title: Hypercontrols in genotype-phenotype analysis reveal ancestral haplotypes associated with essential hypertension.
abstract: The angiotensinogen gene locus has been associated with essential hypertension in most populations analyzed to date. Increased plasma angiotensinogen levels have been proposed as an underlying cause of essential hypertension in whites; however, differences in the genetic regulation of plasma angiotensinogen levels have also been reported for other populations. The aim of this study was to analyze the relationship between angiotensinogen gene polymorphisms and haplotypes with plasma angiotensinogen levels and the risk of essential hypertension in the Mexican population. We genotyped 9 angiotensinogen gene polymorphisms in 706 individuals. Four polymorphisms, A-6, C4072, C6309, and G12775, were associated with increased risk, and the strongest association was found for the C6309 allele (χ(2)=23.9; P=0.0000009), which resulted in an odds ratio of 3.0 (95% CI: 1.8-4.9; P=0.000006) in the recessive model. Two polymorphisms, A-20C (P=0.003) and C3389T (P=0.0001), were associated with increased plasma angiotensinogen levels but did not show association with essential hypertension. The haplotypes H1 (χ(2)=8.1; P=0.004) and H5 (χ(2)=5.1; P=0.02) were associated with essential hypertension. Using phylogenetic analysis, we found that haplotypes 1 and 5 are the human ancestral haplotypes. Our results suggest that the positive association between angiotensinogen gene polymorphisms and haplotypes with essential hypertension is not simply explained by an increase in plasma angiotensinogen concentration. Complex interactions between risk alleles suggest that these haplotypes act as "superalleles."
authors.affiliation: National Institute of Genomic Medicine (INMEGEN), Mexico City, Mexico. eros.osiris.balam@pemex.com
authors.forename: Eros
authors.initials: E
authors.lastname: Balam-Ortiz
authors.forename: Adolfo
authors.initials: A
authors.lastname: Esquivel-Villarreal
authors.forename: David
authors.initials: D
authors.lastname: Huerta-Hernandez
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Fernandez-Lopez
authors.forename: Luis
authors.initials: L
authors.lastname: Alfaro-Ruiz
authors.forename: Omar
authors.initials: O
authors.lastname: Muñoz-Monroy
authors.forename: Ruth
authors.initials: R
authors.lastname: Gutierrez
authors.forename: Enrique
authors.initials: E
authors.lastname: Figueroa-Genis
authors.forename: Karol
authors.initials: K
authors.lastname: Carrillo
authors.forename: Adela
authors.initials: A
authors.lastname: Elizalde
authors.forename: Alfredo
authors.initials: A
authors.lastname: Hidalgo
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rodriguez
authors.forename: Maki
authors.initials: M
authors.lastname: Urushihara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobori
authors.forename: Gerardo
authors.initials: G
authors.lastname: Jimenez-Sanchez
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D044467:American Indian or Alaska Native / Q000208:ethnology / Q000235:genetics*; D000808:Angiotensinogen / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000208:ethnology* / Q000235:genetics*; D008297:Male; D008800:Mexico; D010641:Phenotype; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
chemical_list: D000808:Angiotensinogen