title: Genotype at the P554L variant of the hexose-6 phosphate dehydrogenase gene is associated with carotid intima-medial thickness.
abstract: OBJECTIVE
  The combined thickness of the intima and media of the carotid artery (carotid intima-medial thickness, CIMT) is associated with cardiovascular disease and stroke. Previous studies indicate that carotid intima-medial thickness is a significantly heritable phenotype, but the responsible genes are largely unknown. Hexose-6 phosphate dehydrogenase (H6PDH) is a microsomal enzyme whose activity regulates corticosteroid metabolism in the liver and adipose tissue; variability in measures of corticosteroid metabolism within the normal range have been associated with risk factors for cardiovascular disease. We performed a genetic association study in 854 members of 224 families to assess the relationship between polymorphisms in the gene coding for hexose-6 phosphate dehydrogenase (H6PD) and carotid intima-medial thickness.
  
  
  METHODS
  Families were ascertained via a hypertensive proband. CIMT was measured using B-mode ultrasound. Single nucleotide polymorphisms (SNPs) tagging common variation in the H6PD gene were genotyped. Association was assessed following adjustment for significant covariates including "classical" cardiovascular risk factors. Functional studies to determine the effect of particular SNPs on H6PDH were performed.
  
  
  RESULTS
  There was evidence of association between the single nucleotide polymorphism rs17368528 in exon five of the H6PD gene, which encodes an amino-acid change from proline to leucine in the H6PDH protein, and mean carotid intima-medial thickness (p = 0.00065). Genotype was associated with a 5% (or 0.04 mm) higher mean carotid intima-medial thickness measurement per allele, and determined 2% of the population variability in the phenotype.
  
  
  CONCLUSIONS
  Our results suggest a novel role for the H6PD gene in atherosclerosis susceptibility.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Thahira J
authors.initials: TJ
authors.lastname: Rahman
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Walker
authors.forename: Bongani M
authors.initials: BM
authors.lastname: Mayosi
authors.forename: Darroch H
authors.initials: DH
authors.lastname: Hall
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Avery
authors.forename: John M C
authors.initials: JM
authors.lastname: Connell
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
authors.forename: Bernard
authors.initials: B
authors.lastname: Keavney
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D050197:Atherosclerosis / Q000235:genetics; D002237:Carbohydrate Dehydrogenases / Q000235:genetics*; D059168:Carotid Intima-Media Thickness; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D017386:Sequence Homology, Amino Acid; D055815:Young Adult
chemical_list: D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase