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      Association between CYP3A4 gene rs4646437 polymorphism and the risk of hypertension in Chinese population: a case–control study

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          Abstract

          Using a case–control design, we assessed the association between single nucleotide polymorphisms of CYP3A4 gene rs4646437 polymorphism and the risk of hypertension in Chinese population. We recruited 450 hypertension patients from The First Clinical College, Henan University of Chinese Medicine between June 2017 and May 2018. There was a significant difference in genotype distribution between case group and control group ( χ 2 =18.169, P=0.000). The minor A allele was significantly higher in the case group than that in the control group (31.0 vs 24.8%, P=0.000, odds ratio [OR]=1.36, 95% confidence interval [95% CI]: 1.12–1.66). Significant differences were also observed in other gene models: the GA/AA genotype did not increase the risk of hypertension compared with GG genotype ( OR=1.16, 95% CI: 0.90–1.49, P=0.259). Compared with GG/GA genotype, the AA genotype also increased the risk of hypertension ( OR=2.34, 95% CI: 1.56–3.50, P=0.000). For additive model, the AA genotype was significantly associated with GG genotype ( OR=2.25, 95% CI: 1.49–3.42, P=0.000). The same results were found for AA vs GA ( OR=2.50, 95% CI: 1.60–3.89, P=0.000). For the allele genotype, the A allele frequency was significantly higher in the case group than that in the control group (31.0 vs 24.8%, P=0.002). The A allele of CYP3A4 rs4646437 was associated with an increased risk for hypertension ( OR=1.36, 95% CI: 1.12–1.66, P=0.002). Our results revealed a possible genetic association between CYP3A4 gene rs4646437 and hypertension, and the AA genotype of rs4646437 increased the risk of hypertension in Chinese Han population, and this effect could be confirmed by multivariable analyses.

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          Most cited references25

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          Prevalence, awareness, treatment, and control of hypertension in China: results from a national survey.

          Hypertension is one of the major risk factor for cardiovascular disease worldwide. The objective of this study was to investigate the prevalence, awareness, treatment, and control of hypertension in China. A multistage, stratified sampling method was used to obtain a representative sample of persons aged 18 years or older in the general population of China. Blood pressure (BP) was measured by sphygmomanometer 3 times at 5-minute intervals. Hypertension was defined as a systolic BP ≥ 140mm Hg, or diastolic BP ≥ 90mm Hg, or self-reported use of antihypertensive medications in the last 2 weeks irrespective of the BP. Altogether 50,171 subjects finished the survey across the entire country. The adjusted prevalence of hypertension was 29.6% (95% confidence interval (CI) = 28.9%-30.4%) and was higher among men than among women (31.2%, 95% CI = 30.1%-32.4%; vs. 28.0%, 95% CI = 27.0%-29.0%). The awareness, treatment among all hypertensive participants, control among all hypertensive participants, and control among treated hypertensive participants were 42.6%, 34.1%, 9.3%, and 27.4%, respectively. Multiple lifestyle factors were independently associated with presence of hypertension, including physical inactivity, habitual drinking, chronic use of nonsteroidal anti-inflammatory drugs, high body mass index, and central obesity. Hypertension is an important public health burden in China, and control of hypertension is still suboptimal. Several modifiable lifestyle activities were associated with hypertension and thus should be considered potential targets for intervention, with special attention to socioeconomically disadvantaged subpopulations in China. © American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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            Cytochrome P450 systems--biological variations of electron transport chains.

            Cytochromes P450 (P450) are hemoproteins encoded by a superfamily of genes nearly ubiquitously distributed in different organisms from all biological kingdoms. The reactions carried out by P450s are extremely diverse and contribute to the biotransformation of drugs, the bioconversion of xenobiotics, the bioactivation of chemical carcinogens, the biosynthesis of physiologically important compounds such as steroids, fatty acids, eicosanoids, fat-soluble vitamins and bile acids, the conversion of alkanes, terpenes and aromatic compounds as well as the degradation of herbicides and insecticides. Cytochromes P450 belong to the group of external monooxygenases and thus receive the necessary electrons for oxygen cleavage and substrate hydroxylation from different redox partners. The classical as well as the recently discovered P450 redox systems are compiled in this paper and classified according to their composition.
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              Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

              Summary Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. Funding UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.
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                Author and article information

                Journal
                Biosci Rep
                Biosci. Rep
                ppbioscirep
                BSR
                Bioscience Reports
                Portland Press Ltd.
                0144-8463
                1573-4935
                25 March 2019
                30 April 2019
                17 April 2019
                : 39
                : 4
                : BSR20190296
                Affiliations
                [1 ]The Second Clinical Medical College, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan Province 450046, China
                [2 ]Department of Endocrine and Cardiovascular, People’s Hospital of Huiji District, Zhengzhou, Henan Province 450044, China
                [3 ]Department of Emergency, Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, Henan Province 450002, China
                Author notes
                Correspondence: Dongsheng Guan ( vipmailclient@ 123456163.com )
                Author information
                http://orcid.org/0000-0002-2969-2616
                Article
                10.1042/BSR20190296
                6470406
                30910847
                b85e943b-ea02-4b64-9cf7-81314ec2f092
                © 2019 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

                History
                : 01 February 2019
                : 19 March 2019
                : 21 March 2019
                Page count
                Pages: 8
                Categories
                Research Articles
                Research Article
                40
                15

                Life sciences
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