Body size and composition and risk of site-specific cancers in the UK Biobank and large international consortia: A mendelian randomisation study

Background Evidence for the impact of body size and composition on cancer risk is limited. This mendelian randomisation (MR) study investigates evidence supporting causal relationships of body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), and height with cancer risk. Methods and findings Single nucleotide polymorphisms (SNPs) were used as instrumental variables for BMI (312 SNPs), FMI (577 SNPs), FFMI (577 SNPs), and height (293 SNPs). Associations of the genetic variants with 22 site-specific cancers and overall cancer were estimated in 367,561 individuals from the UK Biobank (UKBB) and with lung, breast, ovarian, uterine, and prostate cancer in large international consortia. In the UKBB, genetically predicted BMI was positively associated with overall cancer (odds ratio [OR] per 1 kg/m2 increase 1.01, 95% confidence interval [CI] 1.00–1.02; p = 0.043); several digestive system cancers: stomach (OR 1.13, 95% CI 1.06–1.21; p < 0.001), esophagus (OR 1.10, 95% CI 1.03, 1.17; p = 0.003), liver (OR 1.13, 95% CI 1.03–1.25; p = 0.012), and pancreas (OR 1.06, 95% CI 1.01–1.12; p = 0.016); and lung cancer (OR 1.08, 95% CI 1.04–1.12; p < 0.001). For sex-specific cancers, genetically predicted elevated BMI was associated with an increased risk of uterine cancer (OR 1.10, 95% CI 1.05–1.15; p < 0.001) and with a lower risk of prostate cancer (OR 0.97, 95% CI 0.94–0.99; p = 0.009). When dividing cancers into digestive system versus non-digestive system, genetically predicted BMI was positively associated with digestive system cancers (OR 1.04, 95% CI 1.02–1.06; p < 0.001) but not with non-digestive system cancers (OR 1.01, 95% CI 0.99–1.02; p = 0.369). Genetically predicted FMI was positively associated with liver, pancreatic, and lung cancer and inversely associated with melanoma and prostate cancer. Genetically predicted FFMI was positively associated with non-Hodgkin lymphoma and melanoma. Genetically predicted height was associated with increased risk of overall cancer (OR per 1 standard deviation increase 1.09; 95% CI 1.05–1.12; p < 0.001) and multiple site-specific cancers. Similar results were observed in analyses using the weighted median and MR–Egger methods. Results based on consortium data confirmed the positive associations between BMI and lung and uterine cancer risk as well as the inverse association between BMI and prostate cancer, and, additionally, showed an inverse association between genetically predicted BMI and breast cancer. The main limitations are the assumption that genetic associations with cancer outcomes are mediated via the proposed risk factors and that estimates for some lower frequency cancer types are subject to low precision. Conclusions Our results show that the evidence for BMI as a causal risk factor for cancer is mixed. We find that BMI has a consistent causal role in increasing risk of digestive system cancers and a role for sex-specific cancers with inconsistent directions of effect. In contrast, increased height appears to have a consistent risk-increasing effect on overall and site-specific cancers.

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Body size and composition and site-specific cancers in UK Biobank: a Mendelian randomisation study

10.1101/2020.02.28.970459 ◽

2020 ◽

Cited By ~ 1

Author(s):

Mathew Vithayathil ◽

Paul Carter ◽

Siddhartha Kar ◽

Amy M. Mason ◽

Stephen Burgess ◽

...

Keyword(s):

Instrumental Variables ◽

Association Studies ◽

Genome Wide Association ◽

Mendelian Randomisation ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Site Specific ◽

Genome Wide ◽

Increased Risk ◽

The Uk

ABSTRACTObjectivesTo investigate the casual role of body mass index, body fat composition and height in cancer.DesignTwo stage mendelian randomisation studySettingPrevious genome wide association studies and the UK BiobankParticipantsGenetic instrumental variables for body mass index (BMI), fat mass index (FMI), fat free mass index (FFMI) and height from previous genome wide association studies and UK Biobank. Cancer outcomes from 367 586 participants of European descent from the UK Biobank.Main outcome measuresOverall cancer risk and 22 site-specific cancers risk for genetic instrumental variables for BMI, FMI, FFMI and height.ResultsGenetically predicted BMI (per 1 kg/m2) was not associated with overall cancer risk (OR 0.99; 95% confidence interval (CI) 0-98-1.00, p=0.105). Elevated BMI was associated with increased risk of stomach cancer (OR 1.15, 95% (CI) 1.05-1.26; p=0.003) and melanoma (OR 0.96, 95% CI 0.92-1.00; p=0.044). For sex-specific cancers, BMI was positively associated with uterine cancer (OR 1.08, 95% CI 1.01-1.14; p=0.015) but inversely associated with breast (OR 0.95, 95% CI 0.92-0.98; p=0.001), prostate (OR 0.95, 95% CI 0.92-0.99; p=0.007) and testicular cancer (OR 0.89, 95% CI 0.81-0.98; p=0.017). Elevated FMI (per 1 kg/m2) was associated with gastrointestinal cancer (stomach cancer OR 4.23, 95% CI 1.18-15.13, p=0.027; colorectal cancer OR 1.94, 95% CI 1.23-3.07; p=0.004). Increased height (per 1 standard deviation, approximately 6.5cm) was associated with increased risk of overall cancer (OR 1.06; 95% 1.04-1.09; p = 2.97×10-8) and most site-specific cancers with the strongest estimates for kidney, non-Hodgkin lymphoma, colorectal, lung, melanoma and breast cancer.ConclusionsThere is little evidence for BMI as a casual risk factor for cancer. BMI may have a causal role for sex-specific cancers, although with inconsistent directions of effect, and FMI for gastrointestinal malignancies. Elevated height is a risk factor for overall cancer and multiple site cancers.

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Metabolic syndrome biomarkers and prostate cancer risk in the UK Biobank

International Journal of Cancer ◽

10.1002/ijc.33255 ◽

2020 ◽

Vol 148 (4) ◽

pp. 825-834

Author(s):

Maria J. Monroy‐Iglesias ◽

Beth Russell ◽

Danielle Crawley ◽

Naomi E. Allen ◽

Ruth C. Travis ◽

...

Keyword(s):

Prostate Cancer ◽

Metabolic Syndrome ◽

Cancer Risk ◽

Prostate Cancer Risk ◽

Uk Biobank ◽

The Uk

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Association of inflammation with depression and anxiety: evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts

Molecular Psychiatry ◽

10.1038/s41380-021-01188-w ◽

2021 ◽

Author(s):

Yuri Milaneschi ◽

Nils Kappelmann ◽

Zheng Ye ◽

Femke Lamers ◽

Sylvain Moser ◽

...

Keyword(s):

Depressive Symptoms ◽

Sleep Problems ◽

Experimental Studies ◽

Anxiety Symptoms ◽

Self Report ◽

Mendelian Randomisation ◽

Depression And Anxiety ◽

Uk Biobank ◽

Increased Risk ◽

The Uk

AbstractWe examined whether inflammation is uniformly associated with all depressive and anxiety symptoms, and whether these associations are potentially causal. Data was from 147,478 individuals from the UK Biobank (UKB) and 2,905 from the Netherlands Study of Depression and Anxiety (NESDA). Circulating C-reactive protein (CRP) was measured in both cohorts and interleukin-6 (IL-6) in NESDA. Genetic instruments for these proteins were obtained from published GWAS and UKB. Depressive and anxiety symptoms were assessed with self-report questionnaires. In NESDA, neurovegetative (appetite, sleep, psychomotor) symptoms were disaggregated as increased vs. decreased. In joint analyses, higher CRP was associated with depressive symptoms of depressed mood (OR = 1.06, 95% CI = 1.05–1.08), altered appetite (OR = 1.25, 95%CI = 1.23–1.28), sleep problems (OR = 1.05, 95%CI = 1.04–1.06), and fatigue (OR = 1.12, 95% CI = 1.11–1.14), and with anxiety symptoms of irritability (OR = 1.06, 95% CI = 1.05–1.08) and worrying control (OR = 1.03, 95% CI = 1.02–1.04). In NESDA, higher IL-6 was additionally associated with anhedonia (OR = 1.30, 95% CI = 1.12–1.52). Higher levels of both CRP (OR = 1.27, 95% CI = 1.13–1.43) and IL-6 (OR = 1.26, 95% CI = 1.07–1.49) were associated with increased sleep. Higher CRP was associated with increased appetite (OR = 1.21, 95% CI = 1.08–1.35) while higher IL-6 with decreased appetite (OR = 1.45, 95% CI = 1.18–1.79). In Mendelian Randomisation analyses, genetically predicted higher IL-6 activity was associated with increased risk of fatigue (estimate = 0.25, SE = 0.08) and sleep problems (estimate = 0.19, SE = 0.07). Inflammation was associated with core depressive symptoms of low mood and anhedonia and somatic/neurovegetative symptoms of fatigue, altered sleep and appetite changes. Less consistent associations were found for anxiety. The IL-6/IL-6R pathway could be causally linked to depression. Experimental studies are required to further evaluate causality, mechanisms, and usefulness of immunotherapies for depressive symptoms.

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Neither Hormonal Factors Nor AGEs Explain Lower Prostate Cancer Risk in Older Men With Diabetes Mellitus

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-01142 ◽

2019 ◽

Vol 104 (12) ◽

pp. 6017-6024

Author(s):

Yi X Chan ◽

Helman Alfonso ◽

P Gerry Fegan ◽

Leon Flicker ◽

Bu B Yeap

Keyword(s):

Prostate Cancer ◽

Diabetes Mellitus ◽

Cancer Risk ◽

Prostate Cancer Risk ◽

Sex Hormone ◽

Inverse Association ◽

Metabolic Disturbances ◽

Hormonal Factors ◽

Increased Risk ◽

Risk Of Cancer

Abstract Context Diabetes mellitus is conventionally associated with an increased risk of cancer; however, inverse associations of diabetes with prostate cancer are well described. Mechanisms are unclear, although hormonal factors, including alterations in sex hormone and IGF1 concentrations due to metabolic disturbances, have been hypothesized to play a role. Objective To assess sex hormones, IGF1, glucose, and advanced glycation end products (AGEs) as potential mediators of the association between diabetes mellitus and prostate cancer. Design and Participants Longitudinal cohort study. The association of baseline diabetes with prostate cancer incidence was assessed using proportional hazards competing risks analysis in 3149 men followed for 12 years. Baseline hormone, glucose, and carboxymethyllysine (CML) levels were examined as potential mediators of this association. Results Diabetes was associated with a lower prostate cancer risk (fully adjusted subhazard ratio, 0.63; 95% CI, 0.43 to 0.92; P = 0.017). This association was unchanged after accounting for testosterone, DHT, estradiol, or SHBG. Similarly, the addition of IGF1 or its binding proteins 1 and 3, or glucose, did not alter this association. CML was not associated with the risk of prostate cancer, and additional correction for CML in the fully adjusted model did not alter the inverse association of diabetes and prostate cancer risk. Conclusions In this study, alterations in sex hormone, IGF1, glucose, and CML levels did not account for the inverse association of diabetes and prostate cancer risk. Further studies are required to provide more insight into underlying causes of this association.

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Genetic liability to insomnia in relation to cardiovascular diseases: a Mendelian randomisation study

European Journal of Epidemiology ◽

10.1007/s10654-021-00737-5 ◽

2021 ◽

Author(s):

Shuai Yuan ◽

Amy M. Mason ◽

Stephen Burgess ◽

Susanna C. Larsson

Keyword(s):

Cardiovascular Diseases ◽

Association Studies ◽

European Ancestry ◽

Mendelian Randomisation ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Genetic Liability ◽

Genome Wide ◽

Increased Risk ◽

The Uk

AbstractThe present study aimed to determine the associations between insomnia and cardiovascular diseases (CVDs) using Mendelian randomisation (MR) analysis. As instrumental variables, we used 208 independent single-nucleotide polymorphisms associated with insomnia at the genome-wide significance threshold in a meta-analysis of genome-wide association studies in the UK Biobank and 23andMe including a total of 397 959 self-reported insomnia cases and 933 057 non-cases. Summary-level data for nine CVDs were obtained from the UK Biobank including 367 586 individuals of European ancestry. After correction for multiple testing, genetic liability to insomnia was associated with higher odds of six CVDs, including peripheral arterial disease (odd ratio (OR) 1.22; 95% confidence interval (CI), 1.21, 1.33), heart failure (OR 1.21; 95% CI, 1.13, 1.30), coronary artery disease (OR 1.19; 95% CI, 1.14, 1.25), ischaemic stroke (OR 1.15; 95% CI, 1.06, 1.25), venous thromboembolism (OR 1.13; 95% CI, 1.07, 1.19) and atrial fibrillation (OR 1.10; 95% CI, 1.05, 1.15). There were suggestive associations for aortic valve stenosis (OR, 1.17; 95% CI, 1.04, 1.32) and haemorrhagic stroke (OR 1.14; 95% CI, 1.00, 1.29) but no association for abdominal aortic aneurysm (OR, 1.14, 95% CI, 0.98, 1.33). The patterns of associations remained with mild attenuation in multivariable MR analyses adjusting for genetically correlated phenotypes and potential mediators, including sleep duration, depression, body mass index, type 2 diabetes and smoking. The present MR study suggests potential causal associations of genetic liability to insomnia with increased risk of a broad range of CVDs.

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Influence of blood pressure on pneumonia risk: Epidemiological association and Mendelian randomisation in the UK Biobank

10.1101/2020.04.19.20071936 ◽

2020 ◽

Author(s):

Seyedeh M. Zekavat ◽

Michael Honigberg ◽

James Pirruccello ◽

Puja Kohli ◽

Elizabeth W. Karlson ◽

...

Keyword(s):

Blood Pressure ◽

Observational Studies ◽

Mendelian Randomisation ◽

List Type ◽

Uk Biobank ◽

Increased Risk ◽

Reduce Risk ◽

Novel Coronavirus ◽

The Uk

AbstractObjectivesTo determine whether elevated blood pressure influences risk for respiratory infection.DesignProspective, population-based epidemiological and Mendelian randomisation studies.SettingUK Biobank.Participants377,143 self-identified British descent (54% women; median age 58 years) participants in the UK Biobank.Main outcome measuresFirst incident pneumonia over an average of 8 follow-up years.Results107,310 (30%) participants had hypertension at UK Biobank enrolment, and 9,969 (3%) developed a pneumonia during follow-up. Prevalent hypertension at baseline was significantly associated with increased risk for incident respiratory disease including pneumonia (hazard ratio 1.36 (95% confidence interval 1.29 to 1.43), P<0.001), acute respiratory distress syndrome or respiratory failure (1.43 (1.29 to 1.59), P<0.001), and chronic lower respiratory disease (1.30 (1.25 to 1.36), P<0.001), independent of age, age2, sex, smoking status, BMI, prevalent diabetes mellitus, prevalent coronary artery disease, and principal components of ancestry. Mendelian randomisation analyses indicated that genetic predisposition to a 5 mmHg increase in blood pressure was associated with increased risk of incident pneumonia for SBP (1.08, (1.04 to 1.13), P<0.001) and DBP (1.11 (1.03 to 1.20), P=0.005). Additionally, consistent with epidemiologic associations, increase in blood pressure genetic risk was significantly associated with reduced forced expiratory volume in the first second, forced vital capacity, and the ratio of the two (P<0.001 for all).ConclusionsThese results strongly suggest that elevated blood pressure independently increases risk for pneumonia and reduces pulmonary function. Maintaining adequate blood pressure control, in addition to other measures, may reduce risk for pneumonia. Whether the present findings are generalizable to novel coronavirus disease 2019 (COVID-19) require further study.Summary BoxSection 1: What is already known on this topicHypertension has been associated with pneumonia in small observational studies.Based on early epidemiologic analyses, hypertension is described as a risk factor for SARS-CoV-2 infection and associated novel coronavirus disease 2019 (COVID-19).The influence of hypertension on pneumonia risk is difficult to assess in traditional observational studies.Section 2: What this study addsOur pre-COVID-19 analyses are consistent with a causal relationship between increased blood pressure and increased risk for incident respiratory infections, as well as between increased blood pressure and reduced pulmonary function.These results support hypertension as a pneumonia risk factor; efforts to optimize blood pressure may reduce risk for pneumonia.

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Alcohol causes an increased risk of head and neck but not breast cancer in individuals from the UK Biobank study: A Mendelian randomisation analysis

10.1101/19002832 ◽

2019 ◽

Author(s):

Nathan Ingold ◽

Hasnat A Amin ◽

Fotios Drenos

Keyword(s):

Breast Cancer ◽

Alcohol Consumption ◽

Head And Neck ◽

Causal Effect ◽

Head And Neck Cancers ◽

Mendelian Randomisation ◽

Uk Biobank ◽

Increased Risk ◽

The Uk ◽

Risk Of Cancer

ABSTACTAlcohol intake and the risk of various types of cancers have been previously correlated. Correlation though does not always mean that a causal relationship between the two is present. Excessive alcohol consumption is also correlated with other lifestyle factors and behaviours, such as smoking and increased adiposity, that also affect the risk of cancer and make the identification and estimation of the causal effect of alcohol on cancer difficult. Here, using individual level data for 322,193 individuals from the UK Biobank, we report the observational and causal effects of alcohol consumption on types of cancer previously suggested as correlated to alcohol. Alcohol was observationally associated with cancers of the lower digestive system, head and neck and breast cancer. No associations were observed when we considered those keeping alcohol consumption below the recommended threshold of 14 units/week. When Mendelian randomisation was used to assess the causal effect of alcohol on cancer, we found that increasing alcohol consumption, especially above the recommended level, was causal to head and neck cancers but not breast cancer. Our results where replicated using a two sample MR method and data from the much larger COGS genome wide analysis of breast cancer. We conclude that alcohol is causally related to head and neck cancers, especially cancer of larynx, but the observed association with breast cancer are likely due to confounding. The suggested threshold of 14 units/week appears suitable to manage the risk of cancer due to alcohol.

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Extent of Food Processing and Risk of Prostate Cancer: The PROtEuS Study in Montreal, Canada

Nutrients ◽

10.3390/nu12030637 ◽

2020 ◽

Vol 12 (3) ◽

pp. 637 ◽

Cited By ~ 4

Author(s):

Karine Trudeau ◽

Marie-Claude Rousseau ◽

Marie-Élise Parent

Keyword(s):

Prostate Cancer ◽

Food Intake ◽

Cancer Risk ◽

Food Processing ◽

Prostate Cancer Screening ◽

Prostate Cancer Risk ◽

Processed Foods ◽

Inverse Association ◽

Minimally Processed ◽

Increased Risk

We studied the association between food intake, based on the extent of processing, and prostate cancer risk in a population-based case-control study conducted in Montreal, Canada in 2005–2012. Incident prostate cancer cases (n = 1919) aged ≤75 years were histologically confirmed. Population controls (n = 1991) were randomly selected from the electoral list and frequency-matched to cases by age (±5 years). A 63-item food frequency questionnaire focusing on the two years prior to diagnosis/interview was administered by interviewers. The NOVA classification was used to categorize foods based on processing level. Unconditional logistic regression estimated the association between food intake and prostate cancer risk, adjusting for age, education, ethnicity, family history, and timing of last prostate cancer screening. Consumption of unprocessed or minimally processed foods showed a slight, inverse association (Odd ratio [OR] 0.86, 95% confidence interval [CI] 0.70–1.07; highest vs. lowest quartile) with prostate cancer. An increased risk was observed with higher intake of processed foods (OR 1.29, 95%CI 1.05–1.59; highest vs. lowest quartile), but not with consumption of ultra-processed food and drinks. The associations with unprocessed/minimally processed foods and processed foods were slightly more pronounced for high-grade cancers (ORs 0.80 and 1.33, respectively). Findings suggest that food processing may influence prostate cancer risk.

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The role of genetic polymorphisms in endolysosomal ion channels TPC2 and P2RX4 in cancer pathogenesis, prognosis, and diagnosis: a genetic association in the UK Biobank

npj Genomic Medicine ◽

10.1038/s41525-021-00221-9 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Abeer F. Alharbi ◽

John Parrington

Keyword(s):

Prostate Cancer ◽

Ion Channels ◽

Genetic Variants ◽

Cancer Recurrence ◽

Malignant Neoplasms ◽

Uk Biobank ◽

Cancer Subtypes ◽

Increased Risk ◽

The Uk ◽

Risk Of Cancer

AbstractRecent studies have implicated important roles for endolysosomal ion channels in cancer biology. We used UK Biobank data to characterise the relationships between genetic variants in two genes coding for endolysosomal ion channels—i.e. TPCN2 and P2RX4—and cancer in terms of the definition of tumour types, susceptibility, and prognosis. We investigated these relationships at both global and local levels with regard to specific types of cancer, including malignant neoplasms of the brain, breast, bronchus, lung, colon, lymphoid and haematopoietic systems, skin, ovary, prostate, rectum, thyroid gland, lip, oral cavity, pharynx, and urinary tract. Apart from rs3829241 (p value < 0.05), all the genetic variants were in Hardy–Weinberg equilibrium. We included 468,436 subjects in the analysis and stratified them into two major cohorts: cancer-free controls (385,253) and cancer cases (83,183). For the first time, we report novel associations between genetic variants of TPCN2 and P2RX4 and cancer/cancer subtypes in the UK Biobank’s population. Genotype GG in TPCN2 rs3750965 was significantly associated with a decreased risk of cancer and an increased risk of lip, oral cavity, and pharynx cancer and cancer recurrence in patients with prostate cancer, and genotypes GA/GG were associated with a significantly lower risk of developing various malignant neoplasms (involving melanoma, prostate, mesothelial, and soft tissues). rs35264875:TA was associated with a high risk of cancer at the global level, with subtypes of cancer at the local level (including breast, colon, prostate, and stated or presumed primary cancer of lymphoid, haematopoietic, and related tissue), and with a significantly low risk of cancer metastasis. rs72932540:GA was associated with a higher incidence of cancer/cancer subtypes (including breast, melanoma, and rectal cancer), and genotypes GA/GG were associated with an increased risk of prostate cancer. The P2RX4 rs25644 allele GG was associated with a high risk of prostate cancer, whereas it was associated with a low risk of cancer recurrence in patients with prostate cancer. Genotypes GA/GG in rs28360472 were associated with an increased risk of breast, mesothelial, and soft tissue cancers but with a decreased risk of colon cancer. We also provide insights into the pathophysiological contributions made by these significant polymorphisms to cancer/cancer subtypes and their effects on expression or channel activity. Further investigations of these genetic variants could help identify novel cancer biomarkers and facilitate the development of new diagnostic and therapeutic strategies. This would constitute a further step towards personalised cancer care.

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Risk of 16 cancers across the full glycemic spectrum: a population-based cohort study using the UK Biobank

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001600 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001600

Author(s):

Christopher T Rentsch ◽

Ruth E Farmer ◽

Sophie V Eastwood ◽

Rohini Mathur ◽

Victoria Garfield ◽

...

Keyword(s):

Breast Cancer ◽

Pancreatic Cancer ◽

Cancer Risk ◽

Glycosylated Hemoglobin ◽

Population Sample ◽

Postmenopausal Breast Cancer ◽

Inverse Association ◽

Uk Biobank ◽

Premenopausal Breast Cancer ◽

The Uk

IntroductionDiabetes is observed to increase cancer risk, leading to hypothesized direct effects of either hyperglycemia or medication. We investigated associations between glycosylated hemoglobin (HbA1c) across the whole glycemic spectrum and incidence of 16 cancers in a population sample with comprehensive adjustment for risk factors and medication.Research design and methodsLinked data from the UK Biobank and UK cancer registry for all individuals with baseline HbA1c and no history of cancer at enrollment were used. Incident cancer was based on International Classification of Diseases – 10th Edition diagnostic codes. Age-standardized incidence rates were estimated by HbA1c category. Associations between HbA1c, modeled as a restricted cubic spline, and cancer risk were estimated using Cox proportional hazards models.ResultsAmong 378 253 individuals with average follow-up of 7.1 years, 21 172 incident cancers occurred. While incidence for many of the 16 cancers was associated with hyperglycemia in crude analyses, these associations disappeared after multivariable adjustment, except for pancreatic cancer (HR 1.55, 95% CI 1.22 to 1.98 for 55 vs 35 mmol/mol), and a novel finding of an inverse association between HbA1c and premenopausal breast cancer (HR 1.27, 95% CI 1.00 to 1.60 for 25 vs 35 mmol/mol; HR 0.71, 95% CI 0.54 to 0.94 for 45 vs 35 mmol/mol), not observed for postmenopausal breast cancer. Adjustment for diabetes medications had no appreciable impact on HRs for cancer.ConclusionsApart from pancreatic cancer, we did not demonstrate any independent positive association between HbA1c and cancer risk. These findings suggest that the potential for a cancer-inducing, direct effect of hyperglycemia may be misplaced.

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