Rare CETP missense variants are linked to male-specific metabolic syndrome across five ancestries, transethnic exome study finds (Genes Genomics 2022)

Background: Metabolic syndrome (MetS) is a group of very common human conditions promoting strong understand the impact of rare variants, beyond exome-wide association studies, to potentially discover causative variants, across different ethnic populations.

Objective: We performed transethnic, exome-wide MetS association studies on MetS in men.

Methods: We analyzed genotype data of 5302 European subjects (2658 cases and 2644 controls), in the discovery stage of the European METabolic Syndrome In Men study, generated from exome chips, and 2481 subjects (714 cases and 1767 controls), in the replication stage, across 6 independent cohorts of 5 ancestries (T2D-GENES consortium), using whole-exome sequencing. We therefore evaluated gene-level and variant-level associations, of rare variants for MetS, using logistic regression (LR) and multivariate analyses (MulA).

Results: Gene-based association found the gene for the cholesteryl ester transfer protein (CETP) (from MulA, p value = 4.67 × 10-9; from LR, p value = 0.009) to well associate with MetS. At two missense variants, from 8 rare variants in CETP, Ala390Pro (rs5880) (from MulA, p value = 1.28 × 10-7; from LR, p value = 1.34 × 10-4) and Arg468Gln (rs1800777) (from MulA, p value = 2.40 × 10-5; from LR, p value = 1.49 × 10-3) significantly associated with MetS across five ancestries.

Conclusions: Our findings highlight novel rare variants of genes that confer MetS susceptibility, in Europeans, that are shared with diverse populations, emphasizing an opportunity to further understand the biological target or genes that underlie MetS, across populations.