Diabetes and cancer risk: A Mendelian randomization study

Abstract

Earlier cohort studies using conventional regression models have consistently shown an increased cancer risk among individuals with type 2 diabetes. However, reverse causality and residual confounding due to common risk factors could exist, and it remains unclear whether diabetes per se contributes to cancer development. Mendelian randomization analyses might clarify the true association between diabetes and cancer risk. We conducted a case–cohort study with 10,536 subcohort subjects and 3,541 newly diagnosed cancer cases derived from 32,949 eligible participants aged 40–69 years within the Japan Public Health Center‐based Prospective Study. With 29 known type 2 diabetes susceptibility variants, we used an inverse variance‐weighted method to estimate hazard ratios for the associations of diabetes with risks of total and site‐specific cancers. The hazard ratios of cancer per doubling of the probability of diabetes were 1.03 (95% confidence interval [CI], 0.92–1.15) overall, 1.08 (95% CI: 0.73–1.59) for the pancreas, 0.80 (95% CI: 0.57–1.14) for the liver and 0.90 (95% CI: 0.74–1.10) for the colorectum. Additional analyses, using publicly available large‐scale genome‐wide association study data on colorectal cancer in Japan, resulted in a narrower CI (hazard ratio: 1.00; 95% CI: 0.93–1.07). In this prospective Mendelian randomization study with a large number of incident cancer cases, we found no strong evidence to support associations between diabetes and overall and site‐specific cancer risks. Our findings suggest that there is little evidence to support the genetic role of type 2 diabetes in cancer development in the Japanese population.

Using genetics to decipher the link between type 2 diabetes and cancer: shared aetiology or downstream consequence?

“…These studies typically use a GRS composed of type 2 diabetes predisposing genetic variants weighted according to their effect on type 2 diabetes risk. These studies are in agreement in that they find no evidence for an association between the two diseases [51][52][53][54][55], consistent with the lack of evidence from studies assessing the association of single type 2 diabetes predisposing genetic variants and cancer.…”

Is Type 2 Diabetes Causally Associated With Cancer Risk? Evidence From a Two-Sample Mendelian Randomization Study

“…However, our findings were in line with a recent individual-level MR study with 10,536 Japanese adults (3,541 cancer cases). Using 29 SNPs as instrumental variables for T2DM, that study found no strong evidence supporting an association between T2DM and overall cancer (42). The discrepancy with our overall cancer findings may be explained by the driver effects of the T2DM-unrelated cancers that contributed a large proportion of cancer cases, including breast cancer (18%), prostate cancer (10%), and colorectal cancer (7%), in the present MR study, or from residual confounding or reverse causation bias in the observational studies.…”

“…Nevertheless, a recent MR study did not observe a positive association between diabetes and pancreatic cancer among Japanese adults. This null finding might be caused by inadequate power, since the study only had 129 pancreatic cancer cases (42).…”

Obstructive sleep apnea syndrome and causal relationship with female breast cancer: a mendelian randomization study

“…Mendelian randomization (MR), using genetic variants as an instrument variable (IV) for the exposure to estimate causal effects of modifiable risk factors on disease outcomes, could overcome the limitations of the AGING observational studies [25]. It have successfully adopted in a wide spectrum of diseases, including cancers, cardiovascular diseases, diabetes, and so on [16,[26][27][28][29][30][31][32][33][34]. In current study, we aims to performed a twosample MR analysis to examine the causal effect of OSAS and etiology of BC.…”