Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.
Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia; Department of Cardiology, Austin Health, Melbourne, Australia.
EBioMedicine. 2017 Apr;18:171-178. doi: 10.1016/j.ebiom.2017.03.036. Epub 2017 Mar 30.
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.
左心室（LV）肥大（LVH）是 2 型糖尿病中常见的遗传特征，与心力衰竭的发展有关。转录因子 Kruppel 样因子 15（KLF15）在心脏中表达，作为实验模型中心脏肥大的抑制剂。本研究调查了 2 型糖尿病患者中 KLF15 基因变异是否与 LVH 相关。在两阶段方法的第一阶段，前瞻性招募了无已知心脏病的 2 型糖尿病患者进行经胸超声心动图评估（墨尔本糖尿病心脏队列）（n=318），并对两个 KLF15 单核苷酸多态性（SNP）（rs9838915、rs6796325）进行基因分型。在第二阶段，在苏格兰泰赛德糖尿病审计和研究遗传学（Go-DARTS）2 型糖尿病队列（n=5631）中研究了 KLF15 SNP 与 LVH 的关联。KLF15 SNP rs9838915 的 A 等位基因在调整年龄、性别、体重指数（BMI）和高血压后（P=0.003）和调整后的间隔（P<0.0001）和后间隔（P=0.004）壁厚度之前和之后以显性方式与 LV 质量相关。35%的患者存在 LVH。中位随访 5.6 年后，有 22 例（7%）首次心力衰竭住院。与无 LVH 和 GG 基因型的患者相比，LVH 和 rs9838915 A 等位基因的心力衰竭住院风险调整后增加 5.5 倍（危险比（HR）5.5（1.6-18.6），P=0.006）。Go-DARTS 队列中 rs9838915 A 等位基因与 LVH 的关联得到复制。我们已经确定了 KLF15 SNP rs9838915 A 等位基因是 2 型糖尿病患者 LVH 的标志物，并在一个大型独立队列中复制了这些发现。需要进行研究以确定这些结果的功能重要性，并确定 SNP rs9838915 A 等位基因是否与其他高危患者群体中的 LVH 相关。
