Non-synonymous single-nucleotide polymorphisms associated with blood pressure and hypertension

Abstract

In this study, we determined the association of 1180 non-synonymous single-nucleotide polymorphisms (SNPs) with systolic blood pressure (SBP) and hypertensive status. A total of 8842 subjects were taken from two community-based cohorts-Ansung (n ¼ 4183) and Ansan (n ¼ 4659), South Korea-which had been established for genome-wide association studies (GWAS). Five SNPs (rs16835244, rs2286672, rs6265, rs17237198 and rs7312017) were significantly associated (P-values: 0.003-0.0001, not corrected for genome-wide significance) with SBP in both cohorts. Of these SNPs, rs16835244 and rs2286672 correlated with risk for hypertension. The rs16835244 SNP replaces Ala288 in arginine decarboxylase (ADC) with serine, and rs2286672 replaces Arg172 in phospholipase D2 (PLD2) with cysteine. A comparison of peptide sequences between vertebrate homologues revealed that the SNPs identified occur at conserved amino-acid residues. In silico analysis of the protein structure showed that the substitution of a polar residue, serine, for a non-polar alanine at amino-acid residue 288 affects a conformational change in ADC, and that Arg172 in PLD2 resides in the PX domain, which is important for membrane trafficking. These results provide insights into the function of these non-synonymous SNPs in the development of hypertension. The study investigating non-synonymous SNPs from GWAS not only by statistical association analysis but also by biological relevance through the protein structure might be a good approach for identifying genetic risk factors for hypertension, in addition to discovering causative variations.

A regulatory SNP in AKAP13 is associated with blood pressure in Koreans

“…This study also demonstrates that our approach of using functional SNPs, such as regulatory SNPs (TFBS-SNPs) in addition to a previous GWAS on nonsynonymous SNPs, 9 identifies the genetic variations that biologically linked to blood pressure regulation.…”

“…Therefore, we employed an alternative approach, using nonsynonymous single-nucleotide polymorphisms (SNPs) in the GWAS data, and identified more SNPs located in arginine decarboxylase, phospholipase D1, brain-derived nuclear factor and an unknown gene (AC089987). 9 Although these nonsynonymous SNPs did not have strong P-values (1.0Â10 -3 oPo4.8Â10 -2 ), they appeared to be biologically linked to blood pressure. 9 This limited success encouraged us to examine other regulatory SNPs that were obtained in the GWAS data of Korean Association REsource, generated by Affymetrix 5.0 SNP array (Affymetrix, Inc., Santa Clara, CA, USA), to identify additional genetic factors that regulate blood pressure.…”

“…9 Although these nonsynonymous SNPs did not have strong P-values (1.0Â10 -3 oPo4.8Â10 -2 ), they appeared to be biologically linked to blood pressure. 9 This limited success encouraged us to examine other regulatory SNPs that were obtained in the GWAS data of Korean Association REsource, generated by Affymetrix 5.0 SNP array (Affymetrix, Inc., Santa Clara, CA, USA), to identify additional genetic factors that regulate blood pressure. Single-nucleotide changes in regulatory regions can produce new regulatory elements that are recognized by alternate transcription factors, 10 and many functional analyses of regulatory SNPs have demonstrated this effect on gene expression experimentally.…”

PLD2 (phospholipase D2)

“…The etiology of hypertension is multi-factorial and includes genetic and environmental components. PLD elevation has been reported in vascular smooth muscle cells from spontaneously hypertensive rats (SHR; an animal model of hypertension) (Kondo et al, 1994;Freeman et al, 1995), and recently, genome-wide association studies (GWASs) showed that PLD2 is mutated (Arg172 to Cys) in patients with a hypertensive status (Hong et al, 2010). Although further studies on the interrelationship between PLD2 and hypertension are required, these GWASs demonstrated the biological relevance of PLD2 in the pathophysiology of hypertension.…”

Recapitulation of genome-wide association studies on pulse pressure and mean arterial pressure in the Korean population

“…rs13002573 and rs1446468 lay in the FIGN locus, both of which were significantly associated with blood pressure and hypertension in the Asian study, 7 suggesting that the FIGN locus regulates blood pressure in humans and is a major risk factor of hypertension. The FIGN encoded a member of ATPases associated with the diverse cellular activities (AAA proteins) group.…”