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

Abstract

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 (PRA), blood pressure, glucose, and glycosylated hemoglobin A1c (HbA1c) in community-dwelling AAs.

Methods: The Jackson Heart Study is a prospective cardiovascular cohort study in AAs with baseline data collection from 2000 to 2004. Kernel machine method was used to perform a single joint test to analyze for an overall association between the phenotypes of interest (aldosterone, PRA, systolic and diastolic blood pressure [SBP, DBP], glucose, and HbA1c) 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 3223 participants (62% female; mean age 55.6 (SD ± 12.8) years), the average SBP and DBP were 127 and 76 mmHg, respectively. The average fasting plasma glucose and HbA1c were 101 mg/dL and 6.0%, respectively. ARMC5 variants were associated with all 6 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 HbA1c and glucose, respectively. Haplotype GCGCGAGC (ch16:31471193-ch16:31473597(rs114871627) was positively associated with PRA and negatively associated with HbA1c.

Conclusions: ARMC5 variants are associated with aldosterone, PRA, blood pressure, fasting glucose, and HbA1c in community-dwelling AAs, suggesting that germline mutations in ARMC5 may underlie cardiometabolic disease in AAs.

Keywords: ARMC5; African Americans; aldosterone; blood pressure; glucose; renin.

Figure 1.

Network plot indicating phenotype-haplotype relationships. The size of a phenotype node is proportional to the number of significant haplotypes in all blocks of the SNVs in the ARMC5 gene. A (+) from the ARMC5 node to a phenotype node indicates that the majority and most significant associations are positive; while a (-) indicates that the majority and the most significant associations are negative. Phenotypes that are connected by dashed lines originated from a blue dot are those that share at least one common significant haplotype. Abbreviations: ARMC5 (Armadillo Repeat Containing 5); Renin (plasma renin activity); SBP (systolic blood pressure); DBP (diastolic blood pressure); FPG (fasting plasma glucose); and HbA1c (hemoglobin A1c).

Figure 2.

Linkage disequilibrium (LD) plot among the SNVs studied and the histogram of the number of significant haplotypes over the blocks. The LD plot is based on both D′ for all 95 SNVs, although LD was not calculated for SNVs with MAF <0.001. For the histogram above the LD plot, only blocks with at least one significant haplotype are shown. The height of the bar indicates the number of significant haplotypes over the block across all phenotypes studied. Also, note that the blocks may overlap one another. Finally, the SNVs are positioned at equal distance rather than drawn according to their actual physical distances. The LD plot should be interpreted with caution: neither D′ nor R², the traditional measures of LD, can accurately capture LD information (43). In fact, LD information involving SNVs with MAF smaller than 0.001 was not provided in the plot.