Background: Resistin, a protein linked with inflammation and cardiometabolic diseases, is one of few proteins for which genome-wide association studies consistently report variants within and near the coding gene (RETN). Here, we took advantage of the reduced linkage disequilibrium in African populations to infer genetic causality for circulating resistin levels by performing genome-wide association studies, whole-exome analysis, fine mapping, Mendelian randomization, and transcriptomic data analyses.
Methods: Genome-wide association studies and fine-mapping analyses for resistin were performed in 5621 African-ancestry individuals, including 3754 continental Africans and 1867 African Americans. Causal variants identified were subsequently used as an instrumental variable in Mendelian randomization analyses for homeostatic modeling-derived insulin resistance index, body mass index, and type 2 diabetes.
Results: The lead variant (rs3219175, in the promoter region of RETN) for the single locus detected was the same for continental Africans (P=5.0×10-111) and for African Americans (9.5×10-38), respectively explaining 12.1% and 8.5% of variance in circulating resistin. Fine-mapping analyses and functional annotation revealed this variant as likely causal affecting circulating resistin levels as a cis-eQTL increasing RETN expression. Additional variants regulating resistin levels were upstream of RETN with genes PCP2, STXBP2, and XAB2 showing the strongest association using integrative analysis of genome-wide association studies with transcriptomic data. Mendelian randomization analyses did not provide evidence for resistin increasing insulin resistance, body mass index, or type 2 diabetes risk in African-ancestry populations.
Conclusions: Taking advantage of the fine-mapping resolution power of African genomes, we identified a single variant (rs3219175) as the likely causal variant responsible for most of the variability in circulating resistin levels. In contrast to findings in some other ancestry populations, we showed that resistin does not seem to increase insulin resistance and related cardiometabolic traits in African-ancestry populations.
Keywords: cardiovascular diseases; cytokines; ethnic groups; genome-wide association study; mendelian randomization analysis; resistin.