Non-progressive breast carcinomas detected at mammography screening: a population study.

BACKGROUND: Some breast carcinomas detected at screening, especially ductal carcinoma in situ, may have limited potential for progression to symptomatic disease. To determine non-progression is a challenge, but if all screening-detected breast tumors eventually reach a clinical stage, the cumulative incidence at a reasonably high age would be similar for women with or without screening, conditional on the women being alive. METHODS: Using high-quality population data with 24 years of follow-up from the gradually introduced BreastScreen Norway program, we studied whether all breast carcinomas detected at mammography screening 50-69 years of age would progress to clinical symptoms within 85 years of age. First, we estimated the incidence rates of breast carcinomas by age in scenarios with or without screening, based on an extended age-period-cohort incidence model. Next, we estimated the frequency of non-progressive tumors among screening-detected cases, by calculating the difference in the cumulative rate of breast carcinomas between the screening and non-screening scenarios at 85 years of age. RESULTS: Among women who attended BreastScreen Norway from the age of 50 to 69 years, we estimated that 1.1% of the participants were diagnosed with a breast carcinoma without the potential to progress to symptomatic disease by 85 years of age. This proportion of potentially non-progressive tumors corresponded to 15.7% [95% CI 3.3, 27.1] of breast carcinomas detected at screening. CONCLUSIONS: Our findings suggest that nearly one in six breast carcinomas detected at screening may be non-progressive.

Pregnancy complications in last pregnancy and mothers' long-term cardiovascular mortality: does the relation differ from that of complications in first pregnancy? A population-based study.

BACKGROUND: Women who experience complications in first pregnancy are at increased risk of cardiovascular disease (CVD) later in life. Little corresponding knowledge is available for complications in later pregnancies. Therefore, we assessed complications (preeclampsia, preterm birth, and offspring small for gestational age) in first and last pregnancies and the risk of long-term maternal CVD death, taking women´s complete reproduction into account. DATA AND METHODS: We linked data from the Medical Birth Registry of Norway to the national Cause of Death Registry. We followed women whose first birth took place during 1967-2013, from the date of their last birth until death, or December 31st 2020, whichever occurred first. We analysed risk of CVD death until 69 years of age according to any complications in last pregnancy. Using Cox regression analysis, we adjusted for maternal age at first birth and level of education. RESULTS: Women with any complications in their last or first pregnancy were at higher risk of CVD death than mothers with two-lifetime births and no pregnancy complications (reference). For example, the adjusted hazard ratio (aHR) for women with four births and any complications only in the last pregnancy was 2.85 (95% CI, 1.93-4.20). If a complication occurred in the first pregnancy only, the aHR was 1.74 (1.24-2.45). Corresponding hazard ratios for women with two births were 1.82 (CI, 1.59-2.08) and 1.41 (1.26-1.58), respectively. CONCLUSIONS: The risk for CVD death was higher among mothers with complications only in their last pregnancy compared to women with no complications, and also higher compared to mothers with a complication only in their first pregnancy.

The association of women's birth size with risk of molecular breast cancer subtypes: a cohort study.

BACKGROUND: Because birth size appears to be positively associated with breast cancer risk, we have studied whether this risk may differ according to molecular breast cancer subtypes. METHODS: A cohort of 22,931 women born 1920-1966 were followed up for breast cancer occurrence from 1961 to 2012, and 870 were diagnosed during follow-up. Archival diagnostic material from 537 patients was available to determine molecular breast cancer subtype, specified as Luminal A, Luminal B (human epidermal growth factor receptor 2 (HER2)-), Luminal B (HER2+), HER2 type, and Triple negative (TN) breast cancer. Information on the women's birth weight, birth length and head circumference at birth was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for each molecular subtype, applying Cox regression, and stratified by maternal height. RESULTS: Birth length (per 2 cm increments) was positively associated with Luminal A (HR = 1.2, 95% CI, 1.0-1.3), Luminal B (HER2+) (HR = 1.3, 95% CI, 1.0-1.7), and TN breast cancer (HR = 1.4, 95% CI, 1.0-1.9). No clear association was found for birth weight and head circumference. The positive associations of birth length were restricted to women whose mothers were relatively tall (above population median). CONCLUSION: We found a positive association of birth length with risk of Luminal A, Luminal B (HER2+) and TN breast cancer that appears to be restricted to women whose mothers were relatively tall. This may support the hypothesis that breast cancer risk is influenced by determinants of longitudinal growth and that this finding deserves further scrutiny.

Impact of MDM2 promoter SNP55 (rs2870820) on risk of endometrial and ovarian cancer.

BACKGROUND: While large GWAS analyses have not found convincing associations between MDM2 promoter SNP55 and gynaecological cancers, SNP55 is in linkage disequilibrium with two other functional SNPs in the same promoter, likely to obscure associations between single SNPs and cancer risk. Here, we assessed the impact of SNP55 on risk of endometrial and ovarian cancer, including sub-analyses stratified for other functional SNPs in the region. MATERIAL AND METHODS: Using a custom LightSNiP assay, we genotyped SNP55 in two large hospital-based cohorts of patients with ovarian (n = 1,332) and endometrial (n = 1,363) cancer and compared genotypes to healthy female controls (n = 1,858). RESULTS: Among individuals harbouring the SNP309TT genotype, the minor SNP55T-allele was associated with a reduced risk of endometrial (dominant model: OR = 0.63; CI = 0.45-0.88; p = 0.01). Regardless of the genotype in neighbouring SNPs, the SNP55T-allele was also associated with a reduced risk of endometrial cancer before 50 years of age (dominant model: OR = 0.56; CI = 0.34-0.90; p = 0.02). No association between SNP55 status and ovarian cancer risk was observed. CONCLUSIONS: MDM2 SNP55T-allele may correlate with reduced risk for endometrial cancer in a SNP309T-, but not SNP309G, context.

Physical activity and the risk of heart failure: a systematic review and dose-response meta-analysis of prospective studies.

Although physical activity is an established protective factor for cardiovascular diseases such as ischemic heart disease and stroke, less is known with regard to the association between specific domains of physical activity and heart failure, as well as the association between cardiorespiratory fitness and heart failure. We conducted a systematic review and meta-analysis of prospective observational studies to clarify the relations of total physical activity, domains of physical activity and cardiorespiratory fitness to risk of heart failure. PubMed and Embase databases were searched up to January 14th, 2020. Summary relative risks (RRs) were calculated using random effects models. Twenty-nine prospective studies (36 publications) were included in the review. The summary RRs for high versus low levels were 0.77 (95% CI 0.70-0.85, I2 = 49%, n = 7) for total physical activity, 0.74 (95% CI 0.68-0.81, I2 = 88.1%, n = 16) for leisure-time activity, 0.66 (95% CI 0.59-0.74, I2 = 0%, n = 2) for vigorous activity, 0.81 (95% CI 0.69-0.94, I2 = 86%, n = 3) for walking and bicycling combined, 0.90 (95% CI 0.86-0.95, I2 = 0%, n = 3) for occupational activity, and 0.31 (95% CI 0.19-0.49, I2 = 96%, n = 6) for cardiorespiratory fitness. In dose-response analyses, the summary RRs were 0.89 (95% CI 0.83-0.95, I2 = 67%, n = 4) per 20 MET-hours per day of total activity and 0.71 (95% CI 0.65-0.78, I2 = 85%, n = 11) per 20 MET-hours per week of leisure-time activity. Nonlinear associations were observed in both analyses with a flattening of the dose-response curve at 15-20 MET-hours/week for leisure-time activity. These findings suggest that high levels of total physical activity, leisure-time activity, vigorous activity, occupational activity, walking and bicycling combined and cardiorespiratory fitness are associated with reduced risk of developing heart failure.

Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies.

Background: Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated. Objective: To characterize breast cancer risk in relation to recent childbirth. Design: Pooled analysis of individual-level data from 15 prospective cohort studies. Setting: The international Premenopausal Breast Cancer Collaborative Group. Participants: Women younger than 55 years. Measurements: During 9.6 million person-years of follow-up, 18 826 incident cases of breast cancer were diagnosed. Hazard ratios (HRs) and 95% CIs for breast cancer were calculated using Cox proportional hazards regression. Results: Compared with nulliparous women, parous women had an HR for breast cancer that peaked about 5 years after birth (HR, 1.80 [95% CI, 1.63 to 1.99]) before decreasing to 0.77 (CI, 0.67 to 0.88) after 34 years. The association crossed over from positive to negative about 24 years after birth. The overall pattern was driven by estrogen receptor (ER)-positive breast cancer; no crossover was seen for ER-negative cancer. Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns. Limitations: Breast cancer diagnoses during pregnancy were not uniformly distinguishable from early postpartum diagnoses. Data on human epidermal growth factor receptor 2 (HER2) oncogene overexpression were limited. Conclusion: Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth. Health care providers should consider recent childbirth a risk factor for breast cancer in young women. Primary Funding Source: The Avon Foundation, the National Institute of Environmental Health Sciences, Breast Cancer Now and the UK National Health Service, and the Institute of Cancer Research.

Weight and weight change and risk of atrial fibrillation: the HUNT study.

AIMS: Although obesity has been associated with risk of atrial fibrillation (AF), the associations of long-term obesity, recent obesity, and weight change with AF risk throughout adulthood are uncertain. METHODS AND RESULTS: An ambispective cohort study was conducted which included 15 214 individuals. The cohort was created from 2006 to 2008 (the baseline) and was followed for incident AF until 2015. Weight and height were directly measured at baseline. Data on previous weight and height were retrieved retrospectively from measurements conducted 10, 20, and 40 years prior to baseline. Average body mass index (BMI) over time and weight change was calculated. During follow-up, 1149 participants developed AF. The multivariable-adjusted hazard ratios were 1.2 (95% confidence interval 1.0-1.4) for average BMI 25.0-29.9 kg/m2 and 1.6 (1.2-2.0) for average BMI ≥30 kg/m2 when compared with normal weight. The association of average BMI with AF risk was only slightly attenuated after adjustment for most recent BMI. In contrast, current BMI was not strongly associated with the risk of AF after adjustment for average BMI earlier in life. Compared with stable BMI, both loss and gain in BMI were associated with increased AF risk. After adjustment for most recent BMI, the association of BMI gain with AF risk was largely unchanged, while the association of BMI loss with AF risk was weakened. CONCLUSION: Long-term obesity and BMI change are associated with AF risk. Obesity earlier in life and weight gain over time exert cumulative effects on AF development even after accounting for most recent BMI.

Low thyroid function is not associated with an accelerated deterioration in renal function.

BACKGROUND: Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups. METHODS: Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models. RESULTS: A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) -4.07 (-6.37 to -1.78) and -2.40 (-3.78 to -1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50-4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function. CONCLUSIONS: Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.

Menopausal hormone therapy and breast cancer risk: effect modification by body mass through life.

It is not known whether increased breast cancer risk caused by menopausal hormone therapy (HT) depends on body mass patterns through life. In a prospective study of 483,241 Norwegian women aged 50-69 years at baseline, 7656 women developed breast cancer during follow-up (2006-2013). We combined baseline information on recalled body mass in childhood/adolescence and current (baseline) body mass index (BMI) to construct mutually exclusive life-course body mass patterns. We assessed associations of current HT use with breast cancer risk according to baseline BMI and life-course patterns of body mass, and estimated relative excess risk due to interaction (RERI). Within all levels of baseline BMI, HT use was associated with increased risk. Considering life-course body mass patterns as a single exposure, we used women who "remained at normal weight" through life as the reference, and found that being "overweight as young" was associated with lower risk (hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.76-0.94), whereas women who "gained weight" had higher risk (HR 1.20, 95% CI 1.12-1.28). Compared to never users of HT who were "overweight as young", HT users who either "remained at normal weight" or "gained weight" in adulthood were at higher risk than expected when adding the separate risks (RERI 0.52, 95% CI 0.09-0.95, and RERI 0.37, 95% CI - 0.07-0.80), suggesting effect modification. Thus, we found that women who remain at normal weight or gain weight in adulthood may be more susceptible to the risk increasing effect of HT compared to women who were overweight as young.

White Blood Cell BRCA1 Promoter Methylation Status and Ovarian Cancer Risk.

Background: The role of normal tissue gene promoter methylation in cancer risk is poorly understood. Objective: To assess associations between normal tissue BRCA1 methylation and ovarian cancer risk. Design: 2 case-control (initial and validation) studies. Setting: 2 hospitals in Norway (patients) and a population-based study (control participants). Participants: 934 patients and 1698 control participants in the initial study; 607 patients and 1984 control participants in the validation study. Measurements: All patients had their blood sampled before chemotherapy. White blood cell (WBC) BRCA1 promoter methylation was determined by using methylation-specific quantitative polymerase chain reaction, and the percentage of methylation-positive samples was compared between population control participants and patients with ovarian cancer, including the subgroup with high-grade serous ovarian cancer (HGSOC). Results: In the initial study, BRCA1 methylation was more frequent in patients with ovarian cancer than control participants (6.4% vs. 4.2%; age-adjusted odds ratio [OR], 1.83 [95% CI, 1.27 to 2.63]). Elevated methylation, however, was restricted to patients with HGSOC (9.6%; OR, 2.91 [CI, 1.85 to 4.56]), in contrast to 5.1% and 4.0% of patients with nonserous and low-grade serous ovarian cancer (LGSOC), respectively. These findings were replicated in the validation study (methylation-positive status in 9.1% of patients with HGSOC vs. 4.3% of control participants-OR, 2.22 [CI 1.40 to 3.52]-4.1% of patients with nonserous ovarian cancer, and 2.7% of those with LGSOC). The results were not influenced by tumor burden, storage time, or WBC subfractions. In separate analyses of young women and newborns, BRCA1 methylation was detected in 4.1% (CI, 1.8% to 6.4%) and 7.0% (CI, 5.0% to 9.1%), respectively. Limitations: Patients with ovarian cancer were recruited at the time of diagnosis in a hospital setting. Conclusion: Constitutively normal tissue BRCA1 promoter methylation is positively associated with risk for HGSOC. Primary Funding Source: Norwegian Cancer Society.

APOBEC3A/B deletion polymorphism and cancer risk.

Activity of the apolipoprotein B mRNA editing enzyme, catalytic-polypeptide-like (APOBEC) enzymes has been linked to specific mutational processes in human cancer genomes. A germline APOBEC3A/B deletion polymorphism is associated with APOBEC-dependent mutational signatures, and the deletion allele has been reported to confer an elevated risk of some cancers in Asian populations, while the results in European populations, so far, have been conflicting. We genotyped the APOBEC3A/B deletion polymorphism in a large population-based sample consisting of 11 106 Caucasian (Norwegian) individuals, including 7279 incident cancer cases (1769 breast, 1360 lung, 1585 colon, and 2565 prostate cancer) and a control group of 3827 matched individuals without cancer (1918 females and 1909 males) from the same population. Overall, the APOBEC3A/B deletion polymorphism was not associated with risk of any of the four cancer types. However, in subgroup analyses stratified by age, we found that the deletion allele was associated with increased risk for lung cancer among individuals <50 years of age (OR 2.17, CI 1.19-3.97), and that the association was gradually reduced with increasing age (P = 0.01). A similar but weaker pattern was observed for prostate cancer. In support of these findings, the APOBEC3A/B deletion was associated with young age at diagnosis among the cancer cases for both cancer forms (lung cancer: P = 0.02; dominant model and prostate cancer: P = 0.03; recessive model). No such associations were observed for breast or colon cancer.

Body mass index, abdominal fatness, weight gain and the risk of psoriasis: a systematic review and dose-response meta-analysis of prospective studies.

Greater body mass index (BMI) has been associated with increased risk of psoriasis in case-control and cross-sectional studies, however, the evidence from prospective studies has been limited. We conducted a systematic review and dose-response meta-analysis of different adiposity measures and the risk of psoriasis to provide a more robust summary of the evidence based on data from prospective studies. PubMed and Embase databases were searched for relevant studies up to August 8th 2017. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random effects model. The summary relative risk (RR) for a 5 unit increment in BMI was 1.19 (95% CI 1.10-1.28, I2 = 83%, n = 7). The association appeared to be stronger at higher compared to lower levels of BMI, pnonlinearity < 0.0001, and the lowest risk was observed at a BMI around 20. The summary RR was 1.24 (95% CI 1.17-1.31, I2 = 0%, pheterogeneity = 0.72, n = 3) per 10 cm increase in waist circumference, 1.37 (95% CI 1.23-1.53, I2 = 0%, pheterogeneity = 0.93, n = 3) per 0.1 unit increase in waist-to-hip ratio, and 1.11 (95% CI 1.07-1.16, I2 = 47%, pheterogeneity = 0.15, n = 3) per 5 kg of weight gain. Adiposity as measured by BMI, waist circumference, waist-to-hip ratio, and weight gain is associated with increased risk of psoriasis.

Body Mass Index, Abdominal Fatness, and Heart Failure Incidence and Mortality: A Systematic Review and Dose-Response Meta-Analysis of Prospective Studies.

BACKGROUND: Obesity has been associated with increased risk of heart failure, but whether overweight also increases risk is unclear. It is also unclear whether abdominal adiposity is more strongly associated with heart failure risk than general adiposity. We conducted a systematic review and meta-analysis of prospective studies to clarify the strength and shape of the dose-response relationship between general and abdominal adiposity and the risk of heart failure. METHODS AND RESULTS: PubMed and Embase databases were searched up to October 10, 2014. Summary relative risks were calculated using random-effects models. A total of 28 studies (27 publications) were included. Twenty-three prospective studies with >15 905 incident cases among 647 388 participants were included in the analysis of body mass index and heart failure incidence, and 4 studies were included for heart failure mortality. The summary relative risk for a 5-unit increment in body mass index was 1.41 (95% confidence interval, 1.34-1.47; I(2)=83%) for heart failure incidence and 1.26 (95% confidence interval, 0.85-1.87; I(2)=95%) heart failure mortality. Although the test for nonlinearity was significant (P<0.0001), this appeared to be attributable to a threshold at a body mass index of ≈23 to 24 kg/m(2); however, there was evidence of increased risk even in the overweight body mass index range. The summary relative risk for a 10-cm increase in waist circumference was 1.29 (95% confidence interval, 1.21-1.37; I(2)=89%) and per 0.1-unit increase in waist-to-hip ratio was 1.29 (95% confidence interval, 1.13-1.47; I(2)=82%). CONCLUSION: Overweight and obesity and abdominal adiposity are associated with increased risk of heart failure.

FGD5 amplification in breast cancer patients is associated with tumour proliferation and a poorer prognosis.

PURPOSE: Proliferation is a hallmark of cancer. Using a combined genomic approach, FGD5 amplification has been identified as a driver of proliferation in Luminal breast cancer. We aimed to describe FGD5 copy number change in breast cancer, and to assess a possible association with tumour proliferation and prognosis. METHODS: We used fluorescence in situ hybridization targeting FGD5 and chromosome 3 centromere (CEP3) on formalin-fixed, paraffin-embedded tissue from 430 primary breast cancers and 108 lymph node metastases, from a cohort of Norwegian breast cancer patients. We tested the association between FGD5 copy number status and proliferation (assessed by Ki67 levels and mitotic count) using Pearson's Chi square test, and assessed the prognostic impact of FGD5 copy number change by estimating cumulative risks of death and hazard ratios. RESULTS: We identified FGD5 amplification (defined as FGD5/CEP3 ratio ≥2 or mean FGD5/tumour cell ≥4) in 9.5% of tumours. Mitotic count and Ki67 levels were higher in tumours with FGD5 copy number increase, compared to tumours with no copy number change. After 10 years of follow-up, cumulative risk of death from breast cancer was higher among cases with FGD5 amplification [48.1% (95% CI 33.8-64.7)], compared to non-amplified cases [27.7% (95% CI 23.4-32.6)]. CONCLUSIONS: FGD5 is a new prognostic marker in breast cancer, and increased copy number is associated with higher tumour proliferation and poorer long-term prognosis.

Insomnia and the Risk of Breast Cancer: The HUNT Study.

OBJECTIVE: The association of insomnia with subsequent breast cancer risk is largely unknown. Therefore, we assessed whether different symptoms of insomnia and their combination are associated with incident breast cancer in a large population-based study. METHODS: In a prospective cohort study, 33,332 women were followed to monitor the occurrence of their first invasive breast cancer identified by the Cancer Registry of Norway. Insomnia symptoms including () nonrestorative sleep and () difficulty initiating and () maintaining sleep were self-reported using a study specific measure reflecting the current Diagnostic and Statistical Manual of Mental Disorders criteria. Hazard ratios and 95% confidence intervals were calculated using multiadjusted Cox proportional hazards models. RESULTS: A total of 862 incident breast cancer cases occurred during a mean follow-up of 14.7 years. No consistent association was observed between the individual insomnia symptoms and breast cancer risk. However, compared to women reporting no insomnia complaints, those who reported having all three aspects of insomnia simultaneously were at increased risk (hazard ratio, 2.38; 95% confidence interval = 1.11-5.09). CONCLUSION: Our results suggest that having only some aspects of insomnia may not predispose someone to breast cancer. In contrast, experiencing all insomnia symptoms simultaneously might confer considerable excess risk.

MDM2 promoter polymorphism del1518 (rs3730485) and its impact on endometrial and ovarian cancer risk.

BACKGROUND: The del1518 (rs3730485) polymorphism is an in/del variant in the MDM2 promoter P1. The variant is in complete linkage disequilibrium with MDM2 SNP309 (rs2279744) and has previously been found associated with an increased risk of colon cancer. In this study we assessed the impact of MDM2 del1518 on risk of ovarian and endometrial cancer. METHODS: Here, we genotyped del1518 in two large hospital-based series of patients diagnosed with ovarian (n = 1,385) or endometrial (n = 1,404) cancer and performed risk estimations as compared to the genotype distribution among 1,872 healthy female controls. RESULTS: In overall analysis we observed no association between del1518 and risk of either ovarian or endometrial cancer. However, stratifying according to SNP309 status, we found the del1518 variant to be associated with a reduced risk of endometrial cancer among individuals carrying the SNP309TT genotype both in the dominant (OR = 0.64; 95% CI = 0.45 - 0.90) and the recessive model (OR = 0.80; 95% CI = 0.65 - 1.00). No such association was observed for ovarian cancer risk. CONCLUSION: We found the MDM2 del1518 del variant to be associated with reduced risk of endometrial cancer among individuals carrying the MDM2 SNP309TT genotype.

Overweight, obesity and height as risk factors for meningioma, glioma, pituitary adenoma and nerve sheath tumor: a large population-based prospective cohort study.

BACKGROUND: In 2016, the International Agency for Research on Cancer (IARC) has announced that avoiding body fatness (i.e. overweight and obesity) contributes to prevent meningioma occurrence, but considered the available evidence for glioma inadequate. The association of body fatness with other CNS tumor subgroups is largely unknown. OBJECTIVES: To assess whether body fatness or body height are associated with risk for meningioma, glioma, pituitary adenoma (PA) or nerve sheath tumor (NST) in a large population-based Norwegian cohort. METHODS: In this prospective cohort study of 1.8 million Norwegian residents, weight and height were measured at baseline and incident intracranial tumors were subsequently identified by linkage to the Cancer Registry of Norway. Cox regression analyses were performed to estimate risk for each tumor subgroup in relation to anthropometric measures, stratified by sex and in different age groups. RESULTS: During 54 million person-years of follow-up 3335 meningiomas, 4382 gliomas, 1071 PAs and 759 NSTs were diagnosed. Obesity (BMI ≥30 kg/m2) was not associated with risk for meningioma or glioma, but was significantly associated with risk for PA (HR 1.43; 95% CI 1.09-1.88) compared with the reference group (BMI 20-24.9 kg/m2). For intracranial NSTs, obesity was associated with reduced tumor risk (HR 0.68; 95% CI 0.46-0.99). Body height was associated with increased risk for all four tumor subgroups. CONCLUSIONS: This study does not confirm overweight or obesity as risk factors for meningioma. Additionally, overweight and obesity can be quite confidently excluded as risk factors for glioma. However, this study indicates that body fatness increases the risk for PA, while it reduces the risk for NST.

Body mass index, abdominal fatness, fat mass and the risk of atrial fibrillation: a systematic review and dose-response meta-analysis of prospective studies.

Different adiposity measures have been associated with increased risk of atrial fibrillation, however, results have previously only been summarized for BMI. We therefore conducted a systematic review and meta-analysis of prospective studies to clarify the association between different adiposity measures and risk of atrial fibrillation. PubMed and Embase databases were searched up to October 24th 2016. Summary relative risks (RRs) were calculated using random effects models. Twenty-nine unique prospective studies (32 publications) were included. Twenty-five studies (83,006 cases, 2,405,381 participants) were included in the analysis of BMI and atrial fibrillation. The summary RR was 1.28 (95% confidence interval: 1.20-1.38, I2 = 97%) per 5 unit increment in BMI, 1.18 (95% CI: 1.12-1.25, I2 = 73%, n = 5) and 1.32 (95% CI: 1.16-1.51, I2 = 91%, n = 3) per 10 cm increase in waist and hip circumference, respectively, 1.09 (95% CI: 1.02-1.16, I2 = 44%, n = 4) per 0.1 unit increase in waist-to-hip ratio, 1.09 (95% CI: 1.02-1.16, I2 = 94%, n = 4) per 5 kg increase in fat mass, 1.10 (95% CI: 0.92-1.33, I2 = 90%, n = 3) per 10% increase in fat percentage, 1.10 (95% CI: 1.08-1.13, I2 = 74%, n = 10) per 5 kg increase in weight, and 1.08 (95% CI: 0.97-1.19, I2 = 86%, n = 2) per 5% increase in weight gain. The association between BMI and atrial fibrillation was nonlinear, p nonlinearity < 0.0001, with a stronger association at higher BMI levels, however, increased risk was observed even at a BMI of 22-24 compared to 20. In conclusion, general and abdominal adiposity and higher body fat mass increase the risk of atrial fibrillation.

Body mass index and physical activity and the risk of diverticular disease: a systematic review and meta-analysis of prospective studies.

PURPOSE: We conducted a systematic review and meta-analysis of prospective studies of the association between body mass index (BMI) and physical activity and diverticular disease risk. METHODS: PubMed and Embase databases were searched up to February 7, 2017. Summary relative risks and 95% confidence intervals (95% CIs) were calculated using a random effects model and nonlinear associations were modeled using fractional polynomial models. RESULTS: Six cohort studies of BMI and diverticular disease risk (28,915 cases, 1,636,777 participants) and five cohort studies of physical activity and diverticular disease risk (2080 cases, 147,869 participants) were included. The summary relative risk (RR) of incident diverticular disease for a 5 unit BMI increment was 1.28 (95% CI: 1.18-1.40, I 2 = 77%, n = 6) for diverticular disease, 1.31 (95% CI: 1.09-1.56, I 2 = 74%, n = 2) for diverticulitis, and 1.20 (95% CI: 1.04-1.40, I 2 = 56%, n = 3) for diverticular disease complications. There was no evidence of a nonlinear association between BMI and diverticular disease risk (p nonlinearity = 0.22), and risk increased even within the normal weight range. Compared to a BMI of 20, the summary RR for a BMI of 22.5, 25.0, 27.5, 30.0, 32.5, 35.0, 37.5, and 40.0 was 1.15 (1.07-1.23), 1.31 (1.17-1.47), 1.50 (1.31-1.71), 1.71 (1.52-1.94), 1.96 (1.77-2.18), 2.26 (2.00-2.54), 2.60 (2.11-3.21), and 3.01 (2.06-4.39), respectively. The summary RR was 0.76 (95% CI: 0.63-0.93, I 2 = 54%, n = 5) for high vs. low physical activity and 0.74 (95% CI: 0.57-0.97, I 2 = 39.5%, p heterogeneity = 0.20, n = 2) for high vs. low vigorous physical activity. CONCLUSIONS: These results suggest that even moderate increases in BMI may increase the risk of diverticular disease as well as diverticular disease complications and that a higher level of physical activity may reduce the risk.

No large-effect low-frequency coding variation found for myocardial infarction.

Genome-wide association studies have identified variants, primarily common, that are associated with coronary artery disease or myocardial infarction (MI), but have not tested the majority of the low frequency and rare variation in the genome. We explored the hypothesis that previously untested low frequency (1-5% minor allele frequency) and rare (<1% minor allele frequency) coding variants are associated with MI. We genotyped 2906 MI cases and 6738 non-MI controls from Norway using the Illumina HumanExome Beadchip, allowing for direct genotyping of 85 972 polymorphic coding variants as well as 48 known GWAS SNPs. We followed-up 34 coding variants in an additional 2350 MI cases and 2318 controls from Norway. We evaluated exome array coverage in a subset of these samples using whole exome sequencing (N = 151). The exome array provided successful genotyping for an estimated 72.5% of Norwegian loss-of-function or missense variants with frequency >1% and 66.2% of variants <1% frequency observed more than once. Despite 80% power in the two-stage study (N = 14 312) to detect association with low-frequency variants with high effect sizes [odds ratio (OR) >1.86 and >1.36 for 1 and 5% frequency, respectively], we did not identify any novel genes or single variants that reached significance. This suggests that low-frequency coding variants with large effect sizes (OR >2) may not exist for MI. Larger sample sizes may identify coding variants with more moderate effects.