Endothelin-1 gene variants and levels associate with adaptation to hypobaric hypoxia in high-altitude natives

High-altitude natives are adapted to hypobaric hypoxia, suggestive of genetic basis of adaptation. Since endothelin-1 (ET-1) is of prime importance in high-altitude disorders in sojourners, we envisaged the role of allelic variants of ET-1 in high-altitude adaptation. Four ET-1 polymorphisms, viz., (CT)n–(CA)n repeat, −3A/−4A, G2288T, and Lys198Asn, were investigated in 426 highlanders (HLs) and 236 lowlanders (LLs). The plasma ET-1 levels, SBP and BMI were significantly lower in the HLs than those in LLs (p < 0.0001). The Longer-repeats (31–45), G allele, Longer-repeats/GG, and Longer-repeats/Lys198Lys combinations were overrepresented in the HLs (p < 0.0001, p = 0.03, p < 0.0001, and p < 0.0001, respectively). The Longer-repeats, −3A/−3A, GG and Lys198Lys genotypes associated with significantly lower ET-1 levels in the HLs (p < 0.0001, p = 0.001, p < 0.0001, and p < 0.0001, respectively). Combinations of Longer-repeats with −3A/−3A, GG, and Lys198Lys genotypes, and −3A/−3A/Lys198Lys combination revealed association with lower ET-1 levels in the HLs (p < 0.001). The study reports over-representation of Longer-repeats, G allele, and wild-type genotype combinations in high-altitude natives. Interaction between these alleles and association with lower ET-1 levels strengthen their association with high-altitude adaptation. Presence of such alleles in sojourners may help in acclimatization.