Impact of glycemic traits, type 2 diabetes and metformin use on breast and prostate cancer risk: a Mendelian randomization study.

Publisher: Published by BMJ in partnership with the American Diabetes Association Country of Publication: England NLM ID: 101641391 Publication Model: eCollection Cited Medium: Internet ISSN: 2052-4897 (Electronic) Linking ISSN: 20524897 NLM ISO Abbreviation: BMJ Open Diabetes Res Care Subsets: MEDLINE

Original Publication: London : Published by BMJ in partnership with the American Diabetes Association

Mendelian Randomization Analysis* ; Polymorphism, Single Nucleotide*; Breast Neoplasms/*etiology ; Diabetes Mellitus, Type 2/*complications ; Glucose Intolerance/*genetics ; Metformin/*adverse effects ; Prostatic Neoplasms/*etiology; Biomarkers/analysis ; Blood Glucose/analysis ; Breast Neoplasms/pathology ; Case-Control Studies ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/pathology ; Ethnicity/genetics ; Female ; Follow-Up Studies ; Genome-Wide Association Study ; Glycated Hemoglobin/analysis ; Humans ; Hypoglycemic Agents/adverse effects ; Male ; Middle Aged ; Phenotype ; Prognosis ; Prostatic Neoplasms/pathology ; Risk Factors

Objectives: Observational studies suggest glycemic traits and type 2 diabetes are positively associated, and metformin inversely associated with breast and prostate cancer risk. However, observational studies are susceptible to unmeasured confounding while studies of metformin use are also vulnerable to immortal time bias. The use of Mendelian randomization may reduce confounding due to random allocation of relevant genetic markers at birth, and may reduce immortal time bias (for metformin-related variants analysis) since the start of exposure is at birth.
Research Design and Methods: We identified strong genetic predictors of fasting glucose, glycated hemoglobin, and type 2 diabetes from the Meta-Analyses of Glucose and Insulin-related traits Consortium and Diabetes Genetics Replication And Meta-analysis Consortium (n=140 595 for glucose; n=123 665 for HbA1c; n=898 130 for type 2 diabetes) and of AMPK -instrumented HbA1c reduction as a proxy of metformin and applied them to large genome-wide association studies of breast cancer (Breast Cancer Association Consortium; BCAC) and prostate cancer (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome; PRACTICAL). We used inverse variance weighting to obtain estimates. Sensitivity analyses included use of MR-Egger, weighted median, exclusion of pleiotropic instruments, and validation using UK Biobank (breast cancer only).
Results: There was no association of fasting glucose (OR 1.03 per mmol/L, 95% CI 0.85 to 1.25), HbA1c (OR 1.02 per %, 95% CI 0.73 to 1.45), or type 2 diabetes (OR 0.98 per log odds, 95% CI 0.95 to 1.01) with breast cancer in BCAC, with similar findings from UK Biobank. There was no association of fasting glucose (OR 0.93 per mmol/L, 95% CI 0.73 to 1.17), HbA1c (OR 0.90 per %, 95% CI 0.58 to 1.40) or type 2 diabetes (OR 1.02 per log odds, 95% CI 0.97 to 1.07) with prostate cancer in PRACTICAL. No strong evidence was observed for AMPK -instrumented HbA1c reduction on cancer risk.
Conclusion: Glycemic traits and type 2 diabetes unlikely cause breast and prostate cancer. Whether metformin can be repurposed for cancer prevention remains unclear.
Competing Interests: Competing interests: None declared.
(© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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U19 CA148112 United States CA NCI NIH HHS; C1287/A10710 United Kingdom CRUK_ Cancer Research UK; C16913/A6135 United Kingdom CRUK_ Cancer Research UK; MC_QA137853 United Kingdom MRC_ Medical Research Council; C1287/A16563 United Kingdom CRUK_ Cancer Research UK; C5047/A10692 United Kingdom CRUK_ Cancer Research UK; C5047/A3354 United Kingdom CRUK_ Cancer Research UK; C5047/A8384 United Kingdom CRUK_ Cancer Research UK; Canada CIHR; C5047/A15007 United Kingdom CRUK_ Cancer Research UK; MC_PC_12028 United Kingdom MRC_ Medical Research Council; C1287/A10118 United Kingdom CRUK_ Cancer Research UK; C5047/A7357 United Kingdom CRUK_ Cancer Research UK; A8197/A16565 United Kingdom CRUK_ Cancer Research UK; C12292/A11174 United Kingdom CRUK_ Cancer Research UK; United Kingdom DH_ Department of Health; U01 CA188392 United States CA NCI NIH HHS; U19 CA148065 United States CA NCI NIH HHS; MC_PC_17228 United Kingdom MRC_ Medical Research Council; C1281/A12014 United Kingdom CRUK_ Cancer Research UK; C8197/A16565 United Kingdom CRUK_ Cancer Research UK; U19 CA148537 United States CA NCI NIH HHS; HHSN268201200008I United States HL NHLBI NIH HHS

Keywords: HbA1c hemoglobin; cancer; genetics; glucose

0 (Biomarkers)
0 (Blood Glucose)
0 (Glycated Hemoglobin A)
0 (Hypoglycemic Agents)
0 (hemoglobin A1c protein, human)
9100L32L2N (Metformin)

Date Created: 20200108 Date Completed: 20200910 Latest Revision: 20221207

20221213

PMC6936416

10.1136/bmjdrc-2019-000872

31908803