Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension study.
Mutations in the WNK1 gene cause Gordon's syndrome, a rare Mendelian form of hypertension. We assessed whether common WNK1 variants might also contribute to essential hypertension (EH), a multifactorial disorder affecting > 25% of the adult population worldwide. A panel of 19 single nucleotide polymorphisms (SNPs) spanning the gene was selected from public databases and was genotyped in 100 white European families to determine the pattern of linkage disequilibrium, haplotype structure and tagging SNPs for the WNK1 locus. Eight tagging SNPs were identified with 90% power to predict common WNK1 haplotypes and SNPs. Family-based association tests were used to test for association with EH and severity of hypertension in 712 severely hypertensive families from the MRC British Genetics of Hypertension study resource. No association was found between WNK1 polymorphisms or haplotypes with hypertension; however, one SNP rs1468326, located 3 kb from the WNK1 promoter, was found to be nominally associated with severity of hypertension, with both systolic blood pressure (BP) (Z = +2.24, P = 0.025) and diastolic BP (Z = +1.99, P = 0.046). We also found nominal support for association of one common WNK1 haplotype with increased systolic BP (Z = +1.91, P = 0.053). This is the first study to perform haplotype association analysis of the WNK1 gene with EH. This finding of association between a SNP near the promoter region and the severity of hypertension suggests that increased expression of WNK1 might contribute to BP variability and susceptibility to EH similar to the mechanism of hypertension observed in Gordon's syndrome.
Newhouse
Stephen J
SJ
Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and the London School of Medicine, London, UK.
Wallace
Chris
C
Dobson
Richard
R
Mein
Charles
C
Pembroke
Janine
J
Farrall
Martin
M
Clayton
David
D
Brown
Morris
M
Samani
Nilesh
N
Dominiczak
Anna
A
Connell
John M
JM
Webster
John
J
Lathrop
G Mark
GM
Caulfield
Mark
M
Munroe
Patricia B
PB
D000328:Adult; D001794:Blood Pressure / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D013577:Syndrome; D006113:United Kingdom; D000076204:WNK Lysine-Deficient Protein Kinase 1; D044465:White People
D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human