the Hypertension Genetic Epidemiology Network (HyperGEN). In logistic mixed models, the MRS was significantly associated with prevalent CKD and was robust to multiple sensitivity analyses, including CKD risk factors. There was modest replication in validation cohorts. In summary, we demonstrated that an eGFR-based CpG score is an independent predictor of prevalent CKD, suggesting that MRS should be further investigated for clinical utility in evaluating CKD risk and progression.