Sequence variants of natriuretic peptide receptor C are common and their frequency differs between African Americans and European Americans

Abstract

Introduction: The growing importance of B-type natriuretic peptide (BNP) as a diagnostic and therapeutic modality in heart failure is well known. One of the primary clearance mechanisms is a non-catalytic receptor, natriuretic peptide receptor C (NPR3). NPR3 sequence variants and haplotypes have not been described in African Americans (AA) and European Americans (EA). Hypothesis: Common polymorphisms in the NPR3 gene exist, and their frequencies differ between African Americans (AA) and European Americans (EA). Methods: Genomic DNA was extracted from 95 African American (AA) and 95 European American (EA) healthy volunteers. Genotype was determined using pyrosequencing. Haplotypes were inferred from genotype results using the Polymorphism and Haplotype Analysis Suite (http://ilya.wustl.edu/∼pgrn/programs.html). Results: Four polymorphisms were validated in the NPR3 gene. One in the promoter region 2664 bases upstream of the transcription start site (A-2664G), one non-synonymous coding polymorphism in exon 8 at codon 521 (A1779G N521D), and two polymorphisms within intron 2; 79 and 84 bp upstream of the exon 3 splice junction (Intron 2 -84G>A, and -79C>T). Each polymorphism occurred commonly with minor allele frequencies ranging from 4.4% to 28%. Genotype distribution differed significantly between AA and EA at 2 of 4 loci (A-2664G and N521D, p=0.037 and p=0.045 respectively). The A1779G and Intron 2 -79C>T polymorphisms were significantly linked in EA (|D|=0.84; p<0.001) but not in the AA group. Of 16 theoretical haplotypes, the 5 most common accounted for >90% of subjects within each racial group. The distribution of haplotypes is shown in figure 1. The two most common haplotypes were the same for both AA and EA. One common haplotype among AA (haplotype 5, 9%) was not observed among EA. Conclusions: Genetic variation in NPR3 is common. The frequency of two variants (A-2664G, and A1779G-N521D) differ significantly between AA and EA. The haplotypes present among AA and EA were generally similar but occurred at differing frequencies. Clinical and functional assessment of these polymorphisms is warranted to evaluate their influence on BNP physiology and pharmacology.