Genome Wide Meta-analysis Highlights the Role of Genetic Variation in RARRES2 in the Regulation of Circulating Serum Chemerin

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−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 (pRARRES2 locus in the regulation of circulating chemerin concentrations.

趋化素（Chemerin）是一种脂肪因子（adipokine），被认为可连接肥胖与脂肪组织的慢性炎症。目前尚未明确决定脂肪组织分泌趋化素的遗传因素。我们针对来自欧洲的3个独立队列开展了血清趋化素的全基因组关联研究（genome-wide association study, GWAS）荟萃分析：分别为德国的Sorbs队列、KORA队列以及芬兰的PPP-Botnia队列，总样本量N=2791。此外，我们通过微阵列（microarray）检测了外周血单核细胞中关联位点内基因的mRNA表达水平，并通过定量逆转录聚合酶链反应（quantitative RT-PCR）检测了脂肪组织中的该类基因表达；同时开展了mRNA表达数量性状位点（expression quantitative trait locus, eQTL）与表达-趋化素关联研究，以对我们发现的位点进行功能验证。在Sorbs队列中，循环趋化素水平的遗传力估计值为16.2%。荟萃分析结果显示，7号染色体上视黄酸受体应答2（retinoic acid receptor responder 2, RARRES2）/富含亮氨酸重复序列蛋白61（Leucine Rich Repeat Containing 61, LRRC61）位点处的30个单核苷酸多态性（single nucleotide polymorphism, SNP）达到全基因组显著性水平（p < 10^-8）：其中rs7806429的关联证据最强，p值为7.8×10^-14，β值为-0.067，解释方差为2.0%。该簇内其余所有单核苷酸多态性均与rs7806429存在连锁不平衡（linkage disequilibrium），在Sorbs队列中最小r²=0.43。男性与女性的亚组分析结果与总队列的分析结果一致，未观察到显著的SNP-性别交互作用。rs7806429与女性内脏脂肪组织中RARRES2的mRNA表达水平相关，证实RARRES2位点参与循环趋化素浓度的调控。