Abstract
Background & Aims The relationship between alcohol consumption and type 2 diabetes risk is often described as a J- or U-shaped curve, with moderate drinkers having a lower risk compared to non-drinkers and heavy drinkers. However, this protective effect appears to be more pronounced in women than in men, suggesting a potential interaction between sex-specific factors and alcohol metabolism. Methods We conducted an interaction genome-wide association study (GWAS) to identify genetic variants that modify the relationship between alcohol consumption and type 2 diabetes risk in a sex-specific manner. We utilized data from the UK Biobank in a case-control approach including 309,568 individuals to investigate the three-way interaction between genetic variants, alcohol consumption, and sex on type 2 diabetes risk. Results We identified genetic variant rs78681203, located between the FOXO6 and EDN2 genes, with a significant sex-specific interaction with alcohol consumption (interaction p = 2.85 × 10−8). The T allele of rs78681203 was associated with an increased risk of type 2 diabetes in women consuming 0 to <4 UK units/week (OR = 1.19, 95% CI: 1.07-1.34) but had a protective effect in women consuming 4 to <28 UK units/week (OR = 0.81, 95% CI: 0.69-0.95). Conversely, in men, the T allele was associated with a higher risk of type 2 diabetes in the 4 to <28 UK units/week group (OR = 1.19, 95% CI: 1.08-1.32) and had a protective effect in the 0 to <4 UK units/week group (OR = 0.85, 95% CI: 0.74-0.99). Conclusions Our findings suggest that genetic variation may play a role in the differential effects of alcohol consumption on type 2 diabetes risk between men and women. Further replication and mechanistic studies are needed to confirm and clarify the role of the identified genetic variant.