Human genetics uncovers <i>MAP3K15</i> as an obesity-independent therapeutic target for diabetes.

ABSTRACT: We performed collapsing analyses on 454,796 UK Biobank (UKB) exomes to detect gene-level associations with diabetes. Recessive carriers of nonsynonymous variants in MAP3K15 were 30% less likely to develop diabetes (P = 5.7 × 10^-10) and had lower glycosylated hemoglobin (β = -0.14 SD units, P = 1.1 × 10^-24). These associations were independent of body mass index, suggesting protection against insulin resistance even in the setting of obesity. We replicated these findings in 96,811 Admixed Americans in the Mexico City Prospective Study (P < 0.05)Moreover, the protective effect of MAP3K15 variants was stronger in individuals who did not carry the Latino-enriched SLC16A11 risk haplotype (P = 6.0 × 10^-4). Separate

SUBMITTER: Nag A 

PROVIDER: S-EPMC9668288 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature