title: Genetic variations of HSD11B2 in hypertensive patients and in the general population, six rare missense/frameshift mutations.
abstract: Mutations in the gene encoding 11beta-hydroxysteroid dehydrogenase type 2, HSD11B2, cause a rare monogenic juvenile hypertensive syndrome called apparent mineralocorticoid excess (AME). In AME, defective HSD11B2 enzyme activity results in overstimulation of the mineralocorticoid receptor (MR) by cortisol, causing sodium retention, hypokalemia, and salt-dependent hypertension. Here, we have studied whether genetic variations in HDS11B2 are implicated in essential hypertension in Japanese hypertensives and the general population. By sequencing the entire coding region and the promoter region of HDS11B2 in 953 Japanese hypertensives, we identified five missense mutations in 11 patients (L14F, n = 5; R74H, n = 1; R147H, n = 3; T156I, n = 1; R335H, n = 1) and one novel frameshift mutation (4884Gdel, n = 1) in a heterozygous state, in addition to 19 genetic variations. All genetic variations identified were rare, with minor allele frequencies less than 0.005. Four of 12 patients with the missense/frameshift mutations showed renal failure. Four missense mutations, L14F, R74H, R147H, and R335H, were successfully genotyped in the general population, with a sample size of 3,655 individuals (2,175 normotensives and 1,480 hypertensives). Mutations L14F, R74H, R147H, and R335H were identified in hypertensives (n = 6, 8, 3, and 0, respectively) and normotensives (n = 8, 12, 5, and 0, respectively) with a similar frequency, suggesting that these missense mutations may not strongly affect the etiology of essential hypertension. Since the allele frequency of all of the genetic variations identified in this study was rare, an association study was not conducted. Taken together, our results indicate that missense mutations in HSD11B2 do not substantially contribute to essential hypertension in Japanese.
authors.affiliation: Division of Hypertension and Nephrology, National Cardiovascular Center, Suita, Japan. kamide@hsp.ncvc.go.jp
authors.forename: Kei
authors.initials: K
authors.lastname: Kamide
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kokubo
authors.forename: Hironori
authors.initials: H
authors.lastname: Hanada
authors.forename: Junko
authors.initials: J
authors.lastname: Nagura
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.forename: Shin
authors.initials: S
authors.lastname: Takiuchi
authors.forename: Chihiro
authors.initials: C
authors.lastname: Tanaka
authors.forename: Mariko
authors.initials: M
authors.lastname: Banno
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Miwa
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Yoshii
authors.forename: Tetsutaro
authors.initials: T
authors.lastname: Matayoshi
authors.forename: Hisayo
authors.initials: H
authors.lastname: Yasuda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Horio
authors.forename: Akira
authors.initials: A
authors.lastname: Okayama
authors.forename: Hitonobu
authors.initials: H
authors.lastname: Tomoike
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Kawano
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyata
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics*; D000368:Aged; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D005260:Female; D016368:Frameshift Mutation; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000208:ethnology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense
chemical_list: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human