Masschelein, Evi, Joke Puype, Siacia Broos, Ruud Van Thienen, Louise Deldicque, Diether Lambrechts, Peter Hespel, and Martine Thomis. A genetic predisposition score associates with reduced aerobic capacity in response to acute normobaric hypoxia in lowlanders. High Alt Med Biol 16:34–42, 2015—Given the high inter-individual variability in the sensitivity to high altitude, we hypothesize the presence of underlying genetic factors. The aim of this study was to construct a genetic predisposition score based on previously identified high-altitude gene variants to explain the inter-individual variation in the reduced maximal O2 uptake (ΔVo2max) in response to acute hypoxia. Ninety-six healthy young male Belgian lowlanders were included. In both normobaric normoxia (Fio2=20.9%) and acute normobaric hypoxia (Fio2=10.7%–12.5%) Vo2max was measured. Forty-one SNPs in 21 genes were genotyped. A stepwise regression analysis was applied to detect a subset of SNPs to be associated with ΔVo2max. This subset of SNPs was included in the genetic predisposition score. A general linear model and regression analysis with age, weight, height, hypoxic protocol group, and Vo2max in normoxia as covariates were used to test the explained variance of the genetic predisposition score. A ROC analysis was performed to discriminate between the low- and high ΔVo2max subgroups. A stepwise regression analysis revealed a subset of SNPs [rs833070 (VEGFA), rs4253778 (PPARA), rs6735530 (EPAS1), rs4341 (ACE), rs1042713 (ADRB2), and rs1042714 (ADRB2)] to be associated with ΔVo2max. The genetic predisposition score was found to be an independent predictive variable with a partial explained variance of 23% (p<0.0001). A ROC analysis showed significant discriminating accuracy (AUC=0.78, 95% confidence interval=0.64–0.91) between the low- and high ΔVo2max subgroups. This six-SNP based genetic predisposition score showed a significantly predictive value for ΔVo2max.
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