Gene-Environment Interaction Between Alcohol Intake and a CACNA1A SNP in Relation to Exfoliation Glaucoma/Glaucoma Suspect

Abstract

Purpose : The CACNA1A rs4926244 locus is a genetic risk factor for exfoliation glaucoma (XFG); however, little is known about the biological underpinnings. As higher alcohol intake has been previously associated with XFG, and alcohol acts on calcium channels, we evaluated the interaction between alcohol intake and rs4926244, the lead SNP in the CACNA1A locus that is also an expression quantitative trait locus (eQTL) of CACNA1A.

Methods : We followed 32,972 participants in the Nurses’ Health Study (1980–2018), the Health Professionals Follow-up Study (1986–2018), and the Nurses’ Health Study II (1991–2019) biennially. Eligible subjects were ≥40 years old, did not have prevalent XFG/XFG suspect (XFGS), reported eye exams during follow-up, and had rs4926244 genotype information. Incident XFG/XFGS cases were confirmed through medical records, and information from repeated food frequency questionnaires were used to derive alcohol intake. We used per-eye Cox proportional hazards models, accounting for inter-eye correlations, to estimate multivariable-adjusted relative risks (MVRRs), 95% confidence intervals (CIs), and p for interactions.

Results : During 1,244,137 eye-years of follow-up, 142 eyes developed XFG/XFGS. We identified a higher association between the C allele of the CACNA1A rs4926244 SNP and the risk of developing XFG/XFGS (MVRR_{per C allele} = 1.76 (95% CI: 1.00-3.12)), while alcohol was not significantly associated (MVRR_{per 1g/day} = 1.00 (95% CI: 0.96-1.03)). We observed a significant crossover interaction between alcohol intake and the rs4926244 C allele (p_interaction = 0.004), where inverse associations with alcohol were observed in non-carriers (MVRR_{≥2.4g/day (median intake) versus <2.4g/day} = 0.35 (95% CI: 0.13-0.91)), while adverse associations with alcohol were observed in carriers (MVRR_{≥2.4g/day (median intake) versus <2.4g/day} = 3.12 (95% CI: 1.01-9.66)).

Conclusions : There is a complex interaction between alcohol intake and rs4926244 risk alleles, potentially involving the regulation of CACNA1A expression, in relation to incident XFG/XFGS; these results should be confirmed in future studies.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.