Potential association between frequent nonsynonymous variant of NPPA and cardioembolic stroke

Abstract

Atrial natriuretic peptide (ANP, also known as NPPA) and brain natriuretic peptide (BNP, also known as NPPB) have been determined as genetic factors for several diseases, including stroke and myocardial infarction, in human and rat models. To investigate the potential association between polymorphisms of the NPPA gene and stroke in a Korean population, nine single-nucleotide polymorphisms (SNPs) of NPPA and NPPB genes were genotyped in a total of 941 Korean subjects, including 674 stroke patients (109 hemorrhagic and 565 ischemic) and 267 unaffected controls. Genotype comparisons of the targeted alleles revealed that there were no significant associations between stroke patients and control subjects, or among hemorrhagic, ischemic, and control groups. However, in logistic analysis for Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification of ischemic stroke, nonsynonymous rs5065 (STOP152Arg) and rs5067 in 3'UTR of NPPA, which were in complete linkage disequilibrium, showed significant associations with cardioembolic stroke. These two SNPs showed higher frequencies in cardioembolic stroke patients than those in controls and ischemic patients with small-vessel occlusion (p=0.002, adjusted p=0.02). It was also found that NPPA rs5065C allele in all of the Korean subjects existed as heterozygous compared with Caucasian and African populations. Although further replications in larger cardioembolic stroke subjects are required, our preliminary findings suggest that the nonsynonymous rs5065C of the NPPA gene, which could produce a new or dysfunctional transcript, is possibly associated with cardioembolism.

FIG. 1.

Haplotypes and LD of the NPPA gene. (A) Linkage disequilibrium (LD) and haplotype block of nine single-nucleotide polymorphisms in the NPPB and NPPA genes. LD plot was prepared using Haploview. Colors are used to display pairwise LD as follows: red, LOD ≥2 and D′=1; shades of pink/red, LOD ≥2 and D′<1; white, LOD<2 and D′<1. The numbers indicate pairwise r² values shown as a percentage. (B) Haplotypes composed of rs198389 in NPPB and rs61757273 in NPPA, and its associations with stroke and cardioembolic stroke (CE).

FIG. 2.

Schematic representation of human NPPA transcripts and the proposed effects of a new transcript potentially derived from STOP152Arg. The coding exons are represented by black blocks, and 5′UTR and 3′UTR by white blocks. The nonsynonymous variant rs5065 (STOP152Arg) has been suggested as a potential risk of cardioembolic stroke in this study as well as a risk of myocardial infarction in another study (Gruchala et al., 2003), whereas further studies are required to elucidate the effects of new transcript potentially derived from STOP152Arg on cardiovascular diseases (Rubattu et al., 2008).