Haplotype analyses of CYP17A1 genetic polymorphisms and coronary artery disease in a Uygur population

Dai, Chunsun; Xie, Xiang; Ma, Yun; Yang, Yi‐Ning; Li, Xiaomei; Fu, Zhen-Yan; Liu, Fen; Chen, Bang‐Dang; Gai, Min-Tao

doi:10.1177/1470320314565840

Cited by 8 publications

(7 citation statements)

References 41 publications

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“…Thus physiological testosterone replacement could be an option to rescue the phenotype in mice 50 without any need of genetic modification of Cyp17a1 expression. Further these data support the GWAS finding that the chromosomal region containing the CYP17A1 gene is associated with CAD and pinpoint CYP17A1 as the causal gene at this locus 2,39,40 .…”

Section: Discussionsupporting

confidence: 83%

“…Such disorders are also associated with various cardiovascular risk factors, including hypertension [32][33][34][35][36][37] , diabetes, and aortic stiffness 38 . Here we focused on CYP17A1, a gene mapping to a locus associated with various cardiovascular disorders, including CAD, MI, diabetes, and arterial stiffness, according to GWAS 3,33,34,[38][39][40] .…”

Section: Discussionmentioning

confidence: 99%

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CYP17A1 deficient XY mice display susceptibility to atherosclerosis, altered lipidomic profile and atypical sex development

Aherrahrou

Kulle

Alenina

et al. 2020

Sci Rep

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CYP17A1 is a cytochrome P450 enzyme with 17-alpha-hydroxylase and C17,20-lyase activities. CYP17A1 genetic variants are associated with coronary artery disease, myocardial infarction and visceral and subcutaneous fat distribution; however, the underlying pathological mechanisms remain unknown. We aimed to investigate the function of CYP17A1 and its impact on atherosclerosis in mice. At 4-6 months, CYP17A1-deficient mice were viable, with a KO:Het:WT ratio approximating the expected Mendelian ratio of 1:2:1. All Cyp17a1 knockout (KO) mice were phenotypically female; however, 58% were Y chromosome-positive, resembling the phenotype of human CYP17A1 deficiency, leading to 46,XY differences/disorders of sex development (DSD). Both male and female homozygous KO mice were infertile, due to abnormal genital organs. Plasma steroid analyses revealed a complete lack of testosterone in XY-KO mice and marked accumulation of progesterone in XX-KO mice. Elevated corticosterone levels were observed in both XY and XX KO mice. In addition, Cyp17a1 heterozygous mice were also backcrossed onto an Apoe KO atherogenic background and fed a western-type diet (WTD) to study the effects of CYP17A1 on atherosclerosis. Cyp17a1 x Apoe double KO XY mice developed more atherosclerotic lesions than Apoe KO male controls, regardless of diet (standard or WTD). Increased atherosclerosis in CYP17A1 XY KO mice lacking testosterone was associated with altered lipid profiles. In mice, CYP17A1 deficiency interferes with sex differentiation. Our data also demonstrate its key role in lipidomic profile, and as a risk factor in the pathogenesis of atherosclerosis. Coronary artery disease (CAD) is a major cause of morbidity and mortality worldwide 1. Inheritance plays an essential role in the pathogenesis of CAD, and recent genome-wide association studies (GWAS) have revealed more than 160 genomic loci associated with this condition 2. One commonly reported genomic locus, for CAD was located at chr10p24.32. The same locus is also associated with myocardial infarction (MI) 3 and visceral and subcutaneous fat distribution 4. This locus harbors the CYP17A1 gene, which encodes the cytochrome P450 17A1 enzyme, also referred to as steroid 17-alpha-monooxygenase or 17α-hydroxylase/17,20-lyase/17,20-desmolase.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

CYP17A1 deficient XY mice display susceptibility to atherosclerosis, altered lipidomic profile and atypical sex development

Aherrahrou

Kulle

Alenina

et al. 2020

Sci Rep

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“…However, environmental factors are not the best predictors of CAD risk, suggesting that genetic variants might influence the development of CAD. Previous studies have reported that a number of genetic polymorphisms might play an important role in the development of CAD including cytochrome P450 17A1 (CYP17A1), toll-like receptors, metallothionein 2A, and retinol binding protein 4, as well as matrix metalloproteinase 1 (Qintao et al, 2014;Wan et al, 2014;Yang et al, 2014;Dai et al, 2015;Guven et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Association of interleukin gene polymorphisms with the risk of coronary artery disease

Ht¹,

Sl²,

Yan³

et al. 2015

Genet. Mol. Res.

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“…Rs1004467, which is in the intron region of CYP17A1, has been associated with cardiovascular diseases. Specifically, two case–control studies have reported rs1004467 to be significantly associated with CAD in Chinese populations ( 14 , 26 ). Furthermore, another case–control study found that rs1004467 in CYP17A1 was associated with arterial stiffness in 326 prediabetic and 743 diabetic subjects ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

A Study on the Association Between Polymorphisms in the Cytochrome P450 Family 17 Subfamily A Member 1 Gene Region and Type 2 Diabetes Mellitus in Han Chinese

Wang

Niu

et al. 2018

Front. Endocrinol.

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BackgroundCytochrome P450 family 17 subfamily A member 1 (CYP17A1) gene encodes a key enzyme in the synthesis and metabolism of steroid hormones and has been associated with various factors, such as hypertension, insulin resistance, and polycystic ovary syndrome. However, whether the gene was associated with type 2 diabetes mellitus (T2DM) has not been reported yet. Therefore, we sought to investigate whether CYP17A1 was associated with T2DM and related traits among Han Chinese.MethodsThree tagging single nucleotide polymorphisms (rs1004467, rs17115149, and rs12413409), in the CYP17A1 gene region were selected and genotyped in a case–control study that included 440 diabetes and 1,320 control subjects. Effects of genetic loci were studied using univariate unconditional logistic regression and multivariate logistic regression analysis adjusted for age, sex, family history, body mass index, smoking, and drinking. Bioinformatics analysis was also conducted using the GEO DataSets and PROMO database to gain hints of possible mechanism.ResultsRs17115149 and rs12413409 polymorphisms were significantly associated with the risk of T2DM, even after adjusting for age, sex, family history, body mass index, smoking, and drinking. In stratified analyses, rs1004467 and rs12413409 showed significant association with T2DM in the older age group (≥65 years) and, in the case of rs12413409, the risk of T2DM was significant in men but not in women. Rs17115149 had significant association with T2DM in the hypertension subgroup, and rs12413409 in the non-hypertension subgroup. Moreover, rs12413409 showed significant association with plasma glucose levels in the recessive model (P = 0.020) among subjects not taking hypoglycemic measures. Bioinformatics analysis revealed significantly higher CYP17A1 gene expression in T2DM patients compared to healthy controls. Finally, the mutant T allele of the rs17115149 polymorphism allowed binding to the RBP-Jkappa transcription factor.ConclusionThis is the first report to identify that variants rs1004467, rs17115149, and rs12413409 of CYP17A1, are related to plasma glucose levels and T2DM among Han Chinese. Our results suggest that CYP17A1 might constitute a risk gene for progression to T2DM.

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Haplotype analyses of CYP17A1 genetic polymorphisms and coronary artery disease in a Uygur population

Cited by 8 publications

References 41 publications

CYP17A1 deficient XY mice display susceptibility to atherosclerosis, altered lipidomic profile and atypical sex development

CYP17A1 deficient XY mice display susceptibility to atherosclerosis, altered lipidomic profile and atypical sex development

Association of interleukin gene polymorphisms with the risk of coronary artery disease

A Study on the Association Between Polymorphisms in the Cytochrome P450 Family 17 Subfamily A Member 1 Gene Region and Type 2 Diabetes Mellitus in Han Chinese

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