title: Genetic predisposition to left ventricular dysfunction: a multigenic and multi-analytical approach.
abstract: BACKGROUND
  Left ventricular dysfunction (LVD) is a complex, multifactorial condition, caused by mechanical, neurohormonal, and genetic factors. We have previously observed association of renin-angiotensin-aldosterone system (RAAS), matrix metalloproteinases (MMPs) and inflammatory pathway genes with LVD. Therefore the present study was undertaken to identify the combination of genetic variants and their possible interactions contributing towards genetic susceptibility to LVD in the background of coronary artery disease (CAD).
  
  
  RESULTS
  The study included 230 healthy controls and 510 consecutive patients with angiographically confirmed CAD. Among them, 162 with reduced left ventricle ejection fraction (LVEF≤45%) were categorized as having LVD. We analyzed 11 polymorphisms of RAAS, MMPs and inflammatory pathways. Single locus analysis showed that AT1 A1166C (p value<0.001; OR=3.67), MMP9 R668Q (p value=0.007; OR=3.48) and NFKB1-94 ATTG ins/del (p value=0.013; OR=2.01) polymorphisms were independently associated with LVD when compared with both non-LVD patients and healthy controls. High-order gene-gene interaction analysis, using classification and regression tree (CART) and multifactor dimensionality reduction (MDR) revealed that AT1 A1166C and NFKB1-94 ATTG ins/del polymorphisms jointly increased the risk of LVD to great extent (p-value=0.001; OR=8.55) and best four-factor interaction model consisted of AT1 A1166C, MMP7 A-181G, MMP9 R668Q and NFKB1-94 ATTG ins/del polymorphisms with testing accuracy of 0.566 and cross validation consistency (CVC)=9/10 (permutation p<0.001) showed increased risk for LVD respectively.
  
  
  CONCLUSIONS
  AT1 A1166C independently and in combination with MMP9 R668Q and NFKB1-94 ATTG ins/del polymorphisms plays important role in conferring genetic susceptibility to LVD in CAD patients.
authors.affiliation: Department of Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014, UP, India.
authors.forename: Avshesh
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Department of Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014, UP, India.
authors.forename: Anshika
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: Department of Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014, UP, India.
authors.forename: Tulika
authors.initials: T
authors.lastname: Mittal
authors.affiliation: Department of Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014, UP, India.
authors.forename: Naveen
authors.initials: N
authors.lastname: Garg
authors.affiliation: Department of Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014, UP, India. Electronic address: balraj@sgpgi.ac.in.
authors.forename: Balraj
authors.initials: B
authors.lastname: Mittal
mesh_terms: D000368:Aged; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D008875:Middle Aged; D052002:NF-kappa B p50 Subunit / Q000235:genetics*; D011110:Polymorphism, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000235:genetics*
chemical_list: C544065:AGTR1 protein, human; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D044140:Receptor, Angiotensin, Type 1; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Genetic predisposition; Higher order gene–gene interaction; LVD; Left ventricular ejection fraction (LVEF); MDR