Genetic variation in Kruppel like factor 15 is associated with left ventricular hypertrophy in patients with type 2 diabetes: discovery and replication cohorts

Sheila K. Patel; Bryan Wai; Chim C. Lang; Daniel Levin; Colin N. A. Palmer; Helen M. Parry; Elena Velkoska; Stephen B. Harrap; Piyush M. Srivastava; Louise M. Burrell

doi:10.1016/j.ebiom.2017.03.036

Genetic variation in Kruppel like factor 15 is associated with left ventricular hypertrophy in patients with type 2 diabetes: discovery and replication cohorts

Sheila K. Patel (Lead / Corresponding author), Bryan Wai, Chim C. Lang (Lead / Corresponding author), Daniel Levin, Colin N. A. Palmer, Helen M. Parry, Elena Velkoska, Stephen B. Harrap, Piyush M. Srivastava, Louise M. Burrell (Lead / Corresponding author)

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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=5,631). 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, 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 5·6 years, 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 (HR 5·5 (1·6- 18·6), P=0·006). The association of rs9838915 A allele with LVH was replicated in the GoDARTS 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.

Original language	English
Pages (from-to)	171-178
Number of pages	8
Journal	EBioMedicine
Volume	18
Early online date	30 Mar 2017
DOIs	https://doi.org/10.1016/j.ebiom.2017.03.036
Publication status	Published - Apr 2017

Keywords

Kruppel like factor 15
Left ventricular hypertrophy
Type 2 diabetes
Genetic association study
Echocardiogram
Heart Failure

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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© 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Final published version, 66.2 KBLicence: CC BY

REnal and Cardiovascular Effects of SGLT2 Inhibition in Combination with Loop DiurEtics in Diabetic Patients with Chronic Heart Failure (RECEDE-CHF)
Lang, C. (Investigator), McCrimmon, R. (Investigator), Mordi, I. (Investigator), Singh, J. (Investigator) & Struthers, A. (Investigator)
British Heart Foundation
29/07/16 → 28/01/19
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Health Informatics Centre
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Patel, S. K., Wai, B., Lang, C. C., Levin, D., Palmer, C. N. A., Parry, H. M., Velkoska, E., Harrap, S. B., Srivastava, P. M., & Burrell, L. M. (2017). Genetic variation in Kruppel like factor 15 is associated with left ventricular hypertrophy in patients with type 2 diabetes: discovery and replication cohorts . EBioMedicine, 18, 171-178. https://doi.org/10.1016/j.ebiom.2017.03.036

@article{0b6638f26af54c5cb8b49189e5bad699,

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=5,631). 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, 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 5·6 years, 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 (HR 5·5 (1·6- 18·6), P=0·006). The association of rs9838915 A allele with LVH was replicated in the GoDARTS 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.",

keywords = "Kruppel like factor 15, Left ventricular hypertrophy, Type 2 diabetes, Genetic association study, Echocardiogram, Heart Failure",

author = "Patel, {Sheila K.} and Bryan Wai and Lang, {Chim C.} and Daniel Levin and Palmer, {Colin N. A.} and Parry, {Helen M.} and Elena Velkoska and Harrap, {Stephen B.} and Srivastava, {Piyush M.} and Burrell, {Louise M.}",

note = "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].",

year = "2017",

month = apr,

doi = "10.1016/j.ebiom.2017.03.036",

language = "English",

volume = "18",

pages = "171--178",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier",

}

Genetic variation in Kruppel like factor 15 is associated with left ventricular hypertrophy in patients with type 2 diabetes: discovery and replication cohorts . / Patel, Sheila K. (Lead / Corresponding author); Wai, Bryan; Lang, Chim C. (Lead / Corresponding author) et al.
In: EBioMedicine, Vol. 18, 04.2017, p. 171-178.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Genetic variation in Kruppel like factor 15 is associated with left ventricular hypertrophy in patients with type 2 diabetes

T2 - discovery and replication cohorts

AU - Patel, Sheila K.

AU - Wai, Bryan

AU - Lang, Chim C.

AU - Levin, Daniel

AU - Palmer, Colin N. A.

AU - Parry, Helen M.

AU - Velkoska, Elena

AU - Harrap, Stephen B.

AU - Srivastava, Piyush M.

AU - Burrell, Louise M.

N1 - 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].

PY - 2017/4

Y1 - 2017/4

N2 - 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=5,631). 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, 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 5·6 years, 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 (HR 5·5 (1·6- 18·6), P=0·006). The association of rs9838915 A allele with LVH was replicated in the GoDARTS 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.

AB - 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=5,631). 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, 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 5·6 years, 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 (HR 5·5 (1·6- 18·6), P=0·006). The association of rs9838915 A allele with LVH was replicated in the GoDARTS 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.

KW - Kruppel like factor 15

KW - Left ventricular hypertrophy

KW - Type 2 diabetes

KW - Genetic association study

KW - Echocardiogram

KW - Heart Failure

U2 - 10.1016/j.ebiom.2017.03.036

DO - 10.1016/j.ebiom.2017.03.036

M3 - Article

C2 - 28400202

SN - 2352-3964

VL - 18

SP - 171

EP - 178

JO - EBioMedicine

JF - EBioMedicine

ER -

Genetic variation in Kruppel like factor 15 is associated with left ventricular hypertrophy in patients with type 2 diabetes: discovery and replication cohorts

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Projects

REnal and Cardiovascular Effects of SGLT2 Inhibition in Combination with Loop DiurEtics in Diabetic Patients with Chronic Heart Failure (RECEDE-CHF)

Equipment

Health Informatics Centre

Cite this