Genetic association analysis of chronic mountain sickness in an Andean high-altitude population.
OBJECTIVE
Millions of people live above an altitude of 2,500 m and are at risk of chronic mountain sickness (CMS), a disorder of excessive red cell and hemoglobin production. Preferential ethnic backgrounds, familial character, and heritability studies have suggested that genetic factors make a major contribution to the pathogenesis of CMS, thus our goals were to exploit a probable founder or population admixture effect in the Andean population to determine the genetic determinants of the extreme erythropoietic responses and CMS.


METHODS
The association of functional candidate genes with severe polycythemia was studied in Andean subjects from Cerro de Pasco, Peru (altitude 4,438 m). We used microsatellites linked to candidate genes known to be involved in hypoxia sensing and erythropoiesis: erythropoietin, erythropoietin-receptor, hypoxia-inducible factor-1a, von Hippel-Lindau, prolyl hydroxylase domain containing 1, 2, 3, and phosphatase and tensin homolog deleted on chromosome ten. Analysis of co-variance (ANCOVA) was used to test the effect of genotypes on hemoglobin values.


RESULTS
Case-control comparisons revealed no significant difference in genotype and allele frequencies at any marker. Initial analysis, with age as a covariate, showed a possible association between PHD3 (marker D14S1049) and severe polycythemia (p=0.05). After the inclusion of alternative co-variates and after adjusting for multiple comparisons, no p values could be considered statistically significant.


CONCLUSIONS
Our study does not find evidence of associations between the polymorphisms linked to the candidate genes and severe polycythemia; this does not, however, exclude that variations in these genes contribute to polycythemia and possibly CMS.
Mejía
Olga M
OM
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Prchal
Josef T
JT
León-Velarde
Fabiola
F
Hurtado
Abdias
A
Stockton
David W
DW
D000328:Adult; D000532:Altitude Sickness / Q000097:blood / Q000453:epidemiology* / Q000235:genetics*; D002908:Chronic Disease; D004920:Erythropoiesis / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D006454:Hemoglobins / Q000032:analysis / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D010568:Peru / Q000453:epidemiology; D010641:Phenotype; D011086:Polycythemia / Q000235:genetics; D011110:Polymorphism, Genetic
D006454:Hemoglobins