title: A role for succinate dehydrogenase genes in low chemoresponsiveness to hypoxia?
abstract: The detection of hypoxia by the carotid bodies elicits a ventilatory response of utmost importance for tolerance to high altitude. Germline mutations in three genes encoding subunit B, C and D of succinate dehydrogenase (SDHB, SDHC and SDHD) have been associated with paragangliomas of the carotid body. We hypothesized that SDH dysfunction within the carotid body could result in low chemoresponsiveness and intolerance to high altitude. The frequency of polymorphisms of SDHs, hypoxia-inducible factor type 1 (HIF1alpha) and angiotensin converting enzyme (ACE) genes was compared between 40 subjects with intolerance to high altitude and a low hypoxic ventilatory response at exercise (HVRe < or = 0.5 ml min(-1) kg(-1); HVR- group) and 41 subjects without intolerance to high altitude and a high HVRe (> or = 0.80 ml min(-1) kg(-1); HVR+). We found no significant association between low or high HVRe and (1) the allele frequencies for nine single nucleotide polymorphisms (SNPs) in the SDHD and SDHB genes, (2) the ACE insertion/deletion polymorphism and (3) four SNPs in the HIF1alpha gene. However, a marginal significant association was found between the synonymous polymorphism c.18A>C of the SDHB gene and chemoresponsiveness: 8/40 (20%) in the HVR- group and 3/41 (7%) in the HVR+ group (p = 0.12). A principal component analysis showed that no subject carrying the 18C allele had both high ventilatory and cardiac response to hypoxia. In conclusion, no clear association was found between gene variants involved in oxygen sensing and chemoresponsiveness, although some mutations in the SDHB and SDHD genes deserve further investigations in a larger population.
authors.affiliation: Université Paris, UFR SMBH EA, Bobigny, France. richalet@smbh.univ-paris13.fr
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Richalet
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
authors.forename: Séverine
authors.initials: S
authors.lastname: Peyrard
authors.forename: Annabelle
authors.initials: A
authors.lastname: Vénisse
authors.forename: Laure
authors.initials: L
authors.lastname: Marelle
authors.forename: Nelly
authors.initials: N
authors.lastname: Burnichon
authors.forename: Anissa
authors.initials: A
authors.lastname: Bouzamondo
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.forename: Michel
authors.initials: M
authors.lastname: Azizi
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Elghozi
mesh_terms: D000328:Adult; D000531:Altitude; D000693:Anaerobiosis; D002344:Carotid Body / Q000201:enzymology / Q000502:physiology*; D015444:Exercise / Q000502:physiology; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D018095:Germ-Line Mutation; D006339:Heart Rate / Q000235:genetics / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D010100:Oxygen / Q000502:physiology*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012123:Pulmonary Ventilation / Q000235:genetics* / Q000502:physiology; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000502:physiology*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; C108096:SDHC protein, human; C491545:SDHD protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A; D010100:Oxygen