Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia

Abstract

Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 × 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10(-12); rs35897051, P = 3.32 × 10(-8)). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10(-12)), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case-control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study.

Figure 1.

Results of the GWAS for serum MPO levels in subjects of European ancestry. The Q–Q (A) and Manhattan (B) plots are shown for the meta-analysis of 9305 subjects from the GeneBank, CHS, FHS and CARDIA cohorts.

Figure 2.

Regional plots for loci demonstrating a significant association with serum MPO levels on chromosomes 1q31.3 (A), 6p21.32 (B), and 20p13 (C). For each locus, a 1 Mb region is shown, centered on the lead SNP (purple diamond). Genes in the selected intervals are indicated in the bottom panel.

Figure 3.

Results of the GWAS for plasma MPO levels in subjects of European ancestry. The Q–Q (A) and Manhattan (B) plots are shown for the meta-analysis of 9260 subjects from the GeneBank, GHS I, GHS II, LURIC1 and LURIC2 cohorts. (C) Regional plot of a 1 Mb interval on chromosome 17q22 demonstrates several independent SNPs that exceed the genome-wide threshold for significance. The bottom panel shows the LD pattern across this region using CEU data from HAPMAP.

Figure 3.

Results of the GWAS for plasma MPO levels in subjects of European ancestry. The Q–Q (A) and Manhattan (B) plots are shown for the meta-analysis of 9260 subjects from the GeneBank, GHS I, GHS II, LURIC1 and LURIC2 cohorts. (C) Regional plot of a 1 Mb interval on chromosome 17q22 demonstrates several independent SNPs that exceed the genome-wide threshold for significance. The bottom panel shows the LD pattern across this region using CEU data from HAPMAP.

Figure 4.

Serum C3a-desArg levels as a function of CFH rs800292 genotype. Serum levels of C3a-desArg are significantly lower in carriers of the A allele compared with GG homozygotes in a dose-dependent manner. Data were measured in a subset of age-, sex- and CAD status-matched GeneBank subjects and shown as untransformed mean ± SE. The P-value was obtained using linear regression analyses with natural-log transformation.