It is unknown how rs SNP located in intron

It is unknown how rs9838915 SNP located in intron 2 influences LV mass. KLF15 is expressed in cardiomyocytes and acts as a repressor of pathological cardiac hypertrophy (Wang et al., 2008; Fisch et al., 2007; Haldar et al., 2010; Leenders et al., 2012) through inhibition of the cardiac transcriptional factors GATA4 and MEF2 (Fisch et al., 2007). One possibility is that genetic variation disrupts the ability of KLF15 to repress hypertrophic transcriptional factors, leading to increased expression of these genes and thus cardiac hypertrophy. KLF15 is also a transcriptional inhibitor of cardiac fibrosis (Wang et al., 2008), which is a key feature of diabetic heart disease (Rubler et al., 1972). It is also possible that the observed genetic variation in KLF15 could lead to increased cardiac fibrosis which would in turn contribute to increased LV mass and myocardial stiffness. Further studies are required to determine whether the association we observe is due to SNP rs9838915 or a neighboring SNP that may be in strong linkage disequilibrium with rs9838915. We performed a bioinformatics analysis to identify putative causal variants underlying the association of the KLF15 SNP rs9838915 with LVH. We explored the co-localisation of the association signal with features indicative of functional genomic elements, including evidence of transcription factor binding, DNase hypersensitivity and histone modification marks. An analysis of the RegulomeDB suggests that SNP rs9838915 is located in a transcription factor binding site and an enhancer element. These functional elements were identified in human LV tissue. We used the SNAP tool (http://www.broadinstitute.org/mpg/snap) by the Broad Institute to identify SNPs that were in LD (r2>0.8) with SNP rs9838915. We identified a SNP located 635bp upstream of rs9838915 that was highly correlated (r2=1.0) and located within an enhancer mg115 identified in human LV, right atrium and ventricle tissue.
Strengths and Limitations We conducted a clinical study investigating the association of KLF15 with echocardiographically determined LV mass in patients at high risk of LVH due to type 2 diabetes. Our finding in the discovery cohort Nick translation the rs9838915 SNP A allele in the KLF15 gene was associated with increased LV mass in type 2 diabetes was replicated in a large, independent cohort. Several limitations deserve comment. The results are restricted to patients with type 2 diabetes of Caucasian ethnicity, and future studies should examine patients without diabetes as well as patients of different ethnic backgrounds. Functional studies were not performed but are required to determine the exact mechanisms by which genetic variation in KLF15 influences LV mass.
Conclusions We identified a gene variant, the rs9838915 SNP in the KLF15 gene that is relevant to increased LV mass in 318 patients with type 2 diabetes, and validated these findings in a large independent cohort of >5000 individuals with type 2 diabetes. Studies are now needed to characterize the functional importance of these results, to understand the biological mechanisms involved, and to determine if the KLF15 SNP rs9838915 A allele is associated with LVH in patients without diabetes.
Funding The work in the Melbourne Diabetes Heart Cohort was supported by a Diabetes Australia Research Program grant [grant number Y12G-PATS] to [S.K.P]; a Career Development Award, University of Melbourne [S.K.P]; National Heart Foundation of Australia [grant number G12M6368] to [L.M.B]; National Health and Medical Research Council of Australia/National Heart Foundation scholarship to [B.W]. The Go-DARTS study was supported by the following: genotyping was facilitated by capital funding from the Scottish Government Chief Scientist Office Generation Scotland initiative (www.generationscotland.org); The Wellcome Trust U.K. type 2 diabetes case control collection (GoDARTS2) was funded by a Wellcome Trust [grant number GR02960] and the GWAS genotyping was performed as part of the Wellcome Trust Case Control Consortium 2 [084726/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z]. Our funders had no role in the study design, data collection, data analysis, interpretation or in writing the manuscript.