ABSTRACT
BackgroundLynch syndrome (LS) is an inherited cancer predisposition syndrome caused by genetic variants affecting DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 Cancer risk in LS is estimated from cohorts of individuals ascertained by individual or family history of cancer, which may upwardly bias estimates. METHODS: 830 carriers of pathogenic or likely pathogenic (path_MMR) MMR gene variants classified by InSiGHT were identified in 454 756 UK Biobank (UKB) participants using whole-exome sequence. Nelson-Aalen survival analysis was used to estimate cumulative incidence of colorectal, endometrial and breast cancer (BC). RESULTS: Cumulative incidence of colorectal and endometrial cancer (EC) by age 70 years was elevated in path_MMR carriers compared with non-carriers (colorectal: 11.8% (95% confidence interval (CI): 9.5% to 14.6%) vs 1.7% (95% CI: 1.6% to 1.7%), endometrial: 13.4% (95% CI: 10.2% to 17.6%) vs 1.0% (95% CI: 0.9% to 1.0%)), but the magnitude of this increase differed between genes. Cumulative BC incidence by age 70 years was not elevated in path_MMR carriers compared with non-carriers (8.9% (95% CI: 6.3% to 12.4%) vs 7.5% (95% CI: 7.4% to 7.6%)). Cumulative cancer incidence estimates in UKB were similar to estimates from the Prospective Lynch Syndrome Database for all genes and cancers, except there was no evidence for elevated EC risk in carriers of pathogenic PMS2 variants in UKB. CONCLUSION: These results support offering incidentally identified carriers of any path_MMR surveillance to manage colorectal cancer risk. Incidentally identified carriers of pathogenic variants in MLH1, MSH2 and MSH6 would also benefit from interventions to reduce EC risk. The results suggest that BC is not an LS-related cancer.
ABSTRACT
AIMS: Association between whole blood viscosity (WBV) and an increased risk of cardiovascular disease (CVD) has been reported. However, the causal relationship between WBV and CVD remains not thoroughly investigated. The aim of this study was to investigate the causal relation between WBV and CVD. METHODS: Two-sample Mendelian randomization (MR) was employed, with inverse variance weighting (IVW) as the primary method, to investigate the casual relationship between WBV and CVD. The calculated WBV and medical records of 378,210 individuals participating in the UK Biobank study were divided into halves and analyzed. RESULTS: The means of calculated WBVs were 16.9 (standard deviation: 0.8) and 55.1 (standard deviation: 17.2) for high shear rate (HSR) and low shear rate (LSR), respectively. 37,859 (10.0%) major cardiovascular events (MACE) consisted of 23,894 (6.3%) cases of myocardial infarction (MI), 9,245 (2.4%) cases of ischemic stroke, 10,377 (2.7%) cases of revascularization, and 5,703 (1.5%) cases of coronary heart disease-related death. In the MR analysis, no evidence was found indicating a causal effect of WBV on MACE (IVW p-value for HSR = 0.81, IVW p-value for LSR = 0.47), MI (0.92, 0.83), ischemic stroke (0.52, 0.74), revascularization (0.71, 0.54), and coronary heart disease-related death (0.83, 0.70). The lack of sufficient evidence for causality persisted in other MR methods, including weighted median and MR-egger. CONCLUSIONS: The Mendelian randomization analysis conducted in this study does not support a causal relationship between calculated WBV and CVD.