Background/Purpose:  Gout and hyperuricemia (serum urate > 7 mg/dL) typically present in the context of one or more comorbidities including type-2 diabetes, chronic renal disease, hypertension and obesity. The joint prevalence of these comorbidities with hyperuricemia is for some trait pairs more than double their marginal prevalence in the general population. However, the extent to which this association reflects genetic or environmental sources is unknown. The purpose is to derive marker-based heritability and genetic correlation estimates between, serum urate (SU), serum creatinine (SC), systolic blood pressure (SBP), blood glucose (BG) and body mass index (BMI), using whole genome regression (WGR) models of clinical data and genotypes from single nucleotide polymorphisms (SNPs).

Methods:  We computed these estimates from a subset of the Framingham Heart Study, consisting of SNP genotypes from the Affymetrix500 array and clinical data measured on a total of 8,200 combined records from cohort 0, exam 13 (N = 1,396), cohort 1, exam 6 (N = 3,237) and cohort 3, exam 1 (N = 3,567). These data were fit with Bayesian multi-trait WGR models. Briefly, the model assumed two random components, one associated to the genetic factors (μ_k , for the kth subject) of BMI, SBP, BG, SU and SC; and the other to the environmental, or random residual errors (ε_k). From these random components individual trait heritabilities and their genetic correlations with 95% posterior credible regions (CR) were estimated.

Results:  With the exception of age and SBP the mean values of the traits were similar among the three cohorts. The mean (SD) for SU, BMI, SC and BG was 5.3 (1.5), mg/dL, 27.2 (5.2) kg/m², 0.8 (0.2) mg/dL, and 98.1 (23.5) mg/dL, respectively. Individuals in cohort 3 were on average (SD) younger, 40.2 (8.9) years, and had lower SBP, 115 (14) mm Hg, than those from cohort 1: 63.0 (6.7) years, and 138 (21) mm Hg. The highest marker based estimates of heritability (CR) were for SU, 0.35 (0.29, 0.42), SC, 0.46 (0.38, 0.54) and BMI, 0.42 (0.38, 0.47). The heritability of BG, 0.21 (0.17, 0.26) and SBP, 0.28 (0.24, 0.33) were lowest of the five traits analyzed, which, with the exception of SC, were all similar to family or pedigree-based heritability estimates reported in the literature. The three highest magnitude bivariate genetic correlations (CR) involved BG, with SU, 0.32 (0.18, 0.46), with SBP, 0.28 (0.15, 0.41), and with BMI 0.41 (0.30, 0.51), and their phenotypic associations involved minimal contribution from environmental (random residual) sources. The highest magnitude environmental correlations were for BMI with SU, 0.42 (0.36, 0.47) and BMI with SBP, 0.23 (0.19, 0.27) and contributed most, compared with genetics, to the phenotypic association of these traits.

Conclusion: Genetic sources of covariance between traits associated with hyperuricemia, gout and its comorbidities are substantial and consistently involve genes associated with BG. BMI consistently accounts for the environmental portion of the phenotypic associations. Therefore the etiology of gout and hyperuricemia may have an axis involving type-2 diabetes with a significant genetic component and one involving obesity that is primarily environmental.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/extensive-genetic-overlap-of-traits-related-to-gout-hyperuricemia-and-its-comorbidities/