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
disequilibrium| 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 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 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.
All genotypes
Normal at this position
You don't carry the risk variant at this secondary TCF7L2 position. About 60% of people of European descent share this genotype. Your diabetes risk from this specific variant is not elevated.
One risk allele at secondary TCF7L2 position
You carry one risk allele at this secondary TCF7L2 position. About 34% of Europeans share this genotype. This adds slightly to diabetes risk, especially in combination with the primary rs7903146 variant.
Two risk alleles at secondary position
You have two risk alleles at this position, adding to overall TCF7L2-related diabetes risk. About 6% of Europeans share this genotype. This is especially significant if you also carry the T allele at rs7903146.