SNP-Alcohol Interaction Associated With Elevated Serum Urate, Gout

Select single-nucleotide polymorphisms (SNPs) and alcohol consumption may be significantly associated with serum urate level, hyperuricemia, and gout, according to findings from a recent study.¹

Nicola Dalbeth, MD, MBChB, head of the department of medicine at the University of Auckland in New Zealand, and a team of investigators leveraged data from more than 450,000 European participants in the UK Biobank and identified novel interactions with alcohol consumption at ADH1B and MLXIPL for association with serum urate level and at ADH1B for association with hyperuricemia and gout, with effects observed only among alcohol consumers.¹

A type of inflammatory arthritis causing pain and swelling in the joints, gout is caused by a buildup of urate due to a combination of genetic and environmental factors. Drinking alcohol and having certain genetic conditions have been linked to an increased risk of gout, although the nature of these interactions and their influence on serum urate level and hyperuricemia is not well-documented.^1,2

“There has not been a systematic analysis of SNPs at all loci identified to be associated with both alcohol consumption and serum urate or gout,” investigators wrote.¹

To address this gap in research, they tested the association of alcohol consumption with serum urate and gout among 458,405 UK Biobank participants of self-reported European ethnicity with available genotyping data. Investigators identified candidate SNPs by comparing serum urate, gout, and alcohol consumption genome-wide association studies for shared signals of association. For each overlapping signal, a lead-shared SNP most strongly associated with serum urate or gout was selected for further interaction analysis.¹

Hyperuricemia was defined as a serum urate level of ≥410 μmol/L (0.41 mmol/L; 7.38 mg/dL) for both men and women, and gout cases were identified using a validated case definition of self-reported gout or urate-lowering therapy use with no previous hospital diagnosis of leukemia or lymphoma. Additionally, investigators obtained self-reported alcohol consumption data through the UK Biobank baseline Touchscreen Questionnaire.¹

In total, 431,555 eligible participants for the serum urate analyses were included in the study, 11% of whom had hyperuricemia. Of note, men had a greater mean serum urate level and prevalence of hyperuricemia (354.7 µmol/L and 20.6%, respectively) than women (270.7 µmol/L and 3.1%, respectively).¹

For the gout analyses, 458,367 eligible participants were included. Those with gout were on average 3.3 years older than controls and were predominantly male (92.3%). Among all study participants, men were more likely to be current alcohol consumers than women (94.9% of men vs 91.9% of women) and consumed greater amounts of alcohol (23.2 units/week versus 13.8 units/week), particularly beer (16.8 units/week versus 4.1 units/week).¹

Upon analysis, alcohol consumption was associated with elevated serum urate and gout. Specifically, investigators pointed out beer intake was associated with the largest μmol/L increase in serum urate level for each unit consumed per week (β 0.75; SE 0.01; P < 1.0 × 10⁻³⁰⁰). Each unit of beer consumed per week had the greatest association with gout (Odds ratio [OR], 1.023; 95% CI, 1.021–1.024; P = 3.9 × 10⁻²⁸⁵).¹

For serum urate level, non-additive interactions were identified between alcohol consumption and rs1229984 at the ADH1B locus (P = 3.0 × 10⁻⁴⁴) and rs6460047 at the MLXIPL locus (P = 1.4 × 10⁻⁴). ADH1B also demonstrated interaction with alcohol consumption for hyperuricemia (P = 7.9 × 10⁻¹³) and gout (P = 8.2 × 10⁻⁹).¹

In the gender-stratified analysis, investigators noted a significant interaction of alcohol intake with ADH1B rs1229984 for association with serum urate level and hyperuricemia among both men (P = 1.1 × 10⁻¹⁷ and P = 4.3 × 10⁻⁹, respectively) and women (P = 1.4 × 10⁻²⁶ and P = 1.1 × 10⁻⁶, respectively). However, the interaction at MLXIPL rs6460047 for association with serum urate level was only significant among men (P = .002). Additionally, beer intake had the most significant interaction with ADH1B for association with serum urate and gout among men, while wine intake had the most significant interaction among women.¹

Among the subgroup of all participants who did not consume any alcohol, the presence of the urate-raising T allele at ADH1B rs1229984 was not associated with serum urate level (P = .46) or hyperuricemia (P = .39). However, among those who did consume alcohol, the T-positive genotype was associated with a 6.2 μmol/L increase in serum urate level compared to the T-negative genotype (P_difference = 1.5 × 10−47), and the odds ratio of hyperuricemia for the T-positive genotype compared to the T-negative genotype in the alcohol-exposed subgroup was 1.3 (P_difference = 4.1 × 10−20).¹

Similarly, investigators pointed out the urate-raising T allele at MLXIPL rs6460047 did not associate with serum urate level among all non-consumers (P = .13) but was associated with a 4.8 µmol/L increase in serum urate level among all consumers (P_difference = 4.0 × 10−25).¹

References:

1. ^{Chuah MH, Leask MP, Topless RK, et al. Interaction of genetic variation at ADH1B and MLXIPL with alcohol consumption for elevated serum urate level and gout among people of European ethnicity. Arthritis Res Ther. 2024;26(1):45. doi:10.1186/s13075-024-03279-9}
2. ^{National Institutes of Health. Overview of Gout. Gout. December 2023. Accessed February 22, 2024. https://www.niams.nih.gov/health-topics/gout}