EPID-10. MITOCHONDRIAL DNA SEQUENCE VARIATION AND RISK OF GLIOMA

Abstract Malignant gliomas are the most common primary adult brain tumors, with poor prognosis and ill-defined etiology. Mitochondrial DNA (mtDNA) sequence variants and haplogroups have been linked with certain cancers, but research on glioma is lacking. We examined the association of germline mtDNA variants and haplogroups with glioma risk in 1,654 glioma cases and 1,065 controls from a US case-control study, and 427 glioma cases and 1,541 controls from the UK Biobank, all genotyped using the UKBiobank array with 276 tiled mtDNA variants. The analysis was restricted to participants of European ancestry, and risk of glioblastoma (GBM) and lower grade glioma (LGG) was examined separately. Distribution of mitochondrial haplogroups (H/HV,I,J,K,R,T,U,V,W,X) were similar in both study populations, with 46.4% and 48.1% of controls in the US and UK studies respectively, identified as H/HV, the most common haplogroup. In the US study there was an inverse association between haplogroup W and glioma (OR=0.43, 95%CI: 0.23–0.79) when compared with the H/HV haplogroup, which was not seen in the UK study (OR=1.10, 95%CI: 0.49–2.49). In the US study, a significant inverse association was observed with the previously reported mtDNA variant m.14798T > C (PMID: 31323957), resulting in the amino acid substitution F18L, for LGG (OR=0.73; 95%CI: 0.53–0.99) though not for GBM (OR=0.86; 95%CI: 0.66–1.11). In the UK study, the F18L substitution was associated with an increased risk of GBM (OR=1.48; 95%CI: 1.07–2.04), and no association was observed for LGG (OR=0.95; 95%CI: 0.53–1.68). Among cases in the US study with isocitrate dehydrogenase 1 (IDH1) status available (747 gliomas), a nonsignificant inverse association of the F18L substitution was observed in glioma cases with wild type (OR=0.72; 95%CI: 0.52–1.01) but not mutant (OR=1.08; 95%CI: 0.70–1.69) IDH1. No other common mtDNA variant (minor allele > 5%) was associated with glioma risk in either study. These associations merit further study.

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Pre-diagnostic leukocyte mitochondrial DNA copy number and colorectal cancer risk

Carcinogenesis ◽

10.1093/carcin/bgz159 ◽

2019 ◽

Vol 40 (12) ◽

pp. 1462-1468 ◽

Cited By ~ 4

Author(s):

Keming Yang ◽

Xin Li ◽

Michele R Forman ◽

Patrick O Monahan ◽

Bret H Graham ◽

...

Keyword(s):

Colorectal Cancer ◽

Mitochondrial Dna ◽

Copy Number ◽

Quantitative Polymerase Chain Reaction ◽

Conditional Logistic Regression ◽

Experimental Studies ◽

Inverse Association ◽

Mitochondrial Dna Copy Number ◽

Increased Risk

Abstract Mitochondrial DNA (mtDNA) is susceptible to oxidative stress and mutation. Few epidemiological studies have assessed the relationship between mtDNA copy number (mtDNAcn) and risk of colorectal cancer (CRC), with inconsistent findings. In this study, we examined the association between pre-diagnostic leukocyte mtDNAcn and CRC risk in a case–control study of 324 female cases and 658 matched controls nested within the Nurses’ Health Study (NHS). Relative mtDNAcn in peripheral blood leukocytes was measured by quantitative polymerase chain reaction-based assay. Conditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association of interest. Results showed lower log-mtDNAcn was significantly associated with increased risk of CRC, in a dose-dependent relationship (P for trend < 0.0001). Compared to the fourth quartile, multivariable-adjusted OR [95% confidence interval (CI)] was 1.10 (0.69, 1.76) for the third quartile, 1.40 (0.89, 2.19) for the second quartile and 2.19 (1.43, 3.35) for the first quartile. In analysis by anatomic subsite of CRC, we found a significant inverse association for proximal colon cancer [lowest versus highest quartile, multivariable-adjusted OR (95% CI) = 3.31 (1.70, 6.45), P for trend = 0.0003]. Additionally, stratified analysis according to the follow-up time since blood collection showed that the inverse association between mtDNAcn and CRC remained significant among individuals with ≥ 5 years’ follow-up, and marginally significant among those with ≥ 10 years’ follow-up since mtDNAcn testing, suggesting that mtDNAcn may serve as a long-term predictor for risk of CRC. In conclusion, pre-diagnostic leukocyte mtDNAcn was inversely associated with CRC risk. Further basic experimental studies are needed to explore the underlying biological mechanisms linking mtDNAcn to CRC carcinogenesis.

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Endocrine therapy use and the risk of cardiovascular disease in postmenopausal breast cancer survivors: two cohort studies in the UK and US

10.1101/19010223 ◽

2019 ◽

Cited By ~ 1

Author(s):

Anthony Matthews ◽

Sharon Peacock Hinton ◽

Susannah Stanway ◽

Alexander R Lyon ◽

Liam Smeeth ◽

...

Keyword(s):

Breast Cancer ◽

Venous Thromboembolism ◽

Aromatase Inhibitor ◽

Incidence Rate ◽

Aromatase Inhibitors ◽

Cardiovascular Outcomes ◽

Increased Risk ◽

The Us ◽

Venous Thromboembolic ◽

The Uk

ABSTRACTObjectiveExamine the effect of tamoxifen and aromatase inhibitors on 12 clinically relevant individual cardiovascular outcomes in postmenopausal female breast cancer survivors using large-scale datasets from the UK and US.DesignTwo prospective cohort studiesSettingPopulation-based using data from the UK Clinical Practice Datalink linked with Hospital Episode Statistics (2002-2016), and the US Surveillance, Epidemiology and End Results-Medicare database (2008-2013).Participants10005 and 22027 postmenopausal women with breast cancer in the UK and US respectively.ExposuresAromatase inhibitor compared with tamoxifen use; the US cohort additionally included a comparison with an “unexposed” group of women with oestrogen or progesterone receptor positive breast cancer but no endocrine therapy use.Outcomes12 clinically relevant individual cardiovascular outcomes (and two composite coronary and venous thromboembolic outcomes)ResultsIn both the UK and the US, there was evidence of an increased risk of coronary artery disease in aromatase inhibitor compared with tamoxifen users (UK incidence rate: 10.18 vs 6.87 per 1000 person-years, HR: 1.29, 0.94-1.76; US incidence rate: 35.26 vs 26.95 per 1000 person-years, HR: 1.29, 1.06-1.55), but the US data showed no increase in risk compared with the unexposed group (incidence rate for tamoxifen vs unexposed: 26.95 vs 38.70 per 1000 person-years, HR: 0.74, 0.60-0.92; incidence rate for aromatase inhibitors vs unexposed: 35.26 vs 28.70, HR: 0.96, 0.83-1.10). Similar patterns were seen for other cardiovascular outcomes such as arrhythmia, heart failure, and valvular heart disease. As expected, there were more venous thromboembolic events in tamoxifen users compared with both aromatase inhibitor users and those unexposed. There was a high degree of consistency between results in the two countries.ConclusionsIncreased risks of several cardiovascular diseases among aromatase inhibitor compared with tamoxifen users appeared to be driven by protective effects of tamoxifen, rather than toxic effects of aromatase inhibitors. We also confirmed the known increased risk of venous thromboembolic events in tamoxifen users.WHAT THIS PAPER ADDSWhat is already known on this topicIt is known that tamoxifen use increases venous thromboembolism risk, but evidence for other cardiovascular outcomes is less clear.Patterns of results are suggestive of a lower risk of coronary heart disease outcomes with tamoxifen compared to both aromatase inhibitor use and no tamoxifen or placebo, but cardiovascular events are often a secondary consideration and inconsistently reported in trials, and most observational studies use composite cardiovascular definitions, ignoring potentially differential effects on specific cardiovascular outcomes.What this study addsAmong postmenopausal women with breast cancer, we found an increased risk of several cardiovascular diseases in aromatase inhibitor compared with tamoxifen users across two countries, which appeared to be driven by protective effects of tamoxifen, rather than toxic effects of aromatase inhibitors. We also found the known increased venous thromboembolism risk in tamoxifen users.There was no evidence that aromatase inhibitors or tamoxifen increases cardiovascular disease risk, other than the known increased venous thromboembolism risk with tamoxifen use. However, there was an apparent protective effect of tamoxifen on other cardiovascular outcomes.

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Abstract P633: Polygenic Susceptibility to Hypertension is Associated With Uncontrolled and Resistant Hypertension in Stroke Survivors

Stroke ◽

10.1161/str.52.suppl_1.p633 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Julian N Acosta ◽

Cameron Both ◽

Natalia Szejko ◽

Stacy Brown ◽

Nils H Petersen ◽

...

Keyword(s):

Resistant Hypertension ◽

Antihypertensive Drugs ◽

European Ancestry ◽

Risk Scores ◽

Uncontrolled Hypertension ◽

Stroke Survivors ◽

Cerebrovascular Event ◽

Uk Biobank ◽

Increased Risk ◽

The Uk

Introduction: Blood pressure (BP) is a highly heritable trait with numerous related genetic risk variants identified. While prior studies showed that polygenic susceptibility to hypertension (PSH) is associated with elevated BP, uncontrolled hypertension (UHTN), resistant hypertension (RHTN), and risk of stroke, its role after a cerebrovascular event remains unknown. We tested the hypothesis that PSH leads to higher BP and increased risk of UHTN and RHTN in stroke survivors. Methods: We conducted a nested study within the UK Biobank, including individuals of European ancestry with a prevalent ischemic or hemorrhagic stroke. To model PSH, we created polygenic risk scores (PRS) for systolic, diastolic, and pulse BP using 732 previously discovered loci. We divided the PRS into quintiles and used linear and logistic regression to test whether higher PSH led to higher observed BP as well as increased risk of UHTN (SBP >140 mmHg or DBP >90 mmHg) and RHTN (UHTN despite being on >=3 antihypertensive drugs) in stroke survivors. Results: Of the 502,536 participants enrolled in the UK Biobank, 5,815 (1.2%) with a prevalent stroke at enrollment were included. We found the following results across quintiles 1 through 5 of the systolic BP-based PRS: mean systolic BP 138.4, 140.6, 141.8, 142.9 and 145.8 mmHg (unadjusted p<0.0001, Figure’s left panel); risk of UHTN 46%, 51%, 52%, 56% and 59% (unadjusted p<0.0001, Figure’s center panel); and risk of RHTN 1.9%, 3.8%, 4.7%, 5.8% and 6.7% (unadjusted p<0.0001, Figure’s right panel). We obtained similar results when both evaluating diastolic and pulse BP-based PRSs and using adjusted multivariable models (all p<0.0001). Conclusion: PSH is associated with observed BP and the risk of UHTN and RHTN in stroke survivors. Follow up research should evaluate whether precision medicine strategies based on BP-related genetic information can help identify patients that could benefit from aggressive diagnostic and/or therapeutic interventions.

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An International Comparison Of Survival Disparities In Patients With Lymphoma and Myeloma

Blood ◽

10.1182/blood.v122.21.2925.2925 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2925-2925

Author(s):

Dianne Pulte ◽

Theresa Redaniel ◽

Mona Jeffreys

Keyword(s):

Older Patients ◽

Excess Mortality ◽

Conflicts Of Interest ◽

Relative Survival ◽

The United States ◽

Life Tables ◽

Younger Patients ◽

Increased Risk ◽

The Us ◽

The Uk

Abstract Background Relative survival in older patients with lymphomas is significantly lower than in younger patients. Possible reasons for the discrepancy may include increased aggressiveness of the disease in older patients, increased frailty and co-morbidities complicating treatment in older patients, and under-treatment of older patients due to concern about increased risk of intolerance to treatment. Distinguishing between these problems on a population basis can be difficult as clinical trial data often provides data only on the “ideal” patient and may not be applicable to the general population. Here, we determine 5-year relative survival and excess mortality by age for patients diagnosed with Hodgkin's lymphoma (HL), non-Hodgkin lymphoma (NHL) and multiple myeloma. Methods Data was obtained from the Surveillance, Epidemiology, and End Results (SEER) database in the United States (US) and Cancer Registry data covering the whole of England (UK) for all patients diagnosed with HL, NHL and myeloma between 1996 and 2010. Five year relative survival was calculated by categories of age (15-24; 25-44; 45-64; 65-74 and 75+ years) using period analysis. Relative survival was calculated using age, race, gender, and country specific life tables. In addition, region specific life tables were used in the UK. Excess mortality modellingwas used to determine excess risk for older compared to younger patients, using patients age 25-44 for the reference group. Results Five year relative survival was lower for older patients diagnosed with HL, NHL, and myeloma in the US and UK. The most dramatic difference in survival by age was observed for patients with HL among whom survival for 15-24 year olds was 96.2% and 92.5% in 2006-10 in the US and UK, respectively but only 51.0% and 22.8%, respectively, for patients age 75+, representing an excess mortality of 14.02 (95% CI 12.22-16.09) and 15.69 (14.21-17.33), respectively, for the US and UK for patients age 75+ compared to 25-44. Similar, although less extreme, differences were observed for NHL and myeloma (see Table). Excess mortality ratios of 1.91 (1.84-1.99) and 3.81 (3.67-3.96) was observed for patients with NHL at age 75+ as compared to 25-44 in the US and UK, respectively. For patients with myeloma, excess mortality ratios of 2.79 (2.52-3.09) and 3.60 (3.27-3.962) for patients age 75+ compared to 25-44 were observed, respectively, for the US and UK. Adjustment for gender, ethnicity, period of diagnosis, and income (UK data only) did not significantly affect excess mortality ratios. Conclusions Survival of patients with lymphoma, especially patients with HL, is dramatically lower for older patients in both the US and UK. Older patients with lymphoma had a higher survival in the US as compared to the UK. This finding suggests that older patients in the UK may experience under-treatment. Physicians should be encouraged to evaluate patients' frailty and co-morbidities as well as their age when considering treatment options for patients with lymphoma and myeloma. Disclosures: No relevant conflicts of interest to declare.

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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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Analysis of CYP2C19 genetic variants with ischaemic events in UK patients prescribed clopidogrel in primary care: a retrospective cohort study

BMJ Open ◽

10.1136/bmjopen-2021-053905 ◽

2021 ◽

Vol 11 (12) ◽

pp. e053905

Author(s):

Luke C Pilling ◽

Deniz Türkmen ◽

Hannah Fullalove ◽

Janice L Atkins ◽

Joao Delgado ◽

...

Keyword(s):

Primary Care ◽

Ischaemic Stroke ◽

Genetic Variants ◽

Retrospective Cohort ◽

Active Form ◽

European Ancestry ◽

Hospital Inpatient ◽

Stroke Incidence ◽

Increased Risk ◽

The Uk

ObjectiveTo determine whether CYP2C19 loss-of-function (LoF) alleles increase risk of ischaemic stroke and myocardial infarction (MI) in UK primary care patients prescribed clopidogrel.DesignRetrospective cohort analysis.SettingPrimary care practices in the UK from January 1999 to September 2017.Participants7483 European-ancestry adults from the UK Biobank study with genetic and linked primary care data, aged 36–79 years at time of first clopidogrel prescription.InterventionsClopidogrel prescription in primary care, mean duration 2.6 years (range 2 months to 18 years).Main outcome measureHospital inpatient-diagnosed ischaemic stroke, MI or angina while treated with clopidogrel.Results28.7% of participants carried at least one CYP2C19 LoF variant. LoF carriers had higher rates of incident ischaemic stroke while treated with clopidogrel compared with those without the variants (8 per 1000 person-years vs 5.2 per 1000 person-years; HR 1.53, 95% CIs 1.04 to 2.26, p=0.031). LoF carriers also had increased risk of MI (HR 1.14, 95% CI 1.04 to 1.26, p=0.008). In combined analysis LoF carriers had increased risk of any ischaemic event (stroke or MI) (HR 1.17, 95% CI 1.06 to 1.29, p=0.002). Adjustment for aspirin coprescription produced similar estimates. In lifetables using observed incidence rates, 22.5% (95% CI 14.4% to 34.0%) of CYP2C19 LoF carriers on clopidogrel were projected to develop an ischaemic stroke by age 79 (oldest age in the study), compared with 15.4% (95% CI 11.4% to 20.5%) in non-carriers, that is, 7.1% excess stroke incidence in LoF carriers by age 79.ConclusionsA substantial proportion of the UK population carry genetic variants that reduce metabolism of clopidogrel to its active form. In family practice patients on clopidogrel, CYP2C19 LoF variants are associated with substantially higher incidence of ischaemic events. Genotype-guided selection of antiplatelet medications may improve outcomes in patients carrying CYP2C19 genetic variants.

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Impact of Genetically Predicted Red Blood Cell Traits on Venous Thromboembolism: Multivariable Mendelian Randomization Study Using UK Biobank

Journal of the American Heart Association ◽

10.1161/jaha.120.016771 ◽

2020 ◽

Vol 9 (14) ◽

Author(s):

Shan Luo ◽

Shiu Lun Au Yeung ◽

Verena Zuber ◽

Stephen Burgess ◽

Catherine Mary Schooling

Keyword(s):

Venous Thromboembolism ◽

General Population ◽

Blood Cell ◽

Red Blood Cell ◽

Mendelian Randomization ◽

Sensitivity Analyses ◽

European Ancestry ◽

Uk Biobank ◽

Increased Risk ◽

The Uk

Background Red blood cell (RBC) transfusion and erythropoiesis‐stimulating agent administration are cornerstones of clinical practice, yet concerns exist as to potential increased risk of thrombotic events. This study aims to identify RBC traits most relevant to venous thromboembolism (VTE) and assess their genetically predicted effects on VTE in the general population. Methods and Results We used multivariable mendelian randomization with bayesian model averaging for exposure selection. We obtained genetic variants predicting any of 12 RBC traits from the largest genome‐wide association study of hematological traits (173 480 participants of European ancestry) and applied them to the UK Biobank (265 424 white British participants). We used univariable mendelian randomization methods as sensitivity analyses for validation. Among 265 424 unrelated participants in the UK Biobank, there were 9752 cases of VTE (4490 men and 5262 women). Hemoglobin was selected as the plausible important RBC trait for VTE (marginal inclusion probability=0.91). The best‐fitting model across all RBC traits contained hemoglobin only (posterior probability=0.46). Using the inverse variance–weighted method, genetically predicted hemoglobin was positively associated (odds ratio, 1.21 per g/dL unit of hemoglobin; 95% CI, 1.05–1.41) with VTE. Sensitivity analyses (mendelian randomization–Egger, weighted median, and mendelian randomization pleiotropy residual sum and outlier test) gave consistent estimates. Conclusions Endogenous hemoglobin is the key RBC trait causing VTE, with a detrimental effect in the general population on VTE. Given men have higher hemoglobin than women, this finding may help explain the sexual disparity in VTE rates. The benefits of therapies and other factors that raise hemoglobin need to be weighed against their risks.

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O-184 Maternally inherited differences in mitochondrial DNA genotype between ART and spontaneously conceived individuals associate with low birthweight

Human Reproduction ◽

10.1093/humrep/deab127.085 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

J Mertens ◽

F Belva ◽

A Van Montfoort ◽

F Zambelli ◽

S Seneca ◽

...

Keyword(s):

Mitochondrial Dna ◽

Mitochondrial Function ◽

Low Birthweight ◽

De Novo ◽

Complex Data ◽

Maternal Transmission ◽

Menstrual Cycles ◽

Increased Risk ◽

Mtdna Variants ◽

Lower Birthweight

Abstract Study question Can mitochondrial DNA (mtDNA) variants explain the differences in birthweight between ART and spontaneously conceived (SC) individuals and how do they originate? Summary answer Children born after ART carry more frequently a different mtDNA variant composition, both maternally inherited and de novo, which are predictive of their birthweight percentile. What is known already Children born after ART show an increased risk of lower birthweight and of developing a mild abnormal cardio-metabolic profile later in life. Variation in the mtDNA associates with overall health in the general population, including cardio-metabolic fitness, and can result in changes in mitochondrial function. We hypothesized that mitochondrial DNA variants could explain the differences in birthweight between ART and SC individuals and that these differences may result from maternal transmission and/or from the ovarian stimulation (OS) used in ART. Study design, size, duration We deep-sequenced the mtDNA of 472 individuals of who 283 ART and 189 SC, 182 mother-child pairs and 113 single oocytes from both natural menstrual cycles and OS cycles. The mtDNA was compared between groups and Fisher linear discriminant analysis was used as predictive model for the birthweight percentile. Participants/materials, setting, methods Mitochondrial DNA was enriched by long-range PCR and subsequently sequenced on an Illumina platform. mtDNA server and MuTect were used for variant calling for variants with a load higher than 1.5%, versus the reference NC_012920.1. An orthogonally rotated factor analysis was used to reduce the dimensionality of the studied dependent variables in the complex data of the heteroplasmic variants. Main results and the role of chance ART individuals carried more frequently haplogroup U4 (p = 0.004) and component analysis indicated that they carry a different mtDNA heteroplasmic variant composition than SC individuals (p = 0.01), driven by non-synonymous protein-coding and rRNA-coding variants. These differences were also predictive of the risk of a lower birthweight percentile, especially for the SC children, together with the absence of haplogroup T, the presence of homoplasmic tRNA-variants, pregnancy-induced hypertension and the embryo culture medium used. The differences in heteroplasmic variation observed in the ART children resulted from both maternal transmission (p = 0.03) and de novo mutagenesis (p = 0.02). Mothers of ART children showed a similar mtDNA genotype as their children and differed in the same variant composition when compared to the mothers of SC children (p = 0.03). Furthermore, the comparison of oocytes from the same donors retrieved in natural menstrual cycles and after one OS cycle showed that OS does not increase de novo mutagenesis. Additionally, clinical parameters such as the total dosage of FSH units, the number of oocytes retrieved, and maternal age did not show any correlation with the differences observed in ART individuals. Limitations, reasons for caution This study is observational with no functional tests being performed. Wider implications of the findings We demonstrate an association between a lower birthweight percentile and a mtDNA variant composition which is more frequently carried by ART children. These non-disease associated mtDNA variants could cause a suboptimal mitochondrial function affecting the birthweight. Long-term health consequences of these differences remain to be further elucidated. Trial registration number Not applicable

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EPID-12. MITOCHONDRIAL DNA SEQUENCE VARIATION AND MENINGIOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.345 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi88-vi88

Author(s):

Claudine Samanic ◽

Jamie Teer ◽

Zachary Thompson ◽

Jordan Creed ◽

Brooke Fridley ◽

...

Keyword(s):

Mitochondrial Dna ◽

Association Studies ◽

African Ancestry ◽

Normal Weight ◽

Minor Allele ◽

Genome Wide Association Studies ◽

Who Grade ◽

Southeastern Us ◽

Mtdna Sequence ◽

Mtdna Variants

Abstract Meningiomas are the most common primary central nervous system tumors. Risk factors include female sex, African American race, a higher body mass index, and exposure to ionizing radiation. Genome-wide association studies have identified two risk loci for meningioma in the nuclear genome (rs12770228 and rs2686876). Whereas mitochondrial DNA (mtDNA) sequence variants and haplogroups have been linked with certain cancers, research on meningioma is lacking. We examined the association of 42 common (minor allele frequency ≥ 5%) germline mtDNA variants, haplogroups, and genes with meningioma risk in 1,080 controls and 478 cases from a case-control study conducted at medical centers in the southeastern US. Participant DNA samples were genotyped using the UK Biobank array that included a set of common and rare mtDNA variants. Risk associations were examined separately for meningioma overall, WHO grade 1 (n=409) and WHO grade 2/3 (n=69) meningiomas. Overall, meningioma risk was significantly higher among women (OR=2.86; 95% CI:2.21-3.71) compared to men, higher among African Americans (OR=2.37, 95% CI:1.41-3.99) compared to Caucasians, and higher among those who were overweight (OR=1.48; 95% CI:1.11-1.98) or obese (OR= 1.73; 95% CI:1.26-2.38) compared to those of normal weight. The variant m.16362T >C (rs62581341) in the mitochondrial control region was positively associated with grade 2/3 meningiomas (OR=2.33; 95% CI: 1.14-4.79), but not with grade 1 tumors (OR=0.99; 95% CI:0.64-1.53). Haplogroup L, a marker for African ancestry, was identified among 3.6% of controls and 8.6% of cases and was associated with meningioma risk overall (OR=2.56; 95% CI:1.52-4.30). When stratifying by self-reported race, the association between haplogroup L and meningioma was only apparent among the small number of self-reported Caucasians with this haplogroup (OR=6.68; 95% CI=1.66-26.91) when compared to non-L haplogroups, combined. No other common mtDNA variant (minor allele >5%), haplogroup, or gene was associated with meningioma risk. These findings merit further study.

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

PLoS Medicine ◽

10.1371/journal.pmed.1003706 ◽

2021 ◽

Vol 18 (7) ◽

pp. e1003706

Author(s):

Mathew Vithayathil ◽

Paul Carter ◽

Siddhartha Kar ◽

Amy M. Mason ◽

Stephen Burgess ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Risk ◽

Digestive System ◽

Uterine Cancer ◽

Mendelian Randomisation ◽

Inverse Association ◽

Uk Biobank ◽

Site Specific ◽

Increased Risk ◽

The Uk

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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