Tibetans are well adapted to high-altitude environments. Among the adaptive 
traits in Tibetans, the relatively low hemoglobin level is considered a blunted 
erythropoietic response to hypoxic challenge. Previously, EPAS1 and EGLN1, the 
major upstream regulators in the hypoxic pathway, were reportedly involved in 
the hemoglobin regulation in Tibetans. In this study, we report a downstream 
gene (HMOX2) involved in heme catabolism, which harbors potentially adaptive 
variants in Tibetans. We first resequenced the entire genomic region (45.6 kb) 
of HMOX2 in Tibetans, which confirmed the previously suspected signal of 
positive selection on HMOX2 in Tibetans. Subsequent association analyses of 
hemoglobin levels in two independent Tibetan populations (a total of 1,250 
individuals) showed a male-specific association between the HMOX2 variants and 
hemoglobin levels. Tibetan males with the derived C allele at rs4786504:T>C 
displayed lower hemoglobin level as compared with the T allele carriers. 
Furthermore, our in vitro experiments indicated that the C allele of rs4786504 
could increase the expression of HMOX2, presumably leading to a more efficient 
breakdown of heme that may help maintain a relatively low hemoglobin level at 
high altitude. Collectively, we propose that HMOX2 contributes to high-altitude 
adaptation in Tibetans by functioning as a modifier in the regulation of 
hemoglobin metabolism.