title: Genetic Variation in Kruppel like Factor 15 Is Associated with Left Ventricular Hypertrophy in Patients with Type 2 Diabetes: Discovery and Replication Cohorts.
abstract: Left ventricular (LV) hypertrophy (LVH) is a heritable trait that is common in type 2 diabetes and is associated with the development of heart failure. The transcriptional factor Kruppel like factor 15 (KLF15) is expressed in the heart and acts as a repressor of cardiac hypertrophy in experimental models. This study investigated if KLF15 gene variants were associated with LVH in type 2 diabetes. In stage 1 of a 2-stage approach, patients with type 2 diabetes and no known cardiac disease were prospectively recruited for a transthoracic echocardiographic assessment (Melbourne Diabetes Heart Cohort) (n=318) and genotyping of two KLF15 single nucleotide polymorphisms (SNPs) (rs9838915, rs6796325). In stage 2, the association of KLF15 SNPs with LVH was investigated in the Genetics of Diabetes Audit and Research in Tayside Scotland (Go-DARTS) type 2 diabetes cohort (n=5631). The KLF15 SNP rs9838915 A allele was associated in a dominant manner with LV mass before (P=0.003) and after (P=0.001) adjustment for age, gender, body mass index (BMI) and hypertension, and with adjusted septal (P<0.0001) and posterior (P=0.004) wall thickness. LVH was present in 35% of patients. Over a median follow up of 5.6years, there were 22 (7%) first heart failure hospitalizations. The adjusted risk of heart failure hospitalization was 5.5-fold greater in those with LVH and the rs9838915 A allele compared to those without LVH and the GG genotype (hazard ratio (HR) 5.5 (1.6-18.6), P=0.006). The association of rs9838915 A allele with LVH was replicated in the Go-DARTS cohort. We have identified the KLF15 SNP rs9838915 A allele as a marker of LVH in patients with type 2 diabetes, and replicated these findings in a large independent cohort. Studies are needed to characterize the functional importance of these results, and to determine if the SNP rs9838915 A allele is associated with LVH in other high risk patient cohorts.
authors.affiliation: Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia. Electronic address: skpatel@unimelb.edu.au.
authors.forename: Sheila K
authors.initials: SK
authors.lastname: Patel
authors.affiliation: Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia; Department of Cardiology, Austin Health, Melbourne, Australia.
authors.forename: Bryan
authors.initials: B
authors.lastname: Wai
authors.affiliation: Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. Electronic address: c.c.lang@dundee.ac.uk.
authors.forename: Chim C
authors.initials: CC
authors.lastname: Lang
authors.affiliation: Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levin
authors.affiliation: Pat McPherson Centre for Pharmacogenomics and Pharmacogenetics, Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
authors.forename: Colin N A
authors.initials: CNA
authors.lastname: Palmer
authors.affiliation: Pat McPherson Centre for Pharmacogenomics and Pharmacogenetics, Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Parry
authors.affiliation: Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.
authors.forename: Elena
authors.initials: E
authors.lastname: Velkoska
authors.affiliation: Department of Physiology, University of Melbourne, Victoria, Australia.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Harrap
authors.affiliation: Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia; Department of Cardiology, Austin Health, Melbourne, Australia.
authors.forename: Piyush M
authors.initials: PM
authors.lastname: Srivastava
authors.affiliation: Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia; Department of Cardiology, Austin Health, Melbourne, Australia. Electronic address: l.burrell@unimelb.edu.au.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Burrell
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000473:pathology*; D004452:Echocardiography; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000150:complications / Q000235:genetics / Q000473:pathology*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012307:Risk Factors
chemical_list: C414172:KLF15 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins
keywords: Echocardiogram; Genetic association study; Heart failure; Kruppel like factor 15; Left ventricular hypertrophy; Type 2 diabetes