rs12255372 — TCF7L2

Secondary TCF7L2 Variant

This is the second most-studied variant in the TCF7L2 gene, located in intron 4 approximately 50 kb from the primary variant rs7903146. While rs7903146 is the primary diabetes risk variant, rs12255372 provides additional information about your TCF7L2 haplotype. The two variants are in moderate linkage disequilibrium¹¹ Linkage disequilibrium means these variants tend to be inherited together because they sit close on the same chromosome, within a 92-kb LD block, meaning they are often co-inherited but not always.

The Mechanism

Like rs7903146, this variant sits in a non-coding region and is thought to influence TCF7L2 expression levels, though rs7903146 appears to be the stronger functional driver. The T allele at this position is associated with decreased insulin secretion and impaired incretin response.

The Evidence

A meta-analysis of 28 studies²² meta-analysis of 28 studies
Wang et al. Association of rs12255372 in the TCF7L2 gene with type 2 diabetes mellitus: a meta-analysis. Braz J Med Biol Res, 2013 confirmed the association with type 2 diabetes with an odds ratio of 1.39 (95% CI: 1.35-1.42). The effect is consistent across European, African, and South Asian populations but weaker in East Asian populations where the T allele is rare (~2% frequency).

The Pounds Lost trial³³ Pounds Lost trial
Mattei et al. Am J Clin Nutr, 2012 also examined rs12255372 and found that T allele carriers who consumed a lower-fat diet had greater reductions in body adiposity, which could improve glycemic control.

Practical Implications

Having risk alleles at both rs7903146 and rs12255372 compounds your overall TCF7L2-related diabetes risk. The dietary recommendations are the same: moderate fat intake and a Mediterranean-style eating pattern.

Interactions

This variant is in moderate linkage disequilibrium with rs7903146. If you carry risk alleles at both positions, your overall TCF7L2-related risk is higher.