The Genetics of Circulating Resistin Level, A Biomarker for Cardiovascular Diseases, Is Informed by Mendelian Randomization and the Unique Characteristics of African Genomes

Abstract

Background - Resistin, a protein linked with inflammation and cardiometabolic diseases, is one of few proteins for which GWAS 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 GWAS, whole-exome analysis, fine-mapping, Mendelian randomization and transcriptomic data analyses. Methods - GWAS and fine-mapping analyses for resistin were performed in 5621 African ancestry individuals, including 3754 continental Africans (AF) and 1867 African Americans (AA). Causal variants identified were subsequently used as an instrumental variable in Mendelian randomization analyses for homeostatic modelling (HOMA) derived insulin resistance index, BMI and type 2 diabetes. Results - The lead variant (rs3219175, in the promoter region of RETN ) for the single locus detected was the same for AF ( P -value 5.0×10 -111 ) and for AA (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 GWAS with transcriptomic data. Mendelian randomization analyses did not provide evidence for resistin increasing insulin resistance, BMI 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.