Investigation of Causal Effect of Type 2 Diabetes Mellitus on Lung Cancer: A Mendelian Randomization Study.
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ABSTRACT: Background
Although several observational studies have attempted to investigate the association between type 2 diabetes mellitus (T2DM) and lung cancer risk, the results are controversial. Here, we intend to examine whether there is a causal association between T2DM and lung cancer risk.Materials and methods
We conducted a Mendelian randomization (MR) study to systematically investigate the effect of T2DM on lung cancer among 13,327 cases and 13,328 controls. A weighted genetic risk score (wGRS) was constructed as a proxy instrument by using 82 previously reported T2DM-related single nucleotide polymorphisms (SNPs). The logistic regression model was utilized to estimate associations of T2DM-related SNPs and wGRS with lung cancer risk. Sensitivity analyses were also performed to assess the robustness of the observed associations.Results
We found no evidence for a causal relationship between T2DM and lung cancer risk (odds ratio, OR = 0.96, 95% confidence interval: 0.91-1.01, p = 0.96), and the association did not vary among populations of different age, sex, smoking status, and histological type. Sensitivity analyses (e.g., MR-Egger test) suggest that pleiotropic effects did not bias the result.Conclusion
In this MR study with a large number of lung cancer cases, we found no evidence to support the causal role of T2DM in lung cancer risk. Further large-scale prospective studies are warranted to replicate our findings.
SUBMITTER: Hong T
PROVIDER: S-EPMC8439278 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeType 1 diabetes mellitus (T1DM) is associated with different types of infections; however, studies on the causal relationship between T1DM and infectious diseases are lacking. Therefore, our study aimed to explore the causalities between T1DM and six high-frequency infections using a Mendelian randomization (MR) approach.MethodsTwo-sample MR studies were conducted to explore the causalities between T1DM and six high-frequency infections: sepsis, acute lower respiratory infections (ALRIs), intestinal infections (IIs), infections of the genitourinary tract (GUTIs) in pregnancy, infections of the skin and subcutaneous tissues (SSTIs), and urinary tract infections (UTIs). Data on summary statistics for T1DM and infections were obtained from the European Bioinformatics Institute database, the United Kingdom Biobank, FinnGen biobank, and Medical Research Council Integrative Epidemiology Unit. All data obtained for summary statistics were from European countries. The inverse-variance weighted (IVW) method was employed as the main analysis. Considering the multiple comparisons, statistical significance was set at p< 0.008. If univariate MR analyses found a significant causal association, multivariable MR (MVMR) analyses were performed to adjust body mass index (BMI) and glycated hemoglobin (HbA1c). MVMR-IVW was performed as the primary analysis, and the least absolute shrinkage and selection operator (LASSO) regression and MVMR-Robust were performed as complementary analyses.ResultsMR analysis showed that susceptibility to IIs increased in patients with T1DM by 6.09% using the IVW-fixed method [odds ratio (OR)=1.0609; 95% confidence interval (CI): 1.0281-1.0947, p=0.0002]. Results were still significant after multiple testing. Sensitivity analyses did not show any significant horizontal pleiotropy or heterogeneity. After adjusting for BMI and HbA1c, MVMR-IVW (OR=1.0942; 95% CI: 1.0666-1.1224, p<0.0001) showed significant outcomes that were consistent with those of LASSO regression and MVMR-Robust. However, no significant causal relationship was found between T1DM and sepsis susceptibility, ALRI susceptibility, GUTI susceptibility in pregnancy, SSTI susceptibility, and UTI susceptibility.ConclusionsOur MR analysis genetically predicted increased susceptibility to IIs in T1DM. However, no causality between T1DM and sepsis, ALRIs, GUTIs in pregnancy, SSTIs, or UTIs was found. Larger epidemiological and metagenomic studies are required to further investigate the observed associations between the susceptibility of certain infectious diseases with T1DM.
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