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)

Research output: Contribution to journalArticle

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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 languageEnglish
Pages (from-to)171-178
Number of pages8
JournalEBioMedicine
Volume18
Early online date30 Mar 2017
DOIs
Publication statusPublished - Apr 2017

Fingerprint

Kruppel-Like Transcription Factors
Left Ventricular Hypertrophy
Medical problems
Type 2 Diabetes Mellitus
Hypertrophy
Polymorphism
Single Nucleotide Polymorphism
Nucleotides
Alleles
Heart Failure
Hospitalization
Cardiomegaly
Scotland
Genes
Heart Diseases
Theoretical Models
Genotype
Hypertension

Keywords

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

Cite this

Patel, Sheila K. ; Wai, Bryan ; Lang, Chim C. ; Levin, Daniel ; Palmer, Colin N. A. ; Parry, Helen M. ; Velkoska, Elena ; Harrap, Stephen B. ; Srivastava, Piyush M. ; Burrell, Louise M. / Genetic variation in Kruppel like factor 15 is associated with left ventricular hypertrophy in patients with type 2 diabetes : discovery and replication cohorts . In: EBioMedicine. 2017 ; Vol. 18. pp. 171-178.
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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.",
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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); Levin, Daniel; Palmer, Colin N. A.; Parry, Helen M.; Velkoska, Elena; Harrap, Stephen B.; Srivastava, Piyush M.; Burrell, Louise M. (Lead / Corresponding author).

In: EBioMedicine, Vol. 18, 04.2017, p. 171-178.

Research output: Contribution to journalArticle

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

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DO - 10.1016/j.ebiom.2017.03.036

M3 - Article

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SP - 171

EP - 178

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

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