Acase-controlstudy Of The Association Between Homeodomain-interacting Protein Kinase-2(HIPK2) Gene Polymophisms And Kidney Stone Disease

[Objective]:To analyze the association of homeodomain-interacting protein kinase-2(HIPK2)gene polymorphisms with kidney stones and explore the risk factors for the development of kidney stones.[Methods]:A total of 2080 unrelated Chinese patients with kidney stones and 4317 healthy controls were enrolled in this study,all subjects were recruited from 12 hospitals in Guangxi(from Nanning,Guigang,Yulin,Fangchenggang,Wuzhou,and Qinzhou)of China from April 2014 to February 2015.A total of 1010 patients with kidney stones were randomly selected,and 1010 age-,sex-and resident area matched healthy controls were randomly selected in this study.DNA was extracted for peripheral blood and HIPK2(rs2058265,rs6464214,and rs7456421)genotypes were examined by SNPscanTM high-throughput SNP classification technology.Chi-square test was utilized to compare the differences of the genotype and allele frequencies between patients and controls.The Hardy–Weinberg equilibrium(HWE)of the three SNPs wereverified by the Chi-square goodness-of-fit test.The association between kidney stone risk and genotypes was estimated by using odds ratios(ORs)and 95% confidence intervals(CIs)from logistic regression analysis before and after adjustment for covariates.Differences of quantitative traits between genotypes were compared by using a general linear model analysis adjusted for covariates.Statistical significance was considered at P<0.05.SPSS version 22.0 was used for statistical analysis.The SHEsis software platform was used to construct the haplotypes(http://analysis.bio-x.cn).[Results]:After gender was stratified,the distributions of the genotype and allele of the three polymorphisms(rs2058265,rs6464214,and rs7456421 in HIPK2)were strongly associated with increased KSD risk in males(rs2058265: OR=2.480,95%CI=1.205–5.106,P=0.014;rs6464214:OR=2.466,95%CI=1.198–5.078,P=0.014;rs7456421:OR=2.846,95% CI=1.362–5.947,P=0.005;r2058265T,OR=1.357,95%CI=1.073–1.715,P=0.011;rs6464214G,OR=1.340,95%CI=1.060–1.693,P=0.014;rs7456421C,OR=1.356,95% CI=1.073–1.713,P=0.011).Patients carrying the T allele of rs2058265,the G allele of rs6464214,or the C allele of rs7456421 showed higher systolic blood pressure,creatinine,and uric acid levels compared with wild-genotype individuals(p<0.005).After analysis haplotype for male participants,the most common haplotype GAG is association with increased KSD risk in males(OR=1.329,95%CI=1.067-1.657,P=0.011),by contrast,the TGC haplotype is association with decreased disease risk in males(OR=0.752,95%CI=0.604–0.938,P= 0.011).[Conclusions]:The polymorphisms(rs2058265,rs6464214,and rs7456421)in HIPK2 gene were strongly associated with increased KSD risk in males.HIPK2 gene polymorphisms were also involved in the changes of KSD-related metabolic traits,HIPK2 may association with the changes in renal function,Interacting with sex hormones,which may contribution to the formation of kidney stones.