Genetic variants for type 2 diabetes and new-onset cancer in Chinese with type 2 diabetes R.C.W. Ma a,b,c, *, W.Y. So a, **, C.H.T. Tam a , A.O. Luk a , J.S.K. Ho a , Y. Wang a , V.K. Lam a , H.M. Lee a , A.P. Kong a , P.C. Tong a , G. Xu a,b,c , C.C. Chow a , M.C. Ng a,1 , X.L. Yang a , J.C. Chan a,b,c a Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong b Hong Kong Institute of Diabetes and Obesity, Chinese University of Hong Kong, Hong Kong c Lee Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong d i a b e t e s r e s e a r c h a n d c l i n i c a l p r a c t i c e 1 0 3 ( 2 0 1 4 ) 3 2 8 – 3 3 7 a r t i c l e i n f o Article history: Received 11 July 2013 Received in revised form 24 October 2013 Accepted 18 December 2013 Available online 27 December 2013 Keywords: Type 2 diabetes Cancer Genetics Cancer prediction Epidemiology a b s t r a c t 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. # 2013 Elsevier Ireland Ltd. All rights reserved. * Corresponding author at: Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong. Tel.: +852 26323307; fax: +852 26373852. ** Corresponding author. Tel.: +852 26323129; fax: +852 26373852. E-mail addresses: rcwma@cuhk.edu.hk (R.C.W. Ma), wingyeeso@cuhk.edu.hk (W.Y. So). 1 Present address: Department of Pediatrics, Section on Medical Genetics, Centers for Diabetes Research and Human Genomics, Wake Forest University School of Medicine, USA. Contents available at ScienceDirect Diabetes Research and Clinical Practice journal homepage: www.elsevier.com/locate/diabres 0168-8227/$ – see front matter # 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.diabres.2013.12.016