Longitudinal Associations Between Vitamin D Status and Cardiometabolic Risk Markers Among Children and Adolescents.

CONTEXT: Vitamin D status has previously been associated with cardiometabolic risk markers in children and adolescents. In particular, it has been suggested that children with obesity are more prone to vitamin D deficiency and unfavorable metabolic outcomes compared with healthy-weight children. OBJECTIVE: To conduct a longitudinal study assessing this association in children and stratify by body mass index (BMI) category. METHODS: Children from the pan-European IDEFICS/I.Family cohort with at least one measurement of serum 25-hydroxyvitamin D [25(OH)D] at cohort entry or follow-up (n = 2171) were included in this study. Linear mixed-effect models were used to assess the association between serum 25(OH)D as an independent variable and z-scores of cardiometabolic risk markers (waist circumference, systolic [SBP] and diastolic blood pressure [DBP], high- [HDL] and low-density lipoprotein, non-HDL, triglycerides [TRG], apolipoprotein A1 [ApoA1] and ApoB, fasting glucose [FG], homeostatic model assessment for insulin resistance [HOMA-IR], and metabolic syndrome score) as dependent variables. RESULTS: After adjustment for age, sex, study region, smoking and alcohol status, sports club membership, screen time, BMI, parental education, and month of blood collection, 25(OH)D levels were inversely associated with SBP, DBP, FG, HOMA-IR, and TRG. The HOMA-IR z-score decreased by 0.07 units per 5 ng/mL increase in 25(OH)D. The 25(OH)D level was consistently associated with HOMA-IR irrespective of sex or BMI category. CONCLUSION: Low serum 25(OH)D concentrations are associated with unfavorable levels of cardiometabolic markers in children and adolescents. Interventions to improve vitamin D levels in children with a poor status early in life may help to reduce cardiometabolic risk.

Association of urinary and ambient black carbon, and other ambient air pollutants with risk of prediabetes and metabolic syndrome in children and adolescents.

The effects of exposure to black carbon (BC) on various diseases remains unclear, one reason being potential exposure misclassification following modelling of ambient air pollution levels. Urinary BC particles may be a more precise measure to analyze the health effects of BC. We aimed to assess the risk of prediabetes and metabolic syndrome (MetS) in relation to urinary BC particles and ambient BC and to compare their associations in 5453 children from IDEFICS/I. Family cohort. We determined the amount of BC particles in urine using label-free white-light generation under femtosecond pulsed laser illumination. We assessed annual exposure to ambient air pollutants (BC, PM2.5 and NO2) at the place of residence using land use regression models for Europe, and we calculated the residential distance to major roads (≤250 m vs. more). We analyzed the cross-sectional relationships between urinary BC and air pollutants (BC, PM2.5 and NO2) and distance to roads, and the associations of all these variables to the risk of prediabetes and MetS, using logistic and linear regression models. Though we did not observe associations between urinary and ambient BC in overall analysis, we observed a positive association between urinary and ambient BC levels in boys and in children living ≤250 m to a major road compared to those living >250 m away from a major road. We observed a positive association between log-transformed urinary BC particles and MetS (ORper unit increase = 1.72, 95% CI = 1.21; 2.45). An association between ambient BC and MetS was only observed in children living closer to a major road. Our findings suggest that exposure to BC (ambient and biomarker) may contribute to the risk of MetS in children. By measuring the internal dose, the BC particles in urine may have additionally captured non-residential sources and reduced exposure misclassification. Larger studies, with longitudinal design including measurement of urinary BC at multiple time-points are warranted to confirm our findings.

Lifestyle and metabolic risk factors in patients with early-onset myocardial infarction: a case-control study.

AIMS: Family history is a known risk factor for early-onset myocardial infarction (EOMI). However, the role of modifiable lifestyle and metabolic factors in EOMI risk is unclear and may differ from that of older adults. METHODS: This case-control study included myocardial infarction (MI) patients aged ≤45 years from the Bremen ST-elevation MI Registry and matched controls randomly selected from the general population (German National Cohort) at the same geographical region. Multiple logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the individual and combined associations of lifestyle and metabolic factors with EOMI risk, overall and according to family history for premature MI. RESULTS: A total of 522 cases and 1191 controls were included. Hypertension, current smoking, elevated waist-to-hip ratio, and diabetes mellitus were strongly associated with the occurrence of EOMI. By contrast, higher frequency of alcohol consumption was associated with decreased EOMI risk. In a combined analysis of the risk factors hypertension, current smoking, body mass index ≥25.0 kg/sqm, and diabetes mellitus, participants having one (OR = 5.4, 95%CI = 2.9-10.1) and two or more risk factors (OR = 42.3, 95%CI = 22.3-80.4) had substantially higher odds of EOMI compared to those with none of these risk factors, regardless of their family history. CONCLUSION: This study demonstrates a strong association of smoking and metabolic risk factors with the occurrence of EOMI. The data suggest that the risk of EOMI goes beyond family history and underlines the importance of primary prevention efforts to reduce smoking and metabolic syndrome in young persons.

Associations between comorbidities and advanced stage diagnosis of lung, breast, colorectal, and prostate cancer: A systematic review and meta-analysis.

Comorbidities and advanced stage diagnosis (ASD) are both associated with poorer cancer outcomes, but the association between comorbidities and ASD is poorly understood. We summarized epidemiological evidence on the association between comorbidities and ASD of selected cancers in a systematic review and meta-analysis. We searched PubMed and Web of Science databases up to June 3rd, 2021 for studies assessing the association between comorbidities and ASD of lung, breast, colorectal, or prostate cancer. Summary odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated using random-effects models. Also, potential variations in the associations between comorbidities and ASD by cancer type were investigated using random-effects meta-regression. Thirty-seven studies were included in this review, including 8,069,397 lung, breast, colorectal, and prostate cancer patients overall. The Charlson comorbidity index score was positively associated with ASD (stages III-IV) of breast cancer but was inversely associated with ASD of lung cancer (pinteraction = 0.004). Regarding specific comorbidities, diabetes was positively associated with ASD (OR = 1.17, 95%CI = 1.09-1.26), whereas myocardial infarction was inversely associated with ASD (OR = 0.84, 95%CI = 0.75-0.95). The association between renal disease and ASD differed by cancer type (pinteraction < 0.001). A positive association was found with prostate cancer (OR = 2.02, 95%CI = 1.58-2.59) and an inverse association with colorectal cancer (OR = 0.84, 95%CI = 0.70-1.00). In summary, certain comorbidities (e.g., diabetes) may be positively associated with ASD of several cancer types. It needs to be clarified whether closer monitoring for early cancer signs or screening in these patients is reasonable, considering the problem of over-diagnosis particularly relevant in patients with short remaining life expectancy such as those with comorbidities. Also, evaluation of the cost-benefit relationship of cancer screening according to the type and severity of comorbidity (rather than summary scores) may be beneficial for personalized cancer screening in populations with chronic diseases.

Clinical presentation of young people (10-24 years old) with brain tumors: results from the international MOBI-Kids study.

INTRODUCTION: We used data from MOBI-Kids, a 14-country international collaborative case-control study of brain tumors (BTs), to study clinical characteristics of the tumors in older children (10 years or older), adolescents and young adults (up to the age of 24). METHODS: Information from clinical records was obtained for 899 BT cases, including signs and symptoms, symptom onset, diagnosis date, tumor type and location. RESULTS: Overall, 64% of all tumors were low-grade, 76% were neuroepithelial tumors and 62% gliomas. There were more males than females among neuroepithelial and embryonal tumor cases, but more females with meningeal tumors. The most frequent locations were cerebellum (22%) and frontal (16%) lobe. The most frequent symptom was headaches (60%), overall, as well as for gliomas, embryonal and 'non-neuroepithelial' tumors; it was convulsions/seizures for neuroepithelial tumors other than glioma, and visual signs and symptoms for meningiomas. A cluster analysis showed that headaches and nausea/vomiting was the only combination of symptoms that exceeded a cutoff of 50%, with a joint occurrence of 67%. Overall, the median time from first symptom to diagnosis was 1.42 months (IQR 0.53-4.80); it exceeded 1 year in 12% of cases, though no particular symptom was associated with exceptionally long or short delays. CONCLUSIONS: This is the largest clinical epidemiology study of BT in young people conducted so far. Many signs and symptoms were identified, dominated by headaches and nausea/vomiting. Diagnosis was generally rapid but in 12% diagnostic delay exceeded 1 year with none of the symptoms been associated with a distinctly long time until diagnosis.

Osteoprotegerin and Cardiovascular Events in High-Risk Populations: Meta-Analysis of 19 Prospective Studies Involving 27 450 Participants.

Background Osteoprotegerin is a cytokine involved in bone metabolism as well as vascular calcification and atherogenesis. Although circulating osteoprotegerin levels are robustly associated with incident cardiovascular disease ( CVD ) in the general population, its relevance as a biomarker among populations at high CVD risk is less clear. Methods and Results Three independent reviewers systematically searched PubMed, EMBASE , and Web of Science to identify prospective studies that had recruited participants on the basis of having conditions related to high CVD risk. A total of 19 studies were eligible for inclusion, reporting on 27 450 patients with diabetes mellitus (2 studies), kidney disease (7 studies), preexisting heart disease (5 studies), or recent acute coronary syndromes (5 studies) at baseline. Over a mean follow-up of 4.2 years, 4066 CVD events were recorded. In a random-effects meta-analysis, the pooled risk ratio for CVD events comparing people in the top versus the bottom tertile of osteoprotegerin concentration was 1.30 (95% confidence interval, 1.12-1.50; P<0.001; I2=68.3%). There was evidence for presence of publication bias ( P value from Egger's test=0.013). Correction for publication bias using the trim-and-fill method reduced the risk ratio to 1.21 (95% confidence interval, 1.03-1.42; P<0.001). The risk ratios did not vary significantly by population type, geographical region, statistical adjustment, sample or assay type, age, sex, or length of follow-up. Conclusions In populations at high CVD risk, elevated circulating osteoprotegerin levels are associated with a higher risk for future CVD events. The magnitude of association appears weaker than in the general population.

Common genetic variation and risk of gallbladder cancer in India: a case-control genome-wide association study.

BACKGROUND: Gallbladder cancer is highly lethal, with notable differences in incidence by geography and ethnic background. The aim of this study was to identify common genetic susceptibility alleles for gallbladder cancer. METHODS: In this case-control genome-wide association study (GWAS), we did a genome-wide scan of gallbladder cancer cases and hospital visitor controls, both of Indian descent, followed by imputation across the genome. Cases were patients aged 20-80 years with microscopically confirmed primary gallbladder cancer diagnosed or treated at Tata Memorial Hospital, Mumbai, India, and enrolled in the study between Sept 12, 2010, and June 8, 2015. We only included patients who had been diagnosed less than 1 year before the date of enrolment and excluded patients with any other malignancies. We recruited visitor controls aged 20-80 years with no history of cancer visiting all departments or units of Tata Memorial Hospital during the same time period and frequency matched them to cases on the basis of age, sex, and current region of residence. We estimated association using logistic regression, adjusting for age, sex, and five eigenvectors. We recruited samples for a replication cohort from patients visiting Tata Memorial Hospital between Aug 4, 2015, and May 17, 2016, and patients visiting the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India, between July, 2010, and May, 2015. We used the same inclusion and exclusion criteria for the replication set. We examined three of the most significant single-nucleotide polymorphisms (SNPs) in the replication cohort and did a meta-analysis of the GWAS discovery and replication sets to get combined estimates of association. FINDINGS: The discovery cohort comprised 1042 gallbladder cancer cases and 1709 controls and the replication cohort contained 428 gallbladder cancer cases and 420 controls. We observed genome-wide significant associations for several markers in the chromosomal region 7q21.12 harbouring both the ABCB1 and ABCB4 genes, with the most notable SNPs after replication and meta-analysis being rs1558375 (GWAS p=3·8 × 10-9; replication p=0·01; combined p=2·3 × 10-10); rs17209837 (GWAS p=2·0 × 10-8; replication p=0·02; combined p=2·3 × 10-9), and rs4148808 (GWAS p=2·4 × 10-8; replication p=0·008; combined p=2·7 × 10-9). Combined estimates of per-allele trend odds ratios were 1·47 (95% CI 1·30-1·66; p=2·31 × 10-10) for rs1558375, 1·61 (1·38-1·89; p=2·26 × 10-9) for rs17209837, and 1·57 (1·35-1·82; p=2·71 × 10-9) for rs4148808. GWAS heritability analysis suggested that common variants are associated with substantial variation in risk of gallbladder cancer (sibling relative risk 3·15 [95% CI 1·80-5·49]). INTERPRETATION: To our knowledge, this study is the first report of common genetic variation conferring gallbladder cancer risk at genome-wide significance. This finding, along with in-silico and biological evidence indicating the potential functional significance of ABCB1 and ABCB4, underlines the likely importance of these hepatobiliary phospholipid transporter genes in the pathology of gallbladder cancer. FUNDING: The Tata Memorial Centre and Department of Biotechnology.

Association of Genome-Wide Association Study (GWAS) Identified SNPs and Risk of Breast Cancer in an Indian Population.

To date, no studies have investigated the association of the GWAS-identified SNPs with BC risk in Indian population. We investigated the association of 30 previously reported and replicated BC susceptibility SNPs in 1,204 cases and 1,212 controls from a hospital based case-control study conducted at the Tata Memorial Hospital, Mumbai. As a measure of total susceptibility burden, the polygenic risk score (PRS) for each individual was defined by the weighted sum of genotypes from 21 independent SNPs with weights derived from previously published estimates of association odds-ratios. Logistic regression models were used to assess risk associated with individual SNPs and overall PRS, and stratified by menopausal and receptor status. A total of 11 SNPs from eight genomic regions (FGFR2, 9q31.2, MAP3K, CCND1, ZM1Z1, RAD51L11, ESR1 and UST) showed statistically significant (p-value ≤ 0.05) evidence of association, either overall or when stratified by menopausal status or hormone receptor status. BC SNPs previously identified in Caucasian population showed evidence of replication in the Indian population mainly with respect to risk of postmenopausal and hormone receptor positive BC.

Understanding rural-urban differences in risk factors for breast cancer in an Indian population.

PURPOSE: Although cancer registry data indicate that there are large differences in breast cancer (BC) rates between rural and urban regions of India, the reasons for these differences are not well understood. METHODS: We conducted a hospital based case-control study (1,637 breast cancer cases; 1,515 visitor controls) in Mumbai, India, during the years 2009-2013. Extensive questionnaire data, anthropometry measurement and blood samples were collected on all participants. Using logistic regression models, we estimated risk based on odds ratio (OR) and 95 % confidence intervals (CI) for various reproductive and anthropometric measures, stratified by rural-urban status depending upon residence in first 20 years of life. RESULTS: Waist-to-hip ratio of ≥0.95 compared to ratio ≤0.84 was strongly associated with risk of BC in both rural and urban populations (ORurban = 4.10, 95 % CI 3.03-5.56; ORrural = 3.01, 95 % CI 1.85-4.90). First full-term pregnancy after the age of 25 compared to first full-term pregnancy below 20 years of age was associated with risk of BC in both urban and rural women (ORurban = 1.78, 95 % CI 1.32-2.41; ORrural = 2.24, 95 % CI 1.13-4.43). The prevalence of age at first full-term pregnancy was significantly lower in rural (mean age at first full-term pregnancy = 19.39 years) versus urban women (mean age at first full-term pregnancy = 22.62 years), whereas mean waist circumference was much higher in urban women (82.13 cm) compared to rural women (79.26 cm). We did not observe any association between breast feeding and risk of BC. CONCLUSIONS: Differences in the prevalence of central adiposity and age at first full-term pregnancy between rural and urban women from India may explain some differences in breast cancer rates between these two populations.

The MOBI-Kids Study Protocol: Challenges in Assessing Childhood and Adolescent Exposure to Electromagnetic Fields from Wireless Telecommunication Technologies and Possible Association with Brain Tumor Risk.

The rapid increase in mobile phone use in young people has generated concern about possible health effects of exposure to radiofrequency (RF) and extremely low frequency (ELF) electromagnetic fields (EMF). MOBI-Kids, a multinational case-control study, investigates the potential effects of childhood and adolescent exposure to EMF from mobile communications technologies on brain tumor risk in 14 countries. The study, which aims to include approximately 1,000 brain tumor cases aged 10-24 years and two individually matched controls for each case, follows a common protocol and builds upon the methodological experience of the INTERPHONE study. The design and conduct of a study on EMF exposure and brain tumor risk in young people in a large number of countries is complex and poses methodological challenges. This manuscript discusses the design of MOBI-Kids and describes the challenges and approaches chosen to address them, including: (1) the choice of controls operated for suspected appendicitis, to reduce potential selection bias related to low response rates among population controls; (2) investigating a young study population spanning a relatively wide age range; (3) conducting a large, multinational epidemiological study, while adhering to increasingly stricter ethics requirements; (4) investigating a rare and potentially fatal disease; and (5) assessing exposure to EMF from communication technologies. Our experience in thus far developing and implementing the study protocol indicates that MOBI-Kids is feasible and will generate results that will contribute to the understanding of potential brain tumor risks associated with use of mobile phones and other wireless communications technologies among young people.

Increase in breast cancer incidence among older women in Mumbai: 30-year trends and predictions to 2025.

BACKGROUND: Increasing trends in the incidence of breast cancer have been observed in India, including Mumbai. These have likely stemmed from an increasing adoption of lifestyle factors more akin to those commonly observed in westernized countries. Analyses of breast cancer trends and corresponding estimation of the future burden are necessary to better plan rationale cancer control programmes within the country. METHODS: We used data from the population-based Mumbai Cancer Registry to study time trends in breast cancer incidence rates 1976-2005 and stratified them according to younger (25-49) and older age group (50-74). Age-period-cohort models were fitted and the net drift used as a measure of the estimated annual percentage change (EAPC). Age-period-cohort models and population projections were used to predict the age-adjusted rates and number of breast cancer cases circa 2025. RESULTS: Breast cancer incidence increased significantly among older women over three decades (EAPC = 1.6%; 95% CI 1.1-2.0), while lesser but significant 1% increase in incidence among younger women was observed (EAPC = 1.0; 95% CI 0.2-1.8). Non-linear period and cohort effects were observed; a trends-based model predicted a close-to-doubling of incident cases by 2025 from 1300 mean cases per annum in 2001-2005 to over 2500 cases in 2021-2025. CONCLUSIONS: The incidence of breast cancer has increased in Mumbai during last two to three decades, with increases greater among older women. The number of breast cancer cases is predicted to double to over 2500 cases, the vast majority affecting older women.

Changing trends of chronic myeloid leukemia in greater Mumbai, India over a period of 30 years.

BACKGROUND: Little is known about burden of chronic myeloid leukemia (CML) in India. There is a recent interest to observe incidence and mortality because of advent of new diagnostic and treatment policies for CML. MATERIALS AND METHODS: We extracted data from the oldest population-based cancer registry of Mumbai for 30 years period from 1976-2005 to observe incidence and mortality rates of CML. We classified the data into four age groups 0-14, 15-29, 30-54 and 55-74 to observe incidence rates in the respective age groups. RESULTS: The age specific rates were highest for the age group of 55-74 years. No significant change in trends of CML was observed for 30 years period. However, there was a significant reduction in incidence rate for recent 15-years period (Estimated average annual percentage change=-3.9). No significant reduction in mortality rate was observed till 2005. CONCLUSION: The study demonstrates that age-specific rates for CML are highest in age group of 55-74 years, although they are lower compared to western populations. Significant reduction in incidence of CML in recent periods might be because of reduced misclassification of leukemias. The data of CML has to be observed for another decade to witness reduction in mortality because of changes in treatment management.