Association of TNFRSF4 gene polymorphisms with essential hypertension.
BACKGROUND
Essential hypertension is a complex disorder that results from the interaction of a number of susceptibility genes and environmental factors. The TNFRSF4 (tumor necrosis factor receptor superfamily, member 4) gene was one of the genes that showed altered renal expression in long-term salt loading in mice. Moreover, association of the TNFRSF4 and TNFSF4 (tumor necrosis factor (ligand) superfamily, member 4) genes with myocardial infarction was recently reported. Since essential hypertension is a well-known risk factor for myocardial infarction, we hypothesized that TNFRSF4 could be a susceptibility gene for essential hypertension.


METHODS
We performed a case-control study of TNFRSF4 in two independent population.


RESULTS
Extensive investigation of single nucleotide polymorphisms of the entire gene suggested that it resided in one linkage disequilibrium block, and four single nucleotide polymorphisms in the 5' flanking region sufficiently represented major haplotypes. In the combined population, the frequency of the most frequent haplotype, C-C-A-A, was significantly lower (P = 8.07 x 10(-5)) and that of the second most frequent haplotype, C-T-G-A, was significantly higher (P = 6.07 x 10(-4)) in hypertensive subjects than in control subjects. This difference was observed only in female patients. The C-T-G-A haplotype showed a lower promoter activity than other haplotypes, suggesting a relationship with disease susceptibility.


CONCLUSIONS
Our results suggest that TNFRSF4 is a female-specific susceptible gene for essential hypertension.
Mashimo
Yoichi
Y
Department of Public Health, Graduate School of Medicine, Chiba University, Chiba, Japan.
Suzuki
Yoichi
Y
Hatori
Kazuko
K
Tabara
Yasuharu
Y
Miki
Tetsuro
T
Tokunaga
Katsushi
K
Katsuya
Tomohiro
T
Ogihara
Toshio
T
Yamada
Michiko
M
Takahashi
Norio
N
Makita
Yoshio
Y
Nakayama
Tomohiro
T
Soma
Masayoshi
M
Hirawa
Nobuhito
N
Umemura
Satoshi
S
Ohkubo
Takayoshi
T
Imai
Yutaka
Y
Hata
Akira
A
D000368:Aged; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D007564:Japan; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D053262:Receptors, OX40 / Q000235:genetics*; D012737:Sex Factors
D053262:Receptors, OX40; C505716:TNFRSF4 protein, human