Genome-wide linkage analysis for uric acid in families enriched for hypertension

Abstract

Uric acid is heritable and associated with hypertension and insulin resistance. We sought to identify genomic regions influencing serum uric acid in families in which two or more siblings had hypertension. Uric acid levels and microsatellite markers were assayed in the Genetic Epidemiology Network of Arteriopathy (GENOA) cohort (1075 whites and 1333 blacks) and the Hypertension Genetic Epidemiology Network (HyperGEN) cohort (1542 whites and 1627 blacks). Genome-wide linkage analyses of uric acid and bivariate linkage analyses of uric acid with an additional surrogate of insulin resistance were completed. Pathway analysis explored gene sets enriched at loci influencing uric acid. In the GENOA white cohort, loci influencing uric acid were identified on chromosome 8 at 135 cM [multipoint logarithm of odds score (MLS) = 2.4], on chromosome 9 at 113 cM (MLS = 3.7) and on chromosome 16 at 93 cM (MLS = 2.3), but did not replicate in HyperGEN. At these loci, there was evidence of pleiotropy with other surrogates of insulin resistance and genes in the fructose and mannose metabolism pathway were enriched. In the HyperGEN-black cohort, there was some evidence of a locus for uric acid on chromosome 4 at 135 cM (MLS = 2.4) that had modest replication in GENOA (MLS = 1.2). Several novel loci linked to uric acid were identified but none showed clear replication. Widespread diuretic use, a medication that raises uric acid levels, was an important study limitation. Bivariate linkage analyses and pathway analysis were consistent with genes regulating insulin resistance and fructose metabolism contributing to the heritability of uric acid.