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Association between cancer antigen 19-9 and diabetes risk: A prospective and Mendelian randomization study.

ABSTRACT: AIMS/INTRODUCTION:Elevated serum cancer antigen 19-9 (CA19-9) levels have been found in diabetes patients in most observational studies; however, whether there is a causal association between CA19-9 and diabetes mellitus is unclear. MATERIALS AND METHODS:Our study was carried out based on the Dongfeng-Tongji cohort comprising 27,009 individuals. We first investigated the associations between serum CA19-9 levels and incident diabetes mellitus risk in a prospective cohort study (12,700 individuals). Then, we explored the potential causal relationship between CA19-9 and diabetes mellitus risk in a cross-sectional study (3,349 diabetes mellitus patients and 8,341 controls) using Mendelian randomization analysis. A weighted genetic risk score was calculated by adding the CA19-9 increasing alleles in five single-nucleotide polymorphisms (rs17271883, rs3760776 and rs3760775 in FUT6, rs11880333 in CA11, rs265548 in B3GNT3, and rs1047781 in FUT2), which were identified in a previous genome-wide association study on serum CA19-9 levels. RESULTS:In the prospective study, a total of 1,004 incident diabetes mellitus patients were diagnosed during a mean 4.54-year follow-up period. Elevated serum CA19-9 level was associated with a higher incident diabetes risk after adjustment for confounders, with a hazard ratio of 1.20 (95% confidence interval 1.11-1.30) per standard deviation (12.17 U/mL) CA19-9 increase. Using the genetic score to estimate the unconfounded effect, we did not find a causal association of CA19-9 with diabetes risk (odds ratio per weighted CA19-9-increasing allele: 0.99, 95% confidence interval 0.94-1.04; P = 0.61). CONCLUSIONS:The present study did not support a causal association of serum CA19-9 with diabetes risk. CA19-9 might be a potential biomarker of incident diabetes mellitus risk.

SUBMITTER: Li Z

PROVIDER: S-EPMC7232271 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Association between cancer antigen 19-9 and diabetes risk: A prospective and Mendelian randomization study.

Li Zhaoyang Z Wang Jing J Han Xu X Wang Fei F Hu Hua H Yuan Jing J Yao Ping P Wei Sheng S Guo Huan H Zheng Dan D Tang Yuhan Y Yang Handong H He Meian M

Journal of diabetes investigation 20191128 3

<h4>Aims/introduction</h4>Elevated serum cancer antigen 19-9 (CA19-9) levels have been found in diabetes patients in most observational studies; however, whether there is a causal association between CA19-9 and diabetes mellitus is unclear.<h4>Materials and methods</h4>Our study was carried out based on the Dongfeng-Tongji cohort comprising 27,009 individuals. We first investigated the associations between serum CA19-9 levels and incident diabetes mellitus risk in a prospective cohort study (12, ...[more]

PMID: 31661606

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Project description:BackgroundTumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear.MethodsWe meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,162 cancer cases and up to 824,556 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 x 10-8) cis-acting SNPs (i.e. in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value ("q-value") < 0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q-value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH4) > 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes.ResultsWe found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR 1.19, 95% CI 1.10-1.29, q-value=0.033, PPH4=84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR 1.42, 95% CI 1.20-1.69, q-value=0.055, PPH4=73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR 0.66, 95% CI 0.53-0.81, q-value=0.067, PPH4=81.8%), macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR 1.14, 95% CI 1.05-1.23, q-value=0.072, PPH4=76.1%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR 0.92, 95% CI 0.88-0.97, q-value=0.15), PPH4=85.6%). For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥ 0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk.ConclusionOur comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 5 circulating inflammatory markers in risk of 5 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated.

Dataset Information

Association between cancer antigen 19-9 and diabetes risk: A prospective and Mendelian randomization study.

Publications

Association between cancer antigen 19-9 and diabetes risk: A prospective and Mendelian randomization study.

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