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Functional characterization of blood pressure‐associated common variants in STK39
Author(s) -
Chang Yen Pei Christy,
Chen Junji,
Wang Ying,
Dorff Sarah,
Wade James,
O'Connell Jeff,
Shuldiner Alan
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.802.3
Subject(s) - genome wide association study , single nucleotide polymorphism , biology , gene , allele , serine , genetics , microbiology and biotechnology , phosphorylation , genotype
We conducted a genome‐wide association study (GWAS) of systolic and diastolic blood pressure (BP) in Amish subjects and identified several SNPs to be robustly associated with BP in a serine/threonine kinase, STK39. Identifying STK39 as a hypertension susceptibility gene is of great biological implication as emerging evidence indicate that STK39 encoded protein, SPAK, interacts with WNK kinases and cation‐chloride transporters in cell‐based assays and participates in an essential sodium‐transport pathway. We demonstrate that in vivo, SPAK is expressed in the distal nephron, where it may interact with these proteins. While none of the associated SNPs from GWAS alter protein structure, we identified several BP‐associated SNPs located in intronic conserved sequence elements (CEs). When tested in reporter gene assays, one of these CEs demonstrated allele‐specific in vitro transcription activity. Oligonucleotides from this CE also showed allele‐specific binding to nuclear protein(s) in electrophoretic mobility shift assays. Hence STK39 may influence BP by allele‐specific DNA‐protein interaction that modifies SPAK expression and renal sodium excretion.