Validation of genetic association in apelin-AGTRL1 system with hypertension in a larger Han Chinese population.
OBJECTIVE
We have recently resequenced apelin and AGTRL1 genes to identify candidate polymorphisms in family-based association with hypertension and related phenotypes. In this study, we aimed to determine and replicate these polymorphisms via a larger, independent case-control study in Shanghai Han Chinese.


METHODS
Two polymorphisms [rs3761581 (A/C) and T-1860C] in apelin gene and two [rs7119375 (G/A), rs10501367 (G/A)] in AGTRL1 gene were genotyped using the TaqMan assay among 969 patients diagnosed with essential hypertension and 980 age and sex-matched controls. Data were analyzed using Haplo.stats program.


RESULTS
In single-locus analysis, significant differences were observed in allele distribution of rs3761581 (P = 0.0156) in men and in rs7119375 (P = 0.0488) genotype distribution in women between patients and controls. Haplotype analysis indicated that haplotypes C-C-G-G (in order of T-1860C, rs3761581, rs7119375 and rs10501367) [adjusted odds ratio (ORadjusted) = 1.67, P = 0.0061] and T-A-A-A (ORadjusted = 1.62, P = 0.0008) conferred an increased risk for hypertension after adjustment for age, onset age, body mass index (BMI) and waist-to-hip ratio, whereas haplotype C-C-A-A (ORadjusted = 0.33, P = 0.0048) conferred a protective effect. In women, increased risk for hypertension was seen for haplotypes T-A-G-G (ORadjusted = 1.30, P = 0.0051), C-C-G-G (ORadjusted = 2.86, P < 0.0001), T-A-A-A (ORadjusted = 1.66, P = 0.0003) and C-C-A-A (ORadjusted = 2.65, P < 0.0001), whereas decreased risk was seen for haplotypes C-A-G-G (ORadjusted = 0.48, P < 0.0001) and T-C-G-G (ORadjusted = 0.40, P < 0.0001). Further haplotype-phenotype analyses indicated the robustness of these associations. For example, haplotype T-A-A-A was significantly associated with obesity index (BMI and waist-to-hip ratio) in both sexes and blood pressures in men (P-sim < 0.05).


CONCLUSIONS
In this exploratory pilot case-control study, we found robust haplotype-based and haplotype-phenotype associations of four well characterized polymorphisms in apelin-AGTRL1 system with hypertension and related phenotypes.
Niu
Wenquan
W
State Key Laboratory of Medical Genomics Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. niuwenquan@yahoo.cn
Wu
Shengnan
S
Zhang
Yi
Y
Li
Weiwei
W
Ji
Kaida
K
Gao
Pingjin
P
Zhu
Dingliang
D
D000073861:Apelin; D000075244:Apelin Receptors; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D002681:China; D017931:DNA Primers / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008024:Ligands; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*
C115436:APLN protein, human; C104575:APLNR protein, human; D000073861:Apelin; D000075244:Apelin Receptors; D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D043562:Receptors, G-Protein-Coupled