Organismal response to hypoxia is essential for critical regulation of erythropoiesis, other physiological functions and survival. There is an evidence of individual variation in response to hypoxia as some but not all of the affected individuals develop polycythemia, and or pulmonary and cerebral edema. A significant population difference in response to hypoxia exist as many Tibetans, Ethiopian and Andean natives developed an adaptive mechanisms to extreme hypoxia. A proportion of any non-adapted individuals exposed to high altitude develop pulmonary edema (HAPE), pulmonary hypertension, cerebral edema and extreme polycythemia. The isolation of causative gene(s) responsible for HAPE and other extreme hypoxia complications would provide a rational basis for specific targeted therapy of HAPE, allow its targeted prevention for at-risk populations, and clarification of its, and pathophysiology of other hypoxic maladaptations. As today, the only suggested linkage in unrelated individual with HAPE has been with endothelial nitric oxide synthase (eNOS) gene. Here we describe a family with multiple members affected with HAPE in three generations. Families with multiple affected members with HAPE have not been described. We first ruled out linkage of HAPE with eNOS gene. We then performed analysis of the whole genome using high-density SNP arrays (Affymetrix v5.0) and assuming a single gene causation of HAPE ruled out a linkage with 34 other candidate genes. Only HIF2A haplotype was shared by individuals who exhibit the HAPE phenotype, and the work on their possible causative role in HAPE is in progress. Clearly a small size of our family does not provide sufficient power for a conclusive analysis of linkage; we hope that collaboration with other investigators referring us more HAPE patients in effort to increase sample size would lead to identification of gene(s) responsible for HAPE and possibly other maladaptive hypoxic complications.
