Association of KCNJ11 and TCF7L2 genetic variants with type 2 diabetes in a Mexican region with high disease prevalence and strong Mayan cultural heritage

Abstract Type 2 diabetes (T2D) affects up to 18.3% of Mexicans, surpassing the global prevalence of 11.1%. Among Amerindian groups, Mayan ancestry has been linked to a higher risk of T2D. Sisal, a southeastern Mexican town with strong Mayan heritage, reports a prevalence of 22%, providing a unique setting to study genetic factors in an underrepresented population. We examined associations of KCNJ11 (rs5215, rs5219) and TCF7L2 (rs7901695, rs11196205) genetic variants with T2D in 232 individuals, including 99 participants diagnosed with T2D and 132 metabolically healthy individuals. Both rs5215 (OR = 2.07 [1.20–3.58], p = 0.009) and rs5219 (OR = 1.89 [1.09–3.27], p = 0.023) showed association under the dominant model and remained robust after adjustment for age, sex, and adiposity measurements. Overdominant models for both variants also indicated increased risk. Therefore, for both KCNJ11´s variants, a copy of their C (rs5215) or T (rs5219) allele increases T2D susceptibility. Rs7901695 showed no association. Rs11196205 exhibited a protective effect under the overdominant model (OR = 0.37 [0.18–0.76], p = 0.007). A similar trend ( p = 0.051) in the same direction was observed in the dominant model. In contrast, the recessive model indicated increased risk for CC homozygotes (OR = 1.79 [1.10–2.91], p = 0.019). Both overdominant and recessive models remained robust after covariable adjustment. A joint model including both rs5219 (Dominant-coding) and rs11196205 (Overdominant-coding) SNVs showed that rs11196205 remained robustly associated with T2D, while the effect of rs5219 was slightly weaker. These findings suggest rs5215-C, rs5219-T (KCNJ11), and rs11196205-C ( TCF7L2 ) increase T2D risk, whereas a single G allele at rs11196205 may mitigate the effect of C in a southeastern Mexican population with prevalent Mayan ancestry.