Association of a transcription factor 21 gene polymorphism with hypertension

Fujimaki, Tetsuo; Oguri, Mitsutoshi; Horibe, Hideki; Kato, Koichi; Matsuoka, Ryu; Abe, Shintaro; Tokoro, Fumitaka; Arai, M.; Noda, Toshiyuki; Watanabe, Soichi; Yamada, Yoshiji

doi:10.3892/br.2014.371

Cited by 42 publications

(36 citation statements)

References 28 publications

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“…This finding suggested that these QTLs in HCASMC may play an important role in the genetic mechanism of HCASMC mediated disease progression. All of the QTLs showed enrichment for blood pressure and hypertension phenotypes which are highly consistent with known SMC functions, and association of TCF21 with blood pressure have been identified by population studies with multiple racial ethnic groups [19][20][21]. The highly significant enrichment of breast cancer variants in the bQTL category is consistent with TCF21 being a known tumor suppressor and that is dysregulated in breast cancer, but the enrichment of breast cancer variants among the caQTLs and clQTLs is surprising and suggests a similar genomic and genetic architecture between HCASMC and breast cancer risk genes [22].…”

Section: Qtls Are Highly Associated With Gwas Cad Locisupporting

confidence: 55%

Quantitative trait loci mapped for TCF21 binding, chromatin accessibility and chromosomal looping in coronary artery smooth muscle cells reveal molecular mechanisms of coronary disease loci

Zhao

Dacre

Nguyen

et al. 2020

Preprint

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Background: To investigate the epigenetic and transcriptional mechanisms of coronary artery disease (CAD) risk, as well as the functional regulation of chromatin structure and function, we have created a catalog of genetic variants associated with three stages of transcriptional cisregulation in primary human coronary artery vascular smooth muscle cells (HCASMC).Results: To this end, we have used a pooling approach with HCASMC lines to map regulatory variation that mediates binding of the CAD associated transcription factor TCF21 with ChIPseq studies (bQTLs), variation that regulates chromatin accessibility with ATACseq studies (caQTLs), and chromosomal looping with HiC methods (clQTLs). We show significant overlap of the QTLs, and their relationship to smooth muscle specific genes and the binding of smooth muscle transcription factors. Further, we use multiple analyses to show that these QTLs are highly associated with CAD GWAS loci and correlated to lead SNPs in these loci where they show allelic effects. We have verified with genome editing that identified functional variants can regulate both chromatin accessibility and chromosomal looping, providing new insights into functional mechanisms regulating chromatin state and chromosomal structure. Finally, we directly link the disease associated TGFβ1-SMAD3 pathway to the CAD associated FN1 gene through a response QTL that modulates both chromatin accessibility and chromosomal looping.Conclusions: Together, these studies represent the most thorough mapping of multiple QTL types in a highly disease relevant primary cultured cell type, and provide novel insights into their functional overlap and mechanisms that underlie these genomic features and their relationship to disease risk. Key wordscoronary artery disease / smooth muscle cells / quantitative trait locus / TCF21 / chromosomal looping / chromatin accessibility / derived from deceased individuals. Because the donors were deceased, and only deidentified information was provided to the investigators, the work was not considered human research. Consent for publicationAll authors have reviewed the manuscript and give their consent to publication.

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Section: Qtls Are Highly Associated With Gwas Cad Locisupporting

confidence: 55%

Quantitative trait loci mapped for TCF21 binding, chromatin accessibility and chromosomal looping in coronary artery smooth muscle cells reveal molecular mechanisms of coronary disease loci

Zhao

Dacre

Nguyen

et al. 2020

Preprint

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“…Increased sortilin 1 expression leads to enhanced low-density lipoprotein (LDL)-uptake into cells, being associated with decreased plasma LDL-cholesterol, and a lower risk of coronary artery disease (21). Our previous study showed that rs599839 of PSRC1 was associated with myocardial infarction (14), hypertension (22) and dyslipidemia (hyper-LDL-cholesterolemia) (23) in Japanese individuals, with the minor G allele being protective against these conditions. The present study has shown that rs599839 of PSRC1 was associated with AF with the minor G allele representing a risk factor for this condition.…”

Section: Discussionmentioning

confidence: 99%

Association of genetic variants with atrial fibrillation

et al. 2015

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Recent genome-wide association studies (GWASs) identified various genes and loci that confer susceptibility to coronary artery disease or myocardial infarction among Caucasian populations. As myocardial ischemia is an important risk factor for atrial fibrillation, we hypothesized that certain polymorphisms may contribute to the genetic susceptibility to atrial fibrillation through affecting the susceptibility to coronary artery disease. The aim of the present study was to examine the possible association of atrial fibrillation in Japanese individuals with 29 polymorphisms identified as susceptibility loci for coronary artery disease or myocardial infarction in the meta-analyses of GWASs in Caucasian populations. The study subjects comprised 5,470 Japanese individuals (305 subjects with atrial fibrillation and 5,165 controls). Genotypes for 29 polymorphisms were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Comparisons of the allele frequencies by the χ test revealed that rs599839 (→) of the proline/serine-rich coiled-coil 1 gene (PSRC1, P=0.0084) and rs11556924 (→, Arg363His) of the zinc finger, C3HC-type containing 1 gene (ZC3HC1, P=0.0076) were significantly (P<0.01) associated with atrial fibrillation. Multivariable logistic regression analysis with adjustment for age, gender, body mass index, estimated glomerular filtration rate, and the prevalence of smoking, hypertension, diabetes mellitus, and dyslipidemia revealed that rs599839 (P=0.0043; odds ratio, 1.56; dominant model) and rs11556924 (P=0.0043; odds ratio, 1.93; dominant model) were significantly associated with atrial fibrillation, with the minor and alleles, respectively, representing risk factors for this condition. PSRC1 and ZC3HC1 may thus be susceptibility loci for atrial fibrillation in Japanese individuals.

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“…Fujimaki et al (2015) reported that rs12190287 polymorphisms are significantly associated with hypertension in Japanese populations. In the current study, we found that rs12190287 polymorphisms are associated with VSDs in a Chinese population.…”

Section: Association Of Tcf21 Rs12190287 With Vsdmentioning

confidence: 99%

TCF21 rs12190287 Polymorphisms Are Associated with Ventricular Septal Defects in a Chinese Population

Yang

Gao²,

Luo³

et al. 2017

Genetic Testing and Molecular Biomarkers

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Aims: TCF21 knockout mice display cardiac defects, including ventricular septal defects (VSDs). Functional rs12190287 polymorphisms located within the 3¢ untranslated region (3¢-UTR) of TCF21 were associated with a risk of coronary heart disease in the European and Eastern populations. However, whether rs12190287 polymorphisms in the TCF21-3¢UTR confer predisposition to congenital heart disease (CHD) is unclear. Methods: A case-control study was designed consisting of 781 nonsyndromic VSD patients and 867 non-CHD control subjects. The genotype frequency of rs12190287 polymorphisms was determined by real-time polymerase chain reaction. Results: There were significant differences in the genotype and allele frequencies of rs12190287 between the cases and controls in a Chinese population. Allele G of rs12190287 was significantly associated with an increased risk of VSD in a Chinese population.Conclusions: Our results demonstrate that rs12190287 polymorphisms confer predisposition to VSDs in the Chinese population studied here.

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Association of a transcription factor 21 gene polymorphism with hypertension

Cited by 42 publications

References 28 publications

Quantitative trait loci mapped for TCF21 binding, chromatin accessibility and chromosomal looping in coronary artery smooth muscle cells reveal molecular mechanisms of coronary disease loci

Quantitative trait loci mapped for TCF21 binding, chromatin accessibility and chromosomal looping in coronary artery smooth muscle cells reveal molecular mechanisms of coronary disease loci

Association of genetic variants with atrial fibrillation

TCF21 rs12190287 Polymorphisms Are Associated with Ventricular Septal Defects in a Chinese Population

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