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

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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.

Section snippets

Materials and methods

Study population. The institutional review committee approved the investigation. The subjects were apprised of the study and a written informed consent was obtained from each. A total of 662 healthy, unrelated subjects of Indian ethnicity, comprising of 426 highlanders (HLs) and 236 lowlanders (LLs), were recruited for the study. Both the HLs and LLs were permanent residents of their respective lands since ancient times [4], [29]. The two groups belong to North India, who had initially migrated

Characteristics of the subjects

Table 1 shows the characteristics of the HLs and LLs. The DBP was comparable in the two groups, whereas, SBP, BMI, and plasma ET-1 levels were significantly lower in the HLs than those in LLs. Notably, the ET-1 levels were 50% lower in the HLs than those in LLs (1.7 ± 0.7 vs 3.5 ± 0.5 pg/ml; p < 0.0001).

(CT)n–(CA)n repeat distribution in the HLs and LLs

Nineteen alleles of the microsatellite with repeats ranging between 13 and 45 were observed in the two groups (Table 2). The distribution of the repeats did not differ significantly when compared

Discussion

At HA, ET-1 due to its exaggerated release is thought to play an important role in the pathogenesis of HAPE [20], [21], which is life threatening in the absence of proper therapeutic measures [10]. It thus becomes crucial to offset the negative consequences of hypoxia in order to adapt to HA. Our finding of lower plasma ET-1 levels in the HLs is indicative of a protective role under hypoxic stress. It is likely that stimulation of ET-1 expression in response to hypoxia is controlled to a

Acknowledgments

The Council of Scientific and Industrial Research supported this work financially. Ven. Thubten Choegyal, Chairman, Ladakh Heart Foundation, Leh, and Mr. Mohd Iqbal, SNM Hospital, Leh, cooperated in collection of blood samples. We acknowledge our Director Prof. S.K. Brhamachari for his support and encouragement.

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  • Abbreviations: HA, high-altitude; ET-1, endothelin-1; HLs, highlanders; LLs, lowlanders; HAPE, high-altitude pulmonary edema; HACE, high-altitude cerebral edema; ACE, angiotensin converting enzyme; NOS3, endothelial nitric oxide synthase; LD, linkage disequilibrium; BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; D′, Lewontin’s coefficient; r2, squared correlation coefficient; NO, nitric oxide; I, insertion; D, deletion.

    1

    Present address: Ladakh Institute of Prevention, Leh, Ladakh, Jammu & Kashmir, India.

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