Triglyceride-glucose index and its additive interaction with ABCG2/SLC2A9 polygenic risk score on hyperuricemia in middle age and older adults: findings from the DLCC and BHMC study

Ann Med. 2024 Dec;56(1):2434186. doi: 10.1080/07853890.2024.2434186. Epub 2024 Nov 28.

Abstract

Objective: We aim to investigate the joint effect of triglyceride-glucose (TyG) index and polygenic risk scores (PRS) of urate transporter genes ABCG2 and SLC2A9 on hyperuricemia.

Methods: Baseline data from two prospective population-based cohort studies, including 30,453 individuals aged 50 years or older, were used to analyze the association between TyG index and hyperuricemia. A case-control study was then designed from the cohorts to investigate the interaction between genetic predisposition and TyG index on hyperuricemia among 595 matched pairs. PRS was constructed using 14 single nucleotide polymorphisms located in the ABCG2 and SLCA29 genes.

Results: In both sexes, higher TyG index levels were correlated with elevated serum urate (SUA) levels (p values in both sexes < 0.001). In men, per unit increase of TyG was associated with a 1.44-fold (95% confidence interval [CI]: 1.35-1.55) higher risk of hyperuricemia after adjusted for covariates. In women, this estimate was 1.69 (1.51-1.89). Demonstrated by the restrict cubic spline model, TyG index was both linearly and non-linearly associated with elevated SUA (both p values < 0.001). Association between TyG index and hyperuricemia was stronger among people with higher genetic risk, and vice versa. Compared to people with TyG < 9 and PRS < 2, the odds ratios (ORs) (95% CIs) for hyperuricemia in the TyG <9 but PRS ≥2, TyG ≥9 but PRS < 2, TyG ≥9 and PRS ≥2 groups were 3.30 (1.53-7.14), 3.16 (1.23-8.11) and 7.55 (2.76-20.65), respectively. Additive interaction was also significant, with 57.5% (30.5%-84.4%) of the excess risk attributable to the additive gene-TyG index interaction.

Conclusions: The impact of genetic predisposition on hyperuricemia was significantly greater among individuals with a higher TyG index. Over 50% of the increased risk can be attributed to the interaction, indicating a crucial synergy between genetic factors and TyG index when estimating hyperuricemia risk.

Keywords: Insulin resistance; ageing; hyperuricemia; interaction; polygenic risk score; triglyceride-glucose index.

Plain language summary

There are both linear and non-linear relationships between TyG index and serum urates.Genetic predisposition on hyperuricemia was significantly greater among individuals with a higher TyG index.Over 50% of the increased risk of hyperuricemia can be attributed to the genetic-phenotype interaction.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2* / genetics
  • Aged
  • Blood Glucose* / metabolism
  • Case-Control Studies
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Risk Score
  • Glucose Transport Proteins, Facilitative* / genetics
  • Humans
  • Hyperuricemia* / blood
  • Hyperuricemia* / genetics
  • Male
  • Middle Aged
  • Multifactorial Inheritance / genetics
  • Neoplasm Proteins* / blood
  • Neoplasm Proteins* / genetics
  • Polymorphism, Single Nucleotide*
  • Prospective Studies
  • Risk Factors
  • Triglycerides* / blood
  • Uric Acid* / blood

Substances

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ABCG2 protein, human
  • Triglycerides
  • Neoplasm Proteins
  • Glucose Transport Proteins, Facilitative
  • SLC2A9 protein, human
  • Blood Glucose
  • Uric Acid

Grants and funding

This study is funded by the National Natural Science Foundation of China [Grant No. 82373669 and 82003531], the Science & Technology Fundamental Resources Investigation Program [Grant No. 2022FY100800], the National Key R&D Program of China [Grant No. 2016YFC0900600], and State Key Laboratory Special Fund [Grant No. 2060204].