Plasma metabolomic profiling in subclinical atherosclerosis: the Diabetes Heart Study

Background Incidence rates of cardiovascular disease (CVD) are increasing, partly driven by the diabetes epidemic. Novel prediction tools and modifiable treatment targets are needed to enhance risk assessment and management. Plasma metabolite associations with subclinical atherosclerosis were investigated in the Diabetes Heart Study (DHS), a cohort enriched for type 2 diabetes (T2D). Methods The analysis included 700 DHS participants, 438 African Americans (AAs), and 262 European Americans (EAs), in whom coronary artery calcium (CAC) was assessed using ECG-gated computed tomography. Plasma metabolomics using liquid chromatography-mass spectrometry identified 853 known metabolites. An ancestry-specific marginal model incorporating generalized estimating equations examined associations between metabolites and CAC (log-transformed (CAC + 1) as outcome measure). Models were adjusted for age, sex, BMI, diabetes duration, date of plasma collection, time between plasma collection and CT exam, low-density lipoprotein cholesterol (LDL-C), and statin use. Results At an FDR-corrected p-value < 0.05, 33 metabolites were associated with CAC in AAs and 36 in EAs. The androgenic steroids, fatty acid, phosphatidylcholine, and bile acid metabolism subpathways were associated with CAC in AAs, whereas fatty acid, lysoplasmalogen, and branched-chain amino acid (BCAA) subpathways were associated with CAC in EAs. Conclusions Strikingly different metabolic signatures were associated with subclinical coronary atherosclerosis in AA and EA DHS participants.

Genome-wide association study of vitamin D concentrations and bone mineral density in the African American-Diabetes Heart Study

Relative to European Americans, African Americans have lower 25-hydroxyvitamin D (25OHD) and vitamin D binding protein (VDBP) concentrations, higher 1,25-dihydroxyvitamin D (1,25(OH)2D3) concentrations and bone mineral density (BMD), and paradoxically reduced burdens of calcified atherosclerotic plaque (subclinical atherosclerosis). To identify genetic factors contributing to vitamin D and BMD measures, association analysis of >14M variants was conducted in a maximum of 697 African American-Diabetes Heart Study participants with type 2 diabetes (T2D). The most significant association signals were detected for VDBP on chromosome 4; variants rs7041 (β = 0.44, SE = 0.019, P = 9.4x10-86) and rs4588 (β = 0.17, SE = 0.021, P = 3.5x10-08) in the group-specific component (vitamin D binding protein) gene (GC). These variants were found to be independently associated. In addition, rs7041 was also associated with bioavailable vitamin D (BAVD; β = 0.16, SE = 0.02, P = 3.3x10-19). Six rare variants were significantly associated with 25OHD, including a non-synonymous variant in HSPG2 (rs116788687; β = -1.07, SE = 0.17, P = 2.2x10-10) and an intronic variant in TNIK (rs143555701; β = -1.01, SE = 0.18, P = 9.0x10-10), both biologically related to bone development. Variants associated with 25OHD failed to replicate in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of vitamin D metabolism and bone mineral density phenotypes in an African American population enriched for T2D could provide insight into ethnic specific differences in vitamin D metabolism and bone mineral density.

JC Viruria Is Associated With Reduced Risk of Diabetic Kidney Disease

Purpose African Americans who shed JC polyomavirus (JCV) in their urine have reduced rates of nondiabetic chronic kidney disease (CKD). We assessed the associations between urinary JCV and urine BK polyomavirus (BKV) with CKD in African Americans with diabetes mellitus. Methods African Americans with diabetic kidney disease (DKD) and controls lacking nephropathy from the Family Investigation of Nephropathy and Diabetes Consortium (FIND) and African American-Diabetes Heart Study (AA-DHS) had urine tested for JCV and BKV using quantitative PCR. Of the 335 individuals tested, 148 had DKD and 187 were controls. Results JCV viruria was detected more often in the controls than in the patients with DKD (FIND: 46.6% vs 32.2%; OR, 0.52; 95% CI, 0.29 to 0.93; P = 0.03; AA-DHS: 30.4% vs 26.2%; OR, 0.63; 95% CI, 0.27 to 1.48; P = 0.29). A joint analysis adjusted for age, sex, and study revealed that JC viruria was inversely associated with DKD (OR, 0.56; 95% CI, 0.35 to 0.91; P = 0.02). Statistically significant relationships between BKV and DKD were not observed. Main Conclusions The results from the present study extend the inverse association between urine JCV and nondiabetic nephropathy in African Americans to DKD. These results imply that common pathways likely involving the innate immune system mediate coincident chronic kidney injury and restriction of JCV replication. Future studies are needed to explore causative pathways and characterize whether the absence of JC viruria can serve as a biomarker for DKD in the African American population.