title: Mutant DD genotype of NFKB1 gene is associated with the susceptibility and severity of coronary artery disease.
abstract: Nuclear factor κappa B (NF-κB) is an important transcription factor in the development and progression of coronary artery disease (CAD). Recent evidence suggests that -94 ATTG ins/del mutant in the promoter of NFKB1 gene is an essential functional mutant. The present study demonstrated the frequencies of the del/del (DD) genotype and del (D) allele were significantly higher in CAD patients than in controls. CAD patients carrying mutant DD genotype had worse stenosis of diseased coronary arteries compared to those carrying ins/ins (II) or ins/del (ID) genotype. Plasma levels of endothelial nitric oxide synthase (eNOS) were lower, while inflammatory cytokine incnterlukin-6 (IL-6) was higher in CAD patients with DD genotype than those with II or ID genotype (both P<0.05). In vitro study showed that mutant human umbilical vein endothelial cells (DD genotype HUVECs) were more susceptible to H2O2-induced apoptosis, which was accompanied with a decreased Bcl-2 expression. Further, mutant HUVECs had lower eNOS but higher IL-6 mRNA levels and decreased phosphorylation of eNOS under H2O2-stimulation (both P<0.05). Compared to wild type cells (II genotype), significantly downregulated protein expression of total NF-κB p50 subunit were observed in mutant HUVECs with or without oxidative stress, and a lower expression of unclear p50 was associated with a decreased p50 nuclear translocation in mutant HUVECs versus wild type cells under H2O2-stimulation (both P<0.05). In conclusion, mutant DD genotype of NFKB1 gene is associated with the risk and severity of CAD. Dwonregulation of NF-κB p50 subunit leads to exacerbated endothelial dysfunction and apoptosis and enhanced inflammatory response that is the potential underlying mechanism.
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
authors.forename: Jun-Yi
authors.initials: JY
authors.lastname: Luo
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Li
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Xinjiang Key Laboratory of Cardiovascular Research, Urumqi, Xinjiang, China.
authors.forename: Bang-Dang
authors.initials: BD
authors.lastname: Chen
authors.affiliation: Xinjiang Key Laboratory of Cardiovascular Research, Urumqi, Xinjiang, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Liu
authors.affiliation: Xinjiang Key Laboratory of Cardiovascular Research, Urumqi, Xinjiang, China.
authors.forename: Xiao-Cui
authors.initials: XC
authors.lastname: Chen
authors.affiliation: Department of Anaesthesiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China. Electronic address: myt-xj@163.com.
authors.forename: Yi-Tong
authors.initials: YT
authors.lastname: Ma
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, Xinjiang, China; Department of Surgery, Central Clinical School, Monash University, Melbourne, Victoria, Australia. Electronic address: xiaoming.gao@bakeridi.edu.au.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Gao
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China. Electronic address: yangyn5126@163.com.
authors.forename: Yi-Ning
authors.initials: YN
authors.lastname: Yang
mesh_terms: D000368:Aged; D000483:Alleles; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D003324:Coronary Artery Disease / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D052002:NF-kappa B p50 Subunit / Q000235:genetics* / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism; D012306:Risk; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; C489548:NFKB1 protein, human; D006861:Hydrogen Peroxide
keywords: Apoptosis; Coronary artery disease; Human umbilical vein endothelial cell; Inflammation; NFKB1 gene