Original Article

Hypertension Research (2008) 31: 1651–1657 doi:10.1291/hypres.31.1651

A Major Haplotype Block at the Rho-Associated Kinase 2 Locus Is Associated with a Lower Risk of Hypertension in a Recessive Manner: The HYPGENE Study

Tuomo Rankinen1, Timothy Church2, Treva Rice3, Nathan Markward1, Steven N Blair4 and Claude Bouchard1

  1. 1Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, USA
  2. 2Preventive Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, USA
  3. 3Division of Biostatistics, Washington University School of Medicine, St. Louis, USA
  4. 4Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, USA

Correspondence: Tuomo Rankinen, Ph.D., Human Genomics Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA. E-mail: rankint@pbrc.edu

Received 2 January 2008; Accepted 27 April 2008.

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Abstract

The goals of our study were to evaluate the haplotype pattern at the Rho-associated kinase 2 (ROCK2) locus and prospectively test the association between the ROCK2 haplotype-tagging single-nucleotide polymorphisms (tagSNPs) with hypertension for verified incident hypertensive patients (n =607) and healthy, normotensive controls (n =586) in a HYPGENE study. Rho-associated kinases (ROCKs) play a central role in signaling pathways that are involved in vascular smooth muscle contraction and endothelial nitric oxide availability. Using a set of stringent criteria (minor allele frequency ≥0.05, pairwise r 2≥0.95), we identified 18 tagSNPs from the 109 SNPs available in the HapMap Caucasian data set. TagSNPs were genotyped using the Illumina BeadStation platform. The 18 tagSNPs consisted of two linkage disequilibrium (LD) blocks. A haplotype defined by four SNPs (rs965665, rs10178332, rs6755196, rs10929732) in LD block 2 was recessively associated with a lower risk of hypertension (p =0.003). Homozygotes for the minor alleles had an 85% lower risk of hypertension than carriers of the common allele. The associations were independent of baseline age, cardiorespiratory fitness, body mass index, sex, and follow-up time. The LD block 2 spans about 137 kb of genomic DNA at the 5'-end of the ROCK2 locus and covers exons encoding the kinase domain of the protein. Our data strongly suggest that a major haplotype block at the ROCK2 locus is recessively associated with a lower risk of hypertension. Identification of functional mutation(s) could thus help in the development of ROCK2-specific treatments.

Keywords:

hypertension, haplotype-tagging single-nucleotide polymorphisms, haplotype block, linkage disequilibrium, Rho-associated kinase 2

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