Association Of MTHFR,CBS Gene Polymorphisms And Dietary Factors With H-type Hypertension In Xinjiang Kazakhs

Objective:To explore the independent and joint associations of homocysteine（Hcy）metabolism-related genes（MTHFR,CBS）and dietary nutrients(folate,vitamin B₆and B₁₂)with H-type hypertension in Kazakhs.These results provide support and a theoretical basis for the pathogenesis research of H-type hypertension.Methods:A case-control study,using data from the“Xinjiang Kazakhs H-type ypertension Cross-sectional study”was conducted.A total of 400 subjects were randomly selected,which included 300 cases and 100 controls.Among them,the case groups included 100 patients with H-type hypertension,100 patients with uncomplicated hypertension,and 100 patients with Hyperhomocysteinemia（HHcy）.Genetic testing of MTHFR（rs1801133,rs1801131,rs2274976）and CBS（rs5742905,rs121964962,rs397589）was performed using Sanger sequencing.Folate and vitamin B₁₂were detected by electrochemiluminescence assay.Vitamin B₆was detected by microplate assay in our laboratory.Hardy-Weinberg equilibrium was tested by Pearson’s chi-square（χ²）test.We applied unconditional logistic regression to analysis was carried out to analyze the association of genes（MTHFR,CBS）and dietary nutrients(folate,vitamin B₆and B₁₂)with H-type hypertension.Gene-gene interactions were analysed using the Generalized multifactor dimensionality reduction（GMDR）0.9 software.Gene‐dietary interactions were assessed using logistic regression including multiplicative interaction models.The linkage disequilibrium and haplotype were calculated using online software SHEsis.Results:1.Compared with the healthy control group,the frequency of rs1801133-T allele was higher（42.0%vs15.5%,P<0.001）and rs1801131-C（16.5%vs 29.5%,P=0.002）was lower in H-type hypertension.The frequency of rs1801133-T allele was higher（35.0%vs 15.5%,P<0.001）and rs2274976-A（4.0%vs 9.5%,P=0.028）was lower in HHcy.Compared with the uncomplicated hypertension group,the frequency of rs1801133-T allele was higher（42.0%vs 24.5%,P<0.001）in H-type hypertension.But rs1801131-C（16.5%vs 28.5%,P=0.004）and rs2274976-A（5.5%vs 12.0%,P=0.021）were lower.2.Compared with the healthy control group,the high level of folate was a protective factor for H-type hypertension（OR=0.38,95%CI:0.17-0.86）.Rs1801133-（CT+TT）was a risk factor（OR=7.41,95%CI:3.26-16.84）,while rs2274976-（GA+AA）was a protective factor（OR=0.20,95%CI:0.06-0.66）.Meanwhile,the high level of folate was a protective factor for HHcy（OR=0.48,95%CI:0.25-0.94）,while rs1801133-（CT+TT）was a risk factor（OR=3.12,95%CI:1.60-6.10）.Compared to the uncomplicated hypertension group,the high level of folate（0.34,95%CI:0.17-0.69）,vitamin B₆（0.46,95%CI:0.23-0.93）and vitamin B₁₂（0.42,95CI%:0.21-0.82）were protective factors for H-type hypertension,while rs1801133-（CT+TT）was a risk factor（OR=3.77,95%CI:1.83-7.77）.3.For H-type hypertension in Kazakhs,antagonism was found between MTHFR rs1801131 and rs1801133,while there were no interactions between gene‐dietary.For HHcy,there was an antagonistic interaction between MTHFR rs1801133 and rs2274976.4.For H-type hypertension in Kazakhs,linkage disequilibrium was noted between MTHFR rs1801131 with rs1801133（D’=0.524）,MTHFR rs2274976 with CBS rs397589（D’=0.697）.The results of haplotype analysis displayed that the most common haplotype was the A-C haplotype for MTHFR rs1801131 with rs1801133.Meanwhile,the A-C haplotype（OR=0.44,95%CI:0.29-0.65）and C-T（OR=0.08,95%CI:0.01-0.49）were protective factors for H-type hypertension,while the A-T haplotype was a risk factor（OR=8.10,95%CI=4.52-14.51）.Furthermore,the most common haplotype was the G-C haplotype for MTHFR rs2274976 with CBS rs397589,while there were no association between haplotypes（A-C,G-A,G-C）and H-type hypertension（P>0.05）.Conclusions:1.The T allele and CT+TT genotypes of MTHFR rs1801133 were risk factors for H-type hypertension in Kazakhs,while the A allele and GA+AA genotypes of MTHFR rs2274976 were protective factors.2.The high level of folate was a protective factor for H-type hypertension,while vitamin B₆and B₁₂supplementation seem to reduce the risk of H-type hypertension,in the uncomplicated hypertension group.3.For H-type hypertension in Kazakhs,antagonistics interaction were found between gene-gene interaction（rs1801133×rs1801131,rs1801133×rs2274976）,while we did not find any interactions between gene‐dietary.