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.
Highlights
Left ventricular (LV) hypertrophy (LVH) is a heritable trait associated with adverse cardiovascular outcomes including heart failure (Levy et al, 1990; de Simone et al, 2002) which is prevalent in type 2 diabetes (Shah et al, 2015)
A key finding in the discovery cohort was that the A allele at rs9838915 single nucleotide polymorphisms (SNPs) in the Kruppel like factor 15 (KLF15) gene was associated with increased LV mass in patients with type 2 diabetes
We replicated the association of the KLF15 SNP rs9838915 A allele with LVH in a large, independent cohort of patients with type 2 diabetes, the Go-Diabetes Audit and Research in Tayside (DARTS) cohort (n = 5631)
Summary
Left ventricular (LV) hypertrophy (LVH) is a heritable trait associated with adverse cardiovascular outcomes including heart failure (Levy et al, 1990; de Simone et al, 2002) which is prevalent in type 2 diabetes (Shah et al, 2015). S.K. Patel et al / EBioMedicine 18 (2017) 171–178 postnatally and down regulated in response to pressure overload and hypertrophic stimuli (Fisch et al, 2007; Haldar et al, 2010). KLF15 null mice develop cardiac hypertrophy and heart failure in response to pressure overload, whilst overexpression of KLF15 reduces cell size (Fisch et al, 2007) and prevents the development of angiotensin II induced hypertrophy (Leenders et al, 2012). In neonatal rat ventricular fibroblasts, transforming growth factor-β1 (TGFβ1) reduced KLF15 expression and induced expression of connective tissue growth factor (CTGF), which is a key mediator of fibrosis (Candido et al, 2003); overexpression of KLF15 decreased both TGFβ1 and CTGF gene expression (Yu et al, 2015)
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