Disentangling Sex Differences in Sulfonylurea Drug Response With Genome-Wide Association Studies in Individuals With Type 2 Diabetes.

Sex-specific genetic effects on HbA1c response; replicated variants at the TMEM64/NECAB1 locus associated with reduced response in males, with lower peak insulin for rs6471250-C.

First sex-stratified genome-wide association study of HbA1c response to sulfonylureas, conducted in 871 participants of the ACCORD trial, with replication in the PMET1 cohort and functional exploration in the SUGAR-MGH cohort. Genome-wide significant loci with sex-specific effects were identified: KAZN, KIF2B, SLC39A10 and SPINK5 (combined sexes), CRACR2A, KCNK2 and TENM2 (males only), NACPH2 (females only). Two suggestive variants at the TMEM64/NECAB1 locus, associated with reduced HbA1c response in ACCORD males, were directly replicated in PMET1 males. In SUGAR-MGH, rs6471250-C was associated with reduced peak insulin in males (p = 0.035) but not females (p = 0.40), suggesting a sex-dependent functional effect.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The methodological message matters more than the loci themselves: ignoring sex as a biological variable in pharmacogenomic GWAS loses signal, and this work demonstrates it for a still widely prescribed drug class. On substance, caution is warranted: 871 participants, replication limited to merely suggestive variants and a functional effect at p = 0.035 support no dosing change. Read it as proof of concept for sex stratification, not as a usable new gene-drug pair.

Analysis by Dr Thibaut Benquey