The genetic etiology of hyperuricemia, gout, and their comorbidities was demonstrated; both hyperuricemia and gout were found to be linked to chronic kidney disease (CKD) and components of metabolic syndrome, such as obesity, type 2 diabetes mellitus (T2D), and hypertension, according to results of an analysis published in European Journal of Human Genetics

Recognizing that CKD, T2D, obesity, and hypertension are all comorbidities with a high prevalence among individuals with hyperuricemia (defined as a serum urate level of >6.8 mg/dL) and gout, the researchers sought to explore the hypothesis that the co-association of traits that represented hyperuricemia and its comorbidities had a genetic basis.

Using multivariate representations of Bayesian whole-genome regression (WGR), the researchers estimated the genetic correlations between serum urate, systolic blood pressure (SBP), blood glucose and body mass index (BMI), and serum creatinine (SCr) levels, based on data from 2 independent family-based datasets: the longitudinal Framingham Heart Study (FHS) and the Hypertension Genetic Epidemiology Network study (HyperGEN).

The current analysis included information about single-nucleotide polymorphism (SNP) genotypes and clinical data calculated from a total of 8200 combined records from 3 cohorts: cohort 0 (original cohort; exam 13; n=1396); cohort 1 (offspring cohort; exam 6; n=3237); and cohort 3 (third-generation; exam 1; n=3567).


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Results of the analysis showed that heritability estimates were consistent between the 2 studies, except for the FHS SBP that was lower at 0.27 (range, 0.23-0.31) than the estimate of 0.50 (range, 0.43-0.56) for the HyperGEN dataset. With the FHS dataset, the minimum heritable estimate was for glucose level at 0.31 (range, 0.26-0.36) and the maximum was for SCr level at 0.49 (range, 0.42-0.57). However, with the HyperGEN dataset, the minimal heritability estimate was lowest for glucose at 0.31 (range, 0.17-0.44) and the maximum heritability estimate was for BMI at 0.56 (range, 0.48- 0.64).

Main genetic findings that were replicated in both the FHS and the HyperGEN datasets included the fact that SCr level was genetically linked to urate level only, as well as the finding that BMI was genetically correlated to urate level, SBP, and glucose level. Since SCr levels are genetically linked to urate levels, but not to metabolic traits, it implies that 1 genetic module of shared loci, which are associated with hyperuricemia and CKD, exists. Further, another module of shared loci may help to explain the association between hyperuricemia and metabolic syndrome.

Study limitations included the inability to infer directionality of causal relationships and that the genetic correlations estimated from genomic data have been questioned.

Researchers concluded that the findings from this study motivate “future quantification of genetic correlations at individual loci, which will increase our knowledge of the genetic etiology of hyperuricemia, gout, and its comorbidities.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Reynolds RJ, Irvin MR, Bridges SL, et al. Genetic correlations between traits associated with hyperuricemia, gout, and comorbidities. Eur J Hum Genet. Published online February 26, 2021. doi:10.1038/s41431-021-00830-z