The Contribution of Genetic Variants of the Peroxisome Proliferator-Activated Receptor-Alpha Gene to High-Altitude Hypoxia Adaptation in Sherpa Highlanders

Abstract

The contribution of genetic variants of the gene encoding peroxisome proliferator-activated receptor-alpha gene (PPARA) to high-altitude hypoxia adaptation in Sherpa highlanders. High Alt Med Biol. 16:000-000, 2018.-Sherpa highlanders, who play invaluable roles in the exploration of Mount Everest, have exceptional tolerance to hypobaric hypoxia. Sherpa people are well known to possess the traits determined by genetic background for high-altitude adaptation. The metabolic adaptation mechanism is one of the biological ways for Sherpa highlanders in protecting them from hypoxia stress at high altitude. Studies have suggested that the gene encoding PPARA is associated with metabolic adaptation in the Himalayan population of Tibetans. This study attempts to investigate the genetic variants of the PPARA in Sherpa highlanders and the association with high-altitude hypoxia adaptation. Seven single-nucleotide polymorphisms (SNPs; rs135547, rs5769178, rs881740, rs4253712, rs5766741, and rs5767700 in introns and rs1800234 in exon 6) in the PPARA were genotyped in 105 Sherpa highlanders who lived in the Khumbu region (3440 m above sea level) and 111 non-Sherpa lowlanders who resided in Kathmandu (1300 m) in Nepal. By means of analyses of genetic distances, genotype distributions, allele frequencies, linkage disequilibrium, and haplotype constructions of the seven SNPs in the Sherpa highlanders versus the non-Sherpa lowlanders, it was revealed that the frequencies of minor alleles of rs4253712, rs5766741, rs5767700, and rs1800234 SNPs, as well as the frequency of haplotype constructed by the minor alleles of rs5766741-rs5767700-rs1800234, were significantly overrepresented in the Sherpa highlanders in comparison with the non-Sherpa lowlanders. The results strongly suggest that the genetic variants of the PPARA are likely to contribute to the high-altitude adaptation in Sherpa highlanders.

Effects of genetics and altitude on lung function

“…The physiological and particular respiratory adaptation of the Tibetans has also been studied, 51,52 since they live in one of the most extreme high‐altitude conditions (an average of approximately 4000 m 53 ). Genetic variations in Tibetans have produced an increase in blood lactate levels and, particularly for Sherpas, it has been identified that PPARA gene expression (PPAR‐alpha is a transcription factor) is involved in regulating the expression of some genes involved in metabolic processes 54 . However, genetic mechanisms that cause these metabolic adaptations remain unidentified 55 .…”

Association of EPAS1 and PPARA Gene Polymorphisms with High-Altitude Headache in Chinese Han Population

“…PPARα, a member of nuclear receptor transcription factors family, is highly expressed in the heart, liver, kidney, and skeletal muscle where energy metabolism is quite active, regulating the lipid metabolism and gluconeogenesis, specifically the fatty acid beta-oxidation in mitochondrial and peroxisomal [41]. Hypoxia condition enhances the procedure of anaerobic glycolysis and lactic acid accumulation in venous blood that is regulated by PPARα to enhance the utilization ratio of oxygen and keep the brain supplied with sufficient ATPs [42]. Decreased fatty acid oxidation in skeletal muscle is observed in Sherpa highlanders and Tibetans because fatty acid oxidation needs more oxygen when producing the same amount of ATPs [42,43].…”

“…Hypoxia condition enhances the procedure of anaerobic glycolysis and lactic acid accumulation in venous blood that is regulated by PPARα to enhance the utilization ratio of oxygen and keep the brain supplied with sufficient ATPs [42]. Decreased fatty acid oxidation in skeletal muscle is observed in Sherpa highlanders and Tibetans because fatty acid oxidation needs more oxygen when producing the same amount of ATPs [42,43]. A putatively advantageous PPARA haplotype exhibited a significantly positive relationship with decreased expression or activity of PPARα and increased serum free fatty acid in Tibetans, demonstrating that PPARA is associated with hypoxia metabolic adaptation [32].…”

Population History and Altitude-Related Adaptation in the Sherpa

“…Sherpa carriers of the positively selected PPARA alleles switch to more efficient fuels such as glucose and display decreased muscular fatty acid oxidation (Horscroft et al, 2017). Most of the PPARA SNPs reported to be under selection appear to be non-coding variants (Kinota et al, 2018). It is unclear if these variants directly affect transcriptional regulation or are linked with functional variants in other genes or nearby inter-genic regions.…”