title: Endothelin-1 gene variants and levels associate with adaptation to hypobaric hypoxia in high-altitude natives.
abstract: 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.
authors.affiliation: Institute of Genomics and Integrative Biology, Delhi-110 007, India; Centre for Biotechnology, Hamdard University, New Delhi-110 062, India.
authors.forename: Charu
authors.initials: C
authors.lastname: Rajput
authors.forename: Shehla
authors.initials: S
authors.lastname: Najib
authors.forename: Tsering
authors.initials: T
authors.lastname: Norboo
authors.forename: Farhat
authors.initials: F
authors.lastname: Afrin
authors.forename: M A
authors.initials: MA
authors.lastname: Qadar Pasha
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D000328:Adult; D000531:Altitude; D000532:Altitude Sickness / Q000503:physiopathology; D044466:Asian People / Q000235:genetics; D019332:Endothelin-1 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D007194:India; D008297:Male; D008875:Middle Aged; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics
chemical_list: D019332:Endothelin-1