Abstract
Chemerin is an adipokine proposed to link obesity and chronic inflammation of adipose tissue. Genetic factors determining chemerin release from adipose tissue are yet unknown. We conducted a meta-analysis of genome-wide association studies (GWAS) for serum chemerin in three independent cohorts from Europe: Sorbs and KORA from Germany and PPP-Botnia from Finland (total N = 2,791). In addition, we measured mRNA expression of genes within the associated loci in peripheral mononuclear cells by micro-arrays, and within adipose tissue by quantitative RT-PCR and performed mRNA expression quantitative trait and expression-chemerin association studies to functionally substantiate our loci. Heritability estimate of circulating chemerin levels was 16.2% in the Sorbs cohort. Thirty single nucleotide polymorphisms (SNPs) at chromosome 7 within the retinoic acid receptor responder 2 (RARRES2)/Leucine Rich Repeat Containing (LRRC61) locus reached genome-wide significance (p<5.0×10−8) in the meta-analysis (the strongest evidence for association at rs7806429 with p = 7.8×10−14, beta = −0.067, explained variance 2.0%). All other SNPs within the cluster were in linkage disequilibrium with rs7806429 (minimum r2 = 0.43 in the Sorbs cohort). The results of the subgroup analyses of males and females were consistent with the results found in the total cohort. No significant SNP-sex interaction was observed. rs7806429 was associated with mRNA expression of RARRES2 in visceral adipose tissue in women (p<0.05 after adjusting for age and body mass index). In conclusion, the present meta-GWAS combined with mRNA expression studies highlights the role of genetic variation in the RARRES2 locus in the regulation of circulating chemerin concentrations.
Highlights
Chemerin has been extensively studied as an adipokine associated with obesity and related phenotypes [1,2,3,4]
We conducted a meta-analysis of genome-wide association studies (GWAS) for serum chemerin in three independent cohorts: the Sorbs (N = 824) and KORA (N = 1630) from Germany and the PPP-Botnia (N = 337) from Finland
Serum chemerin concentrations are positively associated with adipocyte fatty acid binding protein (AFABP) and progranulin levels but not with vaspin and adiponectin concentrations (Table 1)
Summary
Chemerin has been extensively studied as an adipokine associated with obesity and related phenotypes [1,2,3,4]. It is secreted from adipose tissue as an 18-kDa precursor protein which is activated by several extracellular cleavage steps [5,6,7]. The single nucleotide polymorphism (SNP) showing the strongest evidence of association (rs347344; p = 1.461026) was located within epithelial growth factor-like repeats and discoidin I-like domains 3 (EDIL3) playing an important role in angiogenesis, a key step in adipose tissue expansion in obesity [8]
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