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Genetic markers associated with plasma protein C level in African Americans: the atherosclerosis risk in communities (ARIC) study.

ABSTRACT: Protein C is an endogenous anticoagulant protein with anti-inflammatory properties. Single-nucleotide polymorphisms (SNPs) affect the levels of circulating protein C in European Americans. We performed a genome-wide association (GWA) scan of plasma protein C concentration with approximately 2.5 million SNPs in 2,701 African Americans in the Atherosclerosis Risk in Communities Study. Seventy-nine SNPs from the 20q11 and 2q14 regions reached the genome-wide significance threshold of 5 × 10(-8) . A missense variant rs867186 in the PROCR gene at 20q11 is known to affect protein C levels in individuals of European descent and showed the strongest signal (P = 9.84 × 10(-65) ) in African Americans. The minor allele of this SNP was associated with higher protein C levels (? = 0.49 ?g/ml; 10% variance explained). In the 2q14 region, the top SNPs were near or within the PROC gene: rs7580658 (? = 0.15 ?g/ml; 2% variance explained, P = 1.7 × 10(-12) ) and rs1799808 (? = 0.15 ?g/ml; 2% variance explained, P = 2.03 × 10(-12) ). These two SNPs were in strong linkage disequilibrium (LD) with another SNP rs1158867 that resides in a biochemically functional site and in weak to strong LD with the top PROC variants previously reported in individuals of European descent. In addition, two variants outside the PROC region were significantly and independently associated with protein C levels: rs4321325 in CYP27C1 and rs13419716 in MYO7B. In summary, this first GWA study for plasma protein C levels in African Americans confirms the associations of SNPs in the PROC and PROCR regions with circulating levels of protein C across ethnic populations and identifies new candidates for protein C regulation.

SUBMITTER: Munir MS

PROVIDER: S-EPMC4354842 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Genetic markers associated with plasma protein C level in African Americans: the atherosclerosis risk in communities (ARIC) study.

Munir M Shahzeb MS Weng Lu-Chen LC Tang Weihong W Basu Saonli S Pankow James S JS Matijevic Nena N Cushman Mary M Boerwinkle Eric E Folsom Aaron R AR

Genetic epidemiology 20141105 8

Protein C is an endogenous anticoagulant protein with anti-inflammatory properties. Single-nucleotide polymorphisms (SNPs) affect the levels of circulating protein C in European Americans. We performed a genome-wide association (GWA) scan of plasma protein C concentration with approximately 2.5 million SNPs in 2,701 African Americans in the Atherosclerosis Risk in Communities Study. Seventy-nine SNPs from the 20q11 and 2q14 regions reached the genome-wide significance threshold of 5 × 10(-8) . A ...[more]

PMID: 25376901

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Project description:BackgroundLow serum magnesium levels have been associated with multiple chronic diseases. The regulation of serum magnesium homeostasis is not well understood. A previous genome-wide association study (GWAS) of European ancestry (EA) populations identified nine loci for serum magnesium. No such study has been conducted in African-Americans, nor has there been an evaluation of the interaction of magnesium-associated SNPs with environmental factors. The goals of this study were to identify genetic loci associated with serum magnesium in an African-American (AA) population using both genome-wide and candidate region interrogation approaches and to evaluate gene-environment interaction for the magnesium-associated variants in both EA and AA populations. We conducted a GWAS of serum magnesium in 2737 AA participants of the Atherosclerosis Risk in Communities (ARIC) Study and interrogated the regions of the nine published candidate loci in these results. Literature search identified the influence of progesterone on MUC1 expression and insulin on TRPM6 expression.ResultsThe GWAS approach in African-American participants identified a locus near MUC1 as genome-wide significant (rs2974937, beta=-0.013, p=6.1x10(-9)). The candidate region interrogation approach identified two of the nine loci previously discovered in EA populations as containing SNPs that were significantly associated in African-American participants (SHROOM3 and TRPM6). The index variants at these three loci together explained 2.8 % of the variance in serum magnesium concentration in ARIC African-American participants. On the test of gene-environment interaction in ARIC EA participants, the index variant at MUC1 had 2.5 times stronger association in postmenopausal women with progestin use (beta=-0.028, p=7.3x10(-5)) than in those without any hormone use (beta=-0.011, p=7.0x10(-8), p for interaction 0.03). At TRPM6, the index variant had 1.6 times stronger association in those with lower fasting insulin levels (<80 pmol/L: beta=-0.013, p=1.6x10(-7); ≥80 pmol/L: beta=-0.008, p=1.8x10(-2), p for interaction 0.03).ConclusionsWe identified three loci that explained 2.8% of the variance in serum magnesium concentration in ARIC African-American participants. Following-up on functional studies of gene expression identified gene-environment interactions between progestin use and MUC1 and between insulin and TRPM6 on serum magnesium concentration in ARIC European-American participants. These results extend our understanding of the metabolism of serum magnesium.

Project description:BACKGROUND:Evidence suggests glucose transporter-1 (GLUT1) genetic variation affects diabetic nephropathy and albuminuria. Our aim was to evaluate associations with albuminuria of six GLUT1 single nucleotide polymorphisms(SNPs), particularly XbaI and the previously associated Enhancer-2 (Enh2) SNP. METHODS:A two-stage case-control study was nested in a prospective cohort study of 2156 African Americans and 8122 European Americans with urinary albumin-to-creatinine ratio (ACR). Cases comprised albuminuria (N = 825; ? 30 ?g/mg) and macroalbuminuria (N = 173; ? 300 ?g/mg). ACR < 30 ?g/mg classified controls (n = 9453). Logistic regression and odds ratios (OR) assessed associations. The evaluation phase (stage 1, n = 2938) tested associations of albuminuria (n = 305) with six GLUT1 SNPs: rs841839, rs3768043, rs2297977, Enh2(rs841847) XbaI (rs841853), and rs841858. Enh2 was examined separately in the replication phase (stage 2, n = 7340) and the total combined sample (n = 10,278), with all analyses stratified by race and type 2 diabetes. RESULTS:In European Americans, after adjusting for diabetes and other GLUT1 SNPs in stage 1, Enh2 risk genotype (TT) was more common in albuminuric cases (OR = 3.37, P = 0.090) whereas XbaI (OR = 0.94, p = 0.931) and remaining SNPs were not. In stage 1, the Enh2 association with albuminuria was significant among diabetic European Americans (OR = 2.36, P = 0.025). In African Americans, Enh2 homozygosity was rare (0.3%); XbaI was common (18.0% AA) and not associated with albuminuria. In stage 2 (n = 7,340), Enh2 risk genotype had increased but non-significant OR among diabetic European Americans (OR = 1.66, P = 0.192) and not non-diabetics (OR = 0.99, p = 0.953), not replicating stage 1. Combining stages 1 and 2, Enh2 was associated with albuminuria (OR 2.14 [1.20-3.80], P = 0.009) and macroalbuminuria (OR 2.69, [1.02-7.09], P = 0.045) in diabetic European Americans. The Enh2 association with macroalbuminuria among non-diabetic European Americans with fasting insulin (OR = 1.84, P = 0.210) was stronger at the highest insulin quartile (OR = 4.08, P = 0.040). CONCLUSIONS:As demonstrated with type 1 diabetic nephropathy, the GLUT1 Enh2 risk genotype, instead of XbaI, may be associated with type 2 diabetic albuminuria among European Americans, though an association is not conclusive. The association among diabetic European Americans found in stage 1 was not replicated in stage 2; however, this risk association was evident after combining all diabetic European Americans from both stages. Additionally, our results suggest this association may extend to non-diabetics with high insulin concentrations. Rarity of the Enh2 risk genotype among African Americans precludes any definitive conclusions, although data suggest a risk-enhancing role.

Dataset Information

Genetic markers associated with plasma protein C level in African Americans: the atherosclerosis risk in communities (ARIC) study.

Publications

Genetic markers associated with plasma protein C level in African Americans: the atherosclerosis risk in communities (ARIC) study.

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