Association of Genes of the NO Pathway with Altitude Disease and Hypoxic Pulmonary Hypertension

Abstract

Chronic intermittent hypoxia leads to high-altitude pulmonary hypertension, which is associated with high asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis. Therefore, we aimed to understand the relation of single nucleotide polymorphisms in this pathway to high-altitude pulmonary hypertension (HAPH). We genotyped 69 healthy male Chileans subjected to chronic intermittent hypoxia. Acclimatization to altitude was determined using the Lake Louise Score and the presence of acute mountain sickness. Echocardiography was performed after six months in 24 individuals to estimate pulmonary arterial pressure. The minor allele of dimethylarginine dimethylaminohydrolase (DDAH)1 rs233112 was associated with high-baseline plasma ADMA concentration, while individuals homozygous for the major allele of DDAH2 rs805304 had a significantly greater increase in ADMA during chronic intermittent hypoxia. The major allele of alanine glyoxylate aminotransferase-2 (AGXT2) rs37369 was associated with a greater reduction of plasma symmetric dimethylarginine (SDMA). Several genes were associated with high-altitude pulmonary hypertension, and the nitric oxide synthase (NOS)3 and DDAH2 genes were related to acute mountain sickness. In conclusion, DDAH1 determines baseline plasma ADMA, while DDAH2 modulates ADMA increase in hypoxia. AGXT2 may be up-regulated in hypoxia. Genomic variation in the dimethylarginine pathway affects the development of HAPH and altitude acclimatization.

Association of Variability in the DDAH1, DDAH2, AGXT2 and PRMT1 Genes with Circulating ADMA Concentration in Human Whole Blood

“…Since both SNPs, rs805304 and rs805305, are in strong linkage disequilibrium (R 2 = 1.0), our findings for rs805304 in the present study are assumed to be equally valid for rs805305. In line with these prior observations, we recently gathered evidence that carriers of the major allele of DDAH2 rs805304 had a greater increase in ADMA during hypoxia [30]. Taken together, these previous findings and our present data may suggest that DDAH2 underlies transcriptional regulation in pathophysiological conditions (myocardial infarction, diabetes, hypoxia, sepsis), and genetic variability in this gene may impair this regulatory role.…”

“…Minor allele associated with reduced immune checkpoint gene expression; no significant assocation with ADMA in patients with subarachnoid hemorrhage nor in healthy male Chilean individuals. [30,48,49]…”

Dysregulation of the Nitric Oxide/Dimethylarginine Pathway in Hypoxic Pulmonary Vasoconstriction—Molecular Mechanisms and Clinical Significance

“…In a cross-sectional study of Chilean mining workers who had been exposed to intermittent work at elevations of 4,400–4,800 m for more than 5 years, elevated ADMA levels were also significantly associated with elevated mean pulmonary artery pressure ( 24 ). Recent genetic analyses performed in our laboratory revealed significant associations of single nucleotide polymorphisms (SNPs) in the NOS III, DDAH1, AGXT2, and ARG2 genes with high altitude pulmonary hypertension ( 188 ). Specifically, individuals homozygous for the minor allele of DDAH1 SNP rs233112 had higher baseline ADMA plasma concentration but no change in the ADMA response to hypoxia ( 188 ).…”

“…Recent genetic analyses performed in our laboratory revealed significant associations of single nucleotide polymorphisms (SNPs) in the NOS III, DDAH1, AGXT2, and ARG2 genes with high altitude pulmonary hypertension ( 188 ). Specifically, individuals homozygous for the minor allele of DDAH1 SNP rs233112 had higher baseline ADMA plasma concentration but no change in the ADMA response to hypoxia ( 188 ). By contrast, homozygous carriers of the minor allele of the rs805304 SNP in the DDAH2 gene had a diminished ADMA increase during hypoxia but no difference in baseline ADMA concentration.…”

“…To a similar point, we observed a gradual decline of SDMA in humans exposed to chronic intermittent hypoxia at altitude, which paralleled the gradual increase in ADMA as reported above ( 60 ). Homozygous carriers of AGXT2 rs37369 showed a greater reduction in plasma SDMA than carriers of the minor allele of this SNP, suggesting an upregulation of AGXT2 in hypoxia ( 188 ).…”