Introduction:
Chronic (CH) and chronic-intermittent (CIH) exposure to hypoxia at high altitude causes acute or chronic mountain sickness and elevation of mean pulmonary arterial pressure (mPAP). This is paralleled by increased plasma levels of ADMA, an endogenous inhibitor of NO synthesis. ADMA is cleaved by dimethylarginine dimethylaminohydrolase (DDAH1 and DDAH2), whilst symmetric dimethylarginine (SDMA) is cleaved by AGXT2. Arginase (ARG1 and ARG2) competes with endothelial NO synthase (NOS3) for L-arginine as substrate. We have shown previously that baseline ADMA (at sea level) determines mPAP after six months of CIH; cut-off values of 25 mm Hg and 30 mm Hg are being used to diagnose high altitude pulmonary hypertension.
Hypothesis:
We hypothesized that genetic variability in genes coding for core enzymes of ADMA, SDMA, and L-arginine metabolism may predispose individuals for high altitude disease and pulmonary hypertension.
Methods:
We genotyped 16 common single nucleotide polymorphisms in the NOS3, DDAH1, DDAH2, AGXT2, ARG1 and ARG2 genes of 69 healthy male Chilean subjects. Study participants adhered to a CIH regimen (5d at 3,550m, 2d at sea level) for six months. Metabolites were measured by LC-MS/MS; mPAP was estimated by echocardiography at six months, and altitude acclimatization was assessed by Lake Louise Score and arterial oxygen saturation.
Results:
Carriers of the minor allele of DDAH1 rs233112 had a higher mean baseline ADMA level (0.76±0.03 vs. 0.67±0.02 μmol/l; p<0.05), whilst the major allele of DDAH2 rs805304 was linked to an exacerbated increase of ADMA in hypoxia (0.10±0.03 vs. 0.04±0.04 μmol/l; p<0.02). Study participants carrying the minor allele of ARG1 rs2781667 had a relative risk of elevated mPAP (>25 mm Hg) of 1.70 (1.56-1.85; p<0.0001), and carriers of the minor allele of NOS3 rs2070744 had a relative risk of elevated mPAP (>30 mm Hg) of 1.58 (1.47-1.69; p<0.0001). The NOS3 and DDAH2 genes were associated with the incidence of acute mountain sickness.
Conclusions:
We conclude that genetic variability in the L-arginine / ADMA / NO pathway is an important determinant of high altitude pulmonary hypertension and acute mountain sickness. DDAH1 is linked to baseline ADMA, whilst DDAH2 determines the response of ADMA to hypoxia.
Acclimatization to long-term hypoxia: gene expression in ovine carotid arteries
