title: Common variants in genes underlying monogenic hypertension and hypotension and blood pressure in the general population.
abstract: The genes responsible for several monogenic hypertensive and hypotensive disorders have been identified. Our aim was to evaluate whether common variants in these genes affect blood pressure in the general population. We studied 2037 adults from 520 nuclear families characterized for 24-hour ambulatory blood pressure and related cardiovascular traits. We genotyped 298 tagging and putative functional single nucleotide polymorphisms, achieving a median coverage of 82.4% across 11 candidate loci. Five polymorphisms in the KCNJ1 gene coding for the potassium channel, ROMK, showed associations with mean 24-hour systolic or diastolic blood pressure. The strongest association was with an intronic polymorphism, rs2846679, where the minor allele (frequency 16%) was associated with a -1.58 (95% CI -2.47 to -0.69) mm Hg change in mean 24-hour systolic blood pressure, after accounting for age, sex, and familial correlations (P=0.00048). Polymorphisms in the gene were also associated with clinic blood pressure and left ventricular mass as assessed by ECG Sokolow-Lyon voltage (P=0.0081 for rs675759). Associations with mean 24-hour systolic or diastolic blood pressure were also observed for variants in CASR, NR3C2, SCNN1B, and SCNN1G. The findings show that common variants in genes responsible for some Mendelian disorders of hypertension and hypotension affect blood pressure in the general population. Notably, variants in KCNJ1, which causes Bartter syndrome type 2, were strongly associated, potentially providing a novel target for intervention.
authors.affiliation: Department of Health Sciences & Genetics, University of Leicester, UK.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Tobin
authors.forename: Maciej
authors.initials: M
authors.lastname: Tomaszewski
authors.forename: Peter S
authors.initials: PS
authors.lastname: Braund
authors.forename: Cother
authors.initials: C
authors.lastname: Hajat
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Raleigh
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Palmer
authors.forename: Mark
authors.initials: M
authors.lastname: Caulfield
authors.forename: Paul R
authors.initials: PR
authors.lastname: Burton
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
mesh_terms: D000293:Adolescent; D000328:Adult; D001794:Blood Pressure / Q000235:genetics; D053503:Epithelial Sodium Channels / Q000235:genetics; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics*; D007022:Hypotension / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D044169:Receptors, Calcium-Sensing / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D012307:Risk Factors
chemical_list: C095550:CASR protein, human; D053503:Epithelial Sodium Channels; C086989:KCNJ1 protein, human; D024661:Potassium Channels, Inwardly Rectifying; D044169:Receptors, Calcium-Sensing; D018161:Receptors, Mineralocorticoid; C507048:SCNN1B protein, human; C507052:SCNN1G protein, human