Premium
Diabetes mellitus, genetic variants in the insulin‐like growth factor pathway and colorectal cancer risk
Author(s) -
de Kort Sander,
Simons Colinda C.J.M.,
van den Brandt Piet A.,
JanssenHeijnen Maryska L.G.,
Sanduleanu Silvia,
Masclee Ad A.M.,
Weijenberg Matty P.
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32365
Subject(s) - medicine , hazard ratio , single nucleotide polymorphism , type 2 diabetes mellitus , colorectal cancer , proportional hazards model , cohort , oncology , insulin like growth factor , risk factor , allele , type 2 diabetes , diabetes mellitus , cohort study , endocrinology , cancer , genotype , genetics , growth factor , biology , confidence interval , gene , receptor
Genetic variation in the insulin‐like growth factor (IGF) pathway may further increase the risk of colorectal cancer (CRC) associated with type 2 diabetes mellitus (T2DM). Joint effects of T2DM and genetic variation in the IGF pathway on CRC risk can increase mechanistic insights. Participants from the Netherlands Cohort Study ( n = 120, 852) completed a baseline questionnaire in 1986 when 55–69 years old (case–cohort, n subcohort = 5,000, n cases = 3,441 after 16.3 years follow‐up). Self‐reported DM at baseline with onset at ≥30 years was classified as T2DM. Eighteen single nucleotide polymorphisms (SNPs) from the IGF pathway were aggregated in a genetic risk score (GRS). Cox proportional hazard ratios (HRs) for CRC were estimated according to combinations of T2DM status with GRS tertiles and categories of an IGF1 19‐CA repeat polymorphism. Baseline T2DM prevalence was 3.1% in subcohort members and 3.8% in CRC cases. Comparison of combined categories with non‐T2DM individuals in the lowest GRS tertile as reference showed that those in the highest GRS tertiles with and without T2DM had significantly increased CRC risks, particularly those with T2DM (HR = 2.28, 95% CI: 1.11, 4.66). As compared to IGF1 19‐CA wild‐type carriers without T2DM, carrying two IGF1 19‐CA variant repeat alleles were associated with a significantly decreased CRC risk in those without T2DM (HR = 0.76, 95% CI: 0.63–0.91). This association was absent when T2DM was present. Our study of joint effects indicated that the presence of unfavorable alleles in the IGF pathway may further increase the risk of CRC associated with T2DM.