中国 2 型糖尿病患者 2 型糖尿病和新发癌症的遗传变异。

Genetic variants for type 2 diabetes and new-onset cancer in Chinese with type 2 diabetes.

机构信息

Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong; Hong Kong Institute of Diabetes and Obesity, Chinese University of Hong Kong, Hong Kong; Lee Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong.

Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong.

出版信息

Diabetes Res Clin Pract. 2014 Feb;103(2):328-37. doi: 10.1016/j.diabres.2013.12.016. Epub 2013 Dec 27.

DOI:10.1016/j.diabres.2013.12.016

PMID:24468095

Abstract

BACKGROUND

Diabetes is associated with an increased risk of cancer. This study aimed to evaluate associations between recently reported type 2 diabetes (T2D) susceptibility genetic variants and cancer risk in a prospective cohort of Chinese patients with T2D.

METHODS

Seven single nucleotide polymorphisms (SNP) in IGF2BP2, CDKAL1, SLC30A8, CDKN2A/B, HHEX and TCF7L2, all identified from genome-wide association studies of T2D, were genotyped in 5900 T2D patients [age mean ± SD = 57 ± 13 years, % males = 46] without any known cancer at baseline. Associations between new-onset of cancer and SNPs were tested by Cox proportional hazard models with adjustment of conventional risk factors.

RESULTS

During the mean follow-up period of 8.5 ± 3.3 years, 429 patients (7.3%) developed cancer. Of the T2D-related SNPs, the G-alleles of HHEX rs7923837 (hazard ratio [HR] (95% C.I.) = 1.34 (1.08-1.65); P = 6.7 ×10(-3) under dominant model) and TCF7L2 rs290481 (HR (95% C.I.) = 1.16 (1.01-1.33); P = 0.040 under additive model) were positively associated with cancer risk, while the G-allele of CDKAL1 rs7756992 was inversely associated (HR (95% C.I.) = 0.80 (0.65-1.00); P = 0.048 under recessive model). The risk alleles of these significant SNPs exhibited combined effect on increasing cancer risk (per-allele HR (95% C.I.) = 1.25 (1.12-1.39); P = 4.8 × 10(-5)). The adjusted cancer risk was 2.41 (95% C.I. 1.23-4.69) for patients with four risk alleles comparing to patients without risk allele.

CONCLUSIONS

T2D-related variants HHEX rs7923837, TCF7L2 rs290481 and CDKAL1 rs7756992 increased cancer risk in patients with diabetes.

IMPACT

Our findings provide novel insights into the pathogenesis of cancer in diabetes.

摘要

背景

糖尿病与癌症风险增加有关。本研究旨在评估在中国 2 型糖尿病患者前瞻性队列中，最近报道的 2 型糖尿病（T2D）易感性遗传变异与癌症风险之间的关系。

方法

在 5900 名无任何已知癌症的基线 T2D 患者（年龄平均±标准差=57±13 岁，男性百分比=46%）中，对 IGF2BP2、CDKAL1、SLC30A8、CDKN2A/B、HHEX 和 TCF7L2 中所有与全基因组关联研究发现的 7 个单核苷酸多态性（SNP）进行基因分型。通过 Cox 比例风险模型，对新发病例癌症与 SNP 之间的相关性进行调整，以调整传统危险因素。

结果

在平均 8.5±3.3 年的随访期间，429 名患者（7.3%）发生癌症。在与 T2D 相关的 SNP 中，HHEX rs7923837 的 G 等位基因（危险比[HR]（95%CI.）=1.34（1.08-1.65）；P=6.7×10(-3)，显性模型）和 TCF7L2 rs290481 的 G 等位基因（HR（95%CI.）=1.16（1.01-1.33）；P=0.040，加性模型）与癌症风险呈正相关，而 CDKAL1 rs7756992 的 G 等位基因则呈负相关（HR（95%CI.）=0.80（0.65-1.00）；P=0.048，隐性模型）。这些显著 SNP 的风险等位基因表现出对增加癌症风险的综合影响（每个等位基因 HR（95%CI.）=1.25（1.12-1.39）；P=4.8×10(-5)）。与无风险等位基因的患者相比，携带 4 个风险等位基因的患者调整后的癌症风险为 2.41（95%CI.1.23-4.69）。