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NDT Advance Access originally published online on March 3, 2009
Nephrology Dialysis Transplantation 2009 24(8):2414-2420; doi:10.1093/ndt/gfp080
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© The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


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

Andrew D. Rule1, Brooke L. Fridley2, Steven C. Hunt3, Yan Asmann4, Eric Boerwinkle5, James S. Pankow6, Thomas H. Mosley7 and Stephen T. Turner1

1 Division of Nephrology and Hypertension 2 Division of Biostatistics, Mayo Clinic, Rochester, MN 3 Cardiovascular Genetics Division, University of Utah School of Medicine, Salt Lake City, UT 4 Division of Bioinformatics, Mayo Clinic, Rochester, MN 5 Human Genetics Center and Institute of Molecular Medicine, University of Texas-Houston Health Science Center, TX 6 Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 7 Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA

Correspondence and offprint requests to: Andrew D. Rule; E-mail: rule.andrew{at}mayo.edu



  Abstract

Background. 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.

Methods. 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.

Results. 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).

Conclusions. 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.

Keywords: genomics; hypertension; insulin resistance; linkage analysis; uric acid

Received for publication: 16. 7.08
Accepted in revised form: 9. 2.09


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