The Association of ARMC5 with the Renin-Angiotensin-Aldosterone System, Blood Pressure and Glycemia in African Americans.

CONTEXT: Armadillo repeat containing 5 (ARMC5) on Chromosome 16 is an adrenal gland tumor suppressor gene associated with primary aldosteronism, especially among African Americans (AAs). We examined the association of ARMC5 variants with aldosterone, plasma renin activity (renin), blood pressure, glucose and hemoglobin A1c (A1c) in community-dwelling AAs. METHODS: The Jackson Heart Study is a prospective cardiovascular cohort study in AAs with baseline data collection between 2000-2004. Kernel machine method was used to perform a single joint test to analyze for an overall association between the phenotypes of interest (aldosterone, renin, systolic and diastolic blood pressure [SBP, DBP], glucose and A1c) and the ARMC5 single nucleotide variants (SNVs) adjusted for age, sex, BMI, and medications; followed by Baysian Lasso methodology to identify sets of SNVs in terms of associated haplotypes with specific phenotypes. RESULTS: Among 3,223 participants (62% female; mean age 55.6 (SD±12.8) years) the average SBP and DBP were 127 and 76 mmHg, respectively. The average FPG and A1c were 101 mg/dl and 6.0%, respectively. ARMC5 variants were associated with all six phenotypes. Haplotype TCGCC (ch16:31476015-31476093) was negatively associated, whereas haplotype CCCCTTGCG (ch16:31477195-31477460) was positively associated with SBP, DBP, and glucose. Haplotypes GGACG(ch16:31477790-31478013) and ACGCG (ch16:31477834-31478113) were negatively associated with aldosterone and positively associated with A1c and glucose, respectively. Haplotype GCGCGAGC (ch16:31471193-ch16:31473597(rs114871627) was positively associated with PRA and negatively associated with A1c. CONCLUSIONS: ARMC5 variants are associated with aldosterone, PRA, blood pressure, fasting glucose and A1c in community-dwelling AAs, suggesting germline mutations in ARMC5 may underlie cardiometabolic disease in AAs.