Single Nucleotide Polymorphisms of the ALK1 and ENG Genes in Patients with Pulmonary Arterial Hypertension

Abstract

Background: Activin receptor-like kinase-1 (ALK1) and endoglin (ENG) genes are involved in the pathogenesis of the pulmonary arterial hypertension (PAH)-related diseases, hereditary hemorrhagic telangiectasia type 2 and type 1, respectively. Therefore, this study was conducted to investigate mutations in all exons of the ALK1 and ENG genes in the large Japanese PAH population.
Methods: The study subjects were 144 adult PAH patients including 46 patients with idiopathic or familial PAH and 98 with other etiologies. Deoxyribonucleic acid (DNA) was isolated from blood, and the amplified fragments after polymerase chain reaction were sequenced directly to detect mutations and single nucleotide polymorphisms (SNPs) in ALK1 and ENG genes. Furthermore, gene frequency was compared between PAH population and control population using online database or DNA derived from 100 Japanese B cell lines in cases of the absence of online frequency data.
Results: We found no pathogenic mutations in our study subjects, but, we found two missense mutations in the ENG gene, which may not account for the pathogenesis of PAH, and seven possible non-pathogenic SNPs in ALK1 and ENG genes in Japanese PAH patients. Among them, the gene frequency of missense mutations of the ENG gene (c.1096G＞C/p.Asp366His) was statistically higher in IPAH＋FPAH population than the control population.
Conclusions: To our knowledge, this is the first report to elucidate mutations and SNPs of ALK1 and ENG genes in the large Japanese PAH population. In this study, gene frequencies of most SNPs in the ALK1 and ENG genes were not significantly different compared to control population. One missense mutation in the ENG gene was remained to elucidate whether the high frequency is due to the ethnic bias or the possible linking to a hidden pathogenic mutation.