Vitamin D-associated genetic variants in the Brazilian population: Investigating potential instruments for Mendelian randomization. / Variantes genéticas asociadas con la vitamina D en la población brasileña: investigación de potenciales instrumentos para aleatorización mendeliana

INTRODUCTION: Vitamin D is required for bone and mineral metabolism and participates in the regulation of the immune response. It is also linked to several chronic diseases and conditions, usually in populations of European descent. Brazil presents a high prevalence of vitamin D deficiency and insufficiency despite the widespread availability of sunlight in the country. Thus, it is important to investigate the role of vitamin D as a risk factor for disease and to establish causal relationships between vitamin D levels and health-related outcomes in the Brazilian population. OBJECTIVE: To examine genetic variants identified as determinants of serum vitamin D in genome-wide association studies of European populations and check whether the same associations are present in Brazil. If so, these single nucleotide polymorphisms (SNPs) could be developed locally as proxies to use in genetically informed causal inference methods, such as Mendelian randomization. MATERIALS AND METHODS: We extracted SNPs associated with vitamin D from the genomewide association studies catalog. We did a literature search to select papers ascertaining these variants and vitamin D concentrations in Brazil. RESULTS: GC was the gene with the strongest association with vitamin D levels, in agreement with existing findings in European populations. However, VDR was the most investigated gene, regardless of its non-existing association with vitamin D in the genomewide association studies. CONCLUSIONS: More research is needed to validate sound proxies for vitamin D levels in Brazil, for example, prioritizing GC rather than VDR.

Introducción. La vitamina D es necesaria para el metabolismo óseo y mineral, y participa en la regulación de la respuesta inmunitaria. También está relacionada con enfermedades crónicas en poblaciones europeas. En Brasil, existe una prevalencia elevada de deficiencia e insuficiencia de vitamina D, a pesar de la amplia disponibilidad de luz solar. Por lo tanto, es importante investigar el papel de la vitamina D como factor de riesgo de diversas enfermedades y establecer relaciones causales entre los niveles de vitamina D y los problemas de salud en la población brasileña. Objetivo. Examinar variantes genéticas relacionadas con la vitamina D sérica en estudios de asociación genómica de poblaciones europeas y comprobar si estas mismas están presentes en Brasil. De ser así, estos SNPs podrían utilizarse como proxies en métodos de inferencia causal, tales como la aleatorización mendeliana. Materiales y métodos. A partir del catálogo de estudios de asociación de genoma completo se extrajeron SNPs relacionados con los niveles de vitamina D. Luego se hizo una búsqueda bibliográfica para identificar los artículos que evaluaran estos SNPs y la concentración de vitamina D en Brasil. Resultados. GC fue el gen más fuertemente asociado con los niveles de vitamina D, en concordancia con los resultados existentes en poblaciones europeas. Sin embargo, el gen VDR fue el más investigado, aunque no esté vinculado con la vitamina D en los estudios de asociación de genoma completo. Conclusiones. Se necesita más investigación para validar proxies genéticos de los niveles de vitamina D en Brasil y se recomienda priorizar el gen GC en lugar de VDR.

Quantitative PCR as a marker for preemptive therapy and its role in therapeutic control in Trypanosoma cruzi/HIV coinfection.

BACKGROUND: Trypanosoma cruzi and HIV coinfection can evolve with depression of cellular immunity and increased parasitemia. We applied quantitative PCR (qPCR) as a marker for preemptive antiparasitic treatment to avoid fatal Chagas disease reactivation and analyzed the outcome of treated cases. METHODOLOGY: This mixed cross-sectional and longitudinal study included 171 Chagas disease patients, 60 coinfected with HIV. Of these 60 patients, ten showed Chagas disease reactivation, confirmed by parasites identified in the blood, cerebrospinal fluid, or tissues, 12 exhibited high parasitemia without reactivation, and 38 had low parasitemia and no reactivation. RESULTS: We showed, for the first time, the success of the timely introduction of benznidazole in the non-reactivated group with high levels of parasitemia detected by qPCR and the absence of parasites in reactivated cases with at least 58 days of benznidazole. All HIV+ patients with or without reactivation had a 4.0-5.1 higher chance of having parasitemia than HIV seronegative cases. A positive correlation was found between parasites and viral loads. Remarkably, treated T. cruzi/HIV-coinfected patients had 77.3% conversion from positive to negative parasitemia compared to 19.1% of untreated patients. Additionally, untreated patients showed ~13.6 times higher Odds Ratio of having positive parasitemia in the follow-up period compared with treated patients. Treated and untreated patients showed no differences regarding the evolution of Chagas disease. The main factors associated with all-cause mortality were higher parasitemia, lower CD4 counts/µL, higher viral load, and absence of antiretroviral therapy. CONCLUSION: We recommend qPCR prospective monitoring of T. cruzi parasitemia in HIV+ coinfected patients and point out the value of pre-emptive therapy for those with high parasitemia. In parallel, early antiretroviral therapy introduction is advisable, aiming at viral load control, immune response restoration, and increasing survival. We also suggest an early antiparasitic treatment for all coinfected patients, followed by effectiveness analysis alongside antiretroviral therapy.

Burden of respiratory failure in pediatric patients: Analysis of a prospective multicenter cohort in Bogotá, Colombia.

Background and Aims: The approach to the burden of disease is a demographic, economic, and a health problem, which requires the design and application of specific measures of cost of the disease, such as disability-adjusted life years (DALYs), to establish better public health policies in the pediatric population. The aim of this study is to approach the burden of disease in children with acute respiratory failure (ARF) through the calculation of DALYs. Methods: This study was conducted in the framework of a prospective, multicenter cohort in Bogotá, Colombia. Inclusion criteria were all pediatric patients admitted to the emergency department, hospitalization, and intensive care unit with respiratory distress; eligible patients were all those who developed ARF between April 2020 and December 2021. They were followed-up during hospitalization, at 30 and 60 days after admission. The Infant/Toddler Quality of Life Questionnaire and KIDSCREEN quality of life scales were applied for follow-up according to the age group. The results were used to calculate DALYs. Results: Six hundred and eighty-five eligible patients, 296 (43.08%) developed ARF, of these 22 (6.08%) patients died (mortality rate = 7.43%). The total DALYs was 277.164 years. For younger than 9 years, the DALYs were 302.64 years, while for older than 10 years were 40.49 years. Conclusion: ARF is one of the main causes of preventable mortality in pediatrics, its progression to respiratory failure is a highly prevalent condition in pediatric age, a condition that has a great impact on mortality, morbidity, and disability in our patients.

Incidence of appendiceal neoplasms in appendectomy patients.

BACKGROUND: Non-operative management has been suggested as a therapy for uncomplicated appendicitis. Notwithstanding, the risk of missing an appendiceal tumor must be considered, being the surgical piece crucial to rule out neoplasms. Therefore, we aim to determine the incidence of appendiceal neoplasms in patients with acute appendicitis, tumor types and the importance of the anatomopathological study of the surgical piece. STUDY DESIGN: Retrospective study in which we described patients who underwent emergent appendectomy with histopathological findings of appendiceal neoplasms from January 2012 to September 2018. Descriptive analysis included demographic variables, diagnostic methods, and surgical techniques. RESULTS: 2993 patients diagnosed with acute appendicitis who underwent an emergency appendectomy. 64 neoplasms of the appendix were found with an incidence of 2,14%. 67.2% were women, the mean age was 46,4 years (± 19.5). The most frequent appendiceal neoplasms were neuroendocrine tumors (42,2%), followed by appendiceal mucinous neoplasms (35,9%), sessile serrated adenomas (18,8%), and adenocarcinomas (3,1%). In 89,1% of the cases, acute appendicitis was determined by imaging, and 14% of cases were suspected intraoperatively. Appendectomy was performed in 78,1% without additional procedures. CONCLUSIONS: Appendiceal tumors are rare and must be ruled out in patients with suspected acute appendicitis. The incidence of incidental neoplasms is higher in this study than in the previously reported series. This information must be included in decision-making when considering treatment options for acute appendicitis.

What can Mendelian randomization contribute to biological anthropology?

Uncovering causal relationships between exposures and outcomes can be difficult in observational studies because of the potential for confounding and reverse causation to produce biased estimates. Conversely, randomized controlled trials (RCTs) provide the strongest evidence for causality but they are not always feasible. Mendelian randomization (MR) is a method that aims to strengthen causal inference using genetic variants as proxies or instrumental variables (IVs) for exposures, to overcome the above-mentioned biases. Since allele segregation occurs at random from parents to offspring, and alleles for a trait assort independently from those for other traits, MR studies have frequently been compared to "natural" RCTs. In biological anthropology (BA) relationships between variables of interest are usually evaluated using observational data, often remaining descriptive, and other approaches to causal inference have seldom been implemented. Here, we propose the use of MR to investigate cause and effect relationships in BA studies and provide examples to show how that can be done across areas of BA relevance, such as adaptation to the environment, nutrition and life history theory. While we consider MR a useful addition to the biological anthropologist's toolbox, we advocate the adoption of a wide range of methods, affected by different types of biases, in order to better answer the important causal questions for the discipline.

Use of high-flow cannula in pediatric patients with respiratory failure: A prospective cohort study in three high-altitude hospitals.

Background and Aims: Acute respiratory failure (ARF) is a common cause of morbimortality, and a frequent reason for admission to the pediatric intensive care unit (PICU). It requires a high-flow oxygen device as treatment. Our aim is to determine the frequency and main indications for the use of high-flow nasal cannula (HFNC), and the prevalence of HFNC failure and its main causes, in three hospitals. Methods: It is a multicenter prospective cohort study, developed in three hospitals in Bogota. Eligible patients were children older than 1 month and younger than 18 years who presented ARF and required management with an HFNC. The study was carried out between April 2020 and December 2021. The follow-up was carried out at 1, 6, and 48 h after starting the management. Results: Of 685 patients included in the study, 296 developed ARF. The prevalence of patients with ARF who required management with HFNC was 48%. The frequency of the pathologies that cause the ARF was: Bronchiolitis was the most frequent pathology (34.5%), followed by asthmatic crisis (15.5%) and pneumonia (12.7%). The average time of use of HFNC was 81.6 h. Regarding treatment failure with HFNC, 15 patients presented torpid evolution and required invasive mechanical ventilation, with a prevalence of therapeutic failure of the HFNC of 10.6%. Conclusion: The use of HFNC is more frequent in patients with bronchiolitis, in children under 2 years of age and in males, which is in line with what has been reported in the literature. In addition, the failure rate of HFNC is low (10.6%), and it may be useful in other pathologies besides bronchiolitis, such as asthma, pneumonia, among others. It opens the possibility to continue evaluating the role of HFNC in pediatric pathology in new studies.

Medical geneticists, genetic diseases and services in Brazil in the age of personalized medicine.

Aim: In anticipation of the implementation of personalized medicine in Brazil the authors assessed the characteristics of its medical genetics workforce together with the distribution of genetic diseases and services across the country. Materials & methods: The authors used demographic data on medical specialties, and summarized data from the public and private healthcare systems on live births, hospitalization and mortality, for the years 2019 and 2020. Results: The distribution of medical geneticists (MGs) overlapped the country-wide distribution of genetic diseases and services examined, indicating that ∼30% of the patient population has access to a MG specialist. Graduate specialism in medical genetics, registered MGs and suitable workplaces were concentrated in the south and southeast regions, leaving the north and northeast deeply underserved. Conclusion: MGs are concentrated in the wealthiest and most populated areas, while other regions have very limited services. These inequalities should be addressed for a successful transition to personalized medicine.

Personalized, or precision, medicine promotes the incorporation of information on an individual's genetic profile, and environmental and lifestyle exposures in the clinic to prevent and treat diseases. While personalized medicine is closer to being a reality in industrialized countries, it is unclear whether the conditions for its implementation exist in developing nations. The authors assessed the situation in Brazil, a country with a free-at-point-of-care universal health system, and private health insurance coverage for ∼30% of its population. The authors found that a majority of medical geneticists and genetic services were based in the south and southeast regions, which are also the wealthiest and most populated, leaving the other regions largely underserved. In addition, the authors identified a need to curb public­private healthcare asymmetries in medical genetics in order to reduce the observed inequalities.

The Skin We Live in: Pigmentation Traits and Tanning Behaviour in British Young Adults, an Observational and Genetically-Informed Study.

Skin cancer incidence has been increasing worldwide, representing a particularly high burden for populations of European ancestry. Outdoor and indoor tanning using ultraviolet (UV) radiation devices are major risk factors for skin cancer. While tanning behaviours can be modified by targeted interventions to reduce skin cancer rates, there is insufficient evidence on the motivations for tanning preferences and their relationship with pigmentation phenotypes. The present observational and genetically-informed study investigates motives for tanning and the role that pigmentation phenotypes play on outdoor and indoor tanning behaviour in British young adults. This study included 3722 participants from the Avon Longitudinal Study of Parents and Children in South West England, with data on pigmentation features, tanning ability and preferences, and SNP genotypes. Liking to tan and outdoor tanning were strongly influenced by pigmentary traits and tanning ability. However, the association of these phenotypes with UV indoor tanning was weaker. Our results provide evidence to support the implementation of skin cancer preventative interventions that consider individual biological characteristics and motives for undergoing outdoor and indoor tanning.

COVID-19 in children and the influence on the employment activity of their female caregivers: A cross sectional gender perspective study.

Introduction: During the COVID-19 pandemic, women disproportionately assume more unpaid activities, affecting their employment. Objective: Describe the influence of COVID-19 on the employment of caregivers of children and adolescents from a gender perspective. Methods: Cross-sectional study in three high-complexity hospitals in Bogotá, Colombia from April 2020 to June 2021. A subsample of the FARA cohort was taken, including those patients with a positive test for SARS-COV2. We took as our analysis category children older than 8 years and younger than 18 years who had a positive SARS-COV2 test, as well as, caregivers of all children with a positive SARS-COV2 test. This subsample was drawn from the FARA cohort. A survey was applied to them. We carried out a descriptive and stratified analysis by age group, educational, and socioeconomic level. Results: We included 60 surveys of caregivers and 10 surveys of children. The main caregiver in 94.8% of the cases was a female. At the beginning of the pandemic, 63.3% of the caregivers were employed, and 78.9% of those lost their employment. The vast majority of these caregiver were women (96.6%, n = 29). A predominance of loss of work activity was documented in caregivers of children in early childhood 66.6% (n = 20), with lower education 66.6% (n = 20), and from lower strata 56.6% (n = 17). Conclusion: Caregivers of children with COVID-19 with low educational levels and lower socioeconomic conditions, as well as those with children under 5 years showed greater likelihood of employment loss between the interviewed subsample.

Sleep-related traits and attention-deficit/hyperactivity disorder comorbidity: Shared genetic risk factors, molecular mechanisms, and causal effects.

OBJECTIVES: To evaluate the shared genetic components, common pathways and causal relationship between ADHD and sleep-related phenotypes. METHODS: We used the largest genome-wide association summary statistics available for attention-deficit/hyperactivity disorder (ADHD) and various sleep-related phenotypes (insomnia, napping, daytime dozing, snoring, ease getting up, daytime sleepiness, sleep duration and chronotype). We estimated the genomic correlation using cross-trait linkage disequilibrium score regression (LDSR) and investigated the potential common mechanisms using gene-based cross-trait metanalyses and functional enrichment analyses. The causal effect was estimated using two-sample Mendelian randomisation (TSMR), using the inverse variance weighted method as the main estimator. RESULTS: A positive genomic correlation between insomnia, daytime napping, daytime dozing, snoring, daytime sleepiness, short and long sleep duration, and ADHD was observed. Insomnia, daytime sleepiness, and snoring shared genes with ADHD, that are involved in neurobiological functions and regulatory signalling pathways. The TSMR supported a causal effect of insomnia, daytime napping, and short sleep duration on ADHD, and of ADHD on long sleep duration and chronotype. CONCLUSION: Comorbidity between sleep phenotypes and ADHD may be mediated by common genetic factors that play an important role in neuronal signalling pathways. A causal effect of sleep disturbances and short sleep duration on ADHD reinforced their role as predictors of ADHD.

Genetic loci associated with skin pigmentation in African Americans and their effects on vitamin D deficiency.

A recent genome-wide association study (GWAS) in African descent populations identified novel loci associated with skin pigmentation. However, how genomic variations affect skin pigmentation and how these skin pigmentation gene variants affect serum 25(OH) vitamin D variation has not been explored in African Americans (AAs). In order to further understand genetic factors that affect human skin pigmentation and serum 25(OH)D variation, we performed a GWAS for skin pigmentation with 395 AAs and a replication study with 681 AAs. Then, we tested if the identified variants are associated with serum 25(OH) D concentrations in a subset of AAs (n = 591). Skin pigmentation, Melanin Index (M-Index), was measured using a narrow-band reflectometer. Multiple regression analysis was performed to identify variants associated with M-Index and to assess their role in serum 25(OH)D variation adjusting for population stratification and relevant confounding variables. A variant near the SLC24A5 gene (rs2675345) showed the strongest signal of association with M-Index (P = 4.0 x 10-30 in the pooled dataset). Variants in SLC24A5, SLC45A2 and OCA2 together account for a large proportion of skin pigmentation variance (11%). The effects of these variants on M-Index was modified by sex (P for interaction = 0.009). However, West African Ancestry (WAA) also accounts for a large proportion of M-Index variance (23%). M-Index also varies among AAs with high WAA and high Genetic Score calculated from top variants associated with M-Index, suggesting that other unknown genomic factors related to WAA are likely contributing to skin pigmentation variation. M-Index was not associated with serum 25(OH)D concentrations, but the Genetic Score was significantly associated with vitamin D deficiency (serum 25(OH)D levels less than 12 ng/mL) (OR, 1.30; 95% CI, 1.04-1.64). The findings support the hypothesis suggesting that skin pigmentation evolved responding to increased demand for subcutaneous vitamin D synthesis in high latitude environments.

Investigating DNA methylation as a potential mediator between pigmentation genes, pigmentary traits and skin cancer.

Pigmentation characteristics are well-known risk factors for skin cancer. Polymorphisms in pigmentation genes have been associated with these traits and with the risk of malignancy. However, the functional relationship between genetic variation and disease is still unclear. This study aims to assess whether pigmentation SNPs are associated with pigmentary traits and skin cancer via DNA methylation (DNAm). Using a meta-GWAS of whole-blood DNAm from 36 European cohorts (N = 27,750; the Genetics of DNA Methylation Consortium, GoDMC), we found that 19 out of 27 SNPs in 10 pigmentation genes were associated with 391 DNAm sites across 30 genomic regions. We examined the effect of 25 selected DNAm sites on pigmentation traits, sun exposure phenotypes and skin cancer and on gene expression in whole blood. We uncovered an association of DNAm site cg07402062 with red hair in the Avon Longitudinal Study of Parents and Children (ALSPAC). We also found that the expression of ASIP and CDK10 was associated with hair colour, melanoma and basal cell carcinoma. Our results indicate that DNAm and expression of pigmentation genes may play a role as potential mediators of the relationship between genetic variants, pigmentation phenotypes and skin cancer and thus deserve further scrutiny.

Discovery of novel DNA methylation biomarkers for non-invasive sporadic breast cancer detection in the Latino population.

Human diversity is one of the main pitfalls in the development of robust worldwide biomarkers in oncology. Epigenetic variability across human populations is associated with different genetic backgrounds, as well as variable lifestyles and environmental exposures, each of which should be investigated. To identify potential non-invasive biomarkers of sporadic breast cancer in the Uruguayan population, we studied genome-wide DNA methylation using Illumina methylation arrays in leukocytes of 22 women with sporadic breast cancer and 10 healthy women in a case-control study. We described a panel of 38 differentially methylated CpG positions that was able to cluster breast cancer patients (BCP) and controls, and that also recapitulated methylation differences in 12 primary breast tumors and their matched normal breast tissue. Moving forward, we simplified the detection method to improve its applicability in a clinical setting and used an independent well-characterized cohort of 80 leukocyte DNA samples from BCP and 80 healthy controls to validate methylation results at specific cancer-related genes. Our investigations identified methylation at CYFIP1 as a novel epigenetic biomarker candidate for sporadic breast cancer in the Uruguayan population. These results provide a proof-of-concept for the design of larger studies aimed at validating biomarker panels for the Latin American population.

Genomic Diversity in Sporadic Breast Cancer in a Latin American Population.

Among Latin American women, breast cancer incidences vary across populations. Uruguay and Argentina have the highest rates in South America, which are mainly attributed to strong, genetic European contributions. Most genetic variants associated with breast cancer were described in European populations. However, the vast majority of genetic contributors to breast cancer risk remain unknown. Here, we report the results of a candidate gene association study of sporadic breast cancer in 176 cases and 183 controls in the Uruguayan population. We analyzed 141 variants from 98 loci that have been associated with overall breast cancer risk in European populations. We found weak evidence for the association of risk variants rs294174 (ESR1), rs16886165 (MAP3K1), rs2214681 (CNTNAP2), rs4237855 (VDR), rs9594579 (RANKL), rs8183919 (PTGIS), rs2981582 (FGFR2), and rs1799950 (BRCA1) with sporadic breast cancer. These results provide useful insight into the genetic susceptibility to sporadic breast cancer in the Uruguayan population and support the use of genetic risk scores for individualized screening and prevention.

Genetic ancestry, skin color and social attainment: The four cities study.

INTRODUCTION: The Black population in the US is heterogeneous but is often treated as monolithic in research, with skin pigmentation being the primary indicator of racial classification. Objective: This paper examines the differences among Blacks by comparing genetic ancestry, skin color and social attainment of 259 residents across four US cities-Norman, Oklahoma; Cincinnati, Ohio; Harlem, New York; and Washington, District of Columbia. METHODS: Participants were recruited between 2004 and 2006 at community-based forums. Cross-sectional data were analyzed using chi-square tests, correlation analyses and logistic regression. RESULTS: There were variations in ancestry, melanin index and social attainment across some cities. Overall, men with darker skin color, and women with lighter skin color were significantly more likely to be married. Darker skin individuals with significantly more West African ancestry reported attainment of graduate degrees, and professional occupations than lighter skin individuals. CONCLUSIONS: Our findings suggest differences in skin pigmentation by geography and support regional variations in ancestry of US Blacks. Biomedical research should consider genetic ancestry and local historical/social context rather than relying solely on skin pigmentation as a proxy for race.

Genetic Epidemiology in Latin America: Identifying Strong Genetic Proxies for Complex Disease Risk Factors.

Epidemiology seeks to determine the causal effects of exposures on outcomes related to the health and wellbeing of populations. Observational studies, one of the most commonly used designs in epidemiology, can be biased due to confounding and reverse causation, which makes it difficult to establish causal relationships. In recent times, genetically informed methods, like Mendelian randomization (MR), have been developed in an attempt to overcome these disadvantages. MR relies on the association of genetic variants with outcomes of interest, where the genetic variants are proxies or instruments for modifiable exposures. Because genotypes are sorted independently and at random at the time of conception, they are less prone to confounding and reverse causation. Implementation of MR depends on, among other things, a strong association of the genetic variants with the exposure, which has usually been defined via genome-wide association studies (GWAS). Because GWAS have been most often carried out in European populations, the limited identification of strong instruments in other populations poses a major problem for the application of MR in Latin America. We suggest potential solutions that can be realized with the resources at hand and others that will have to wait for increased funding and access to technology.

Allergy, asthma, and the risk of breast and prostate cancer: a Mendelian randomization study.

PURPOSE: The relationship of allergic diseases, such as asthma, hay fever, and eczema, with cancer is under debate. Observational studies have reported conflicting findings, but such studies are susceptible to confounding and reverse causation. Understanding the potential role of allergy in carcinogenesis may shed new light on the biological mechanisms underpinning intrinsic immunity and cancer. METHODS: We conducted a Mendelian randomization study, using germline genetic variants as instrumental variables, to determine the causal relevance of allergic disease and on two most common malignancies: breast cancer and prostate cancer. We used the summary statistics from the largest ever genome-wide association studies conducted on allergic disease (ncase = 180,129), asthma (ncase = 14,085), breast (ncase = 122,977), and prostate cancer (ncase = 79,148) and calculated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer for allergic disease. RESULTS: We did not observe any evidence to support a causal association between allergic disease and risk of breast cancer overall [OR 1.00 (95% CI 0.96-1.04), p = 0.95] or by subtype (estrogen receptor (ER)+ [0.99 (0.95-1.04), p = 0.71], ER- [1.05 (0.99-1.10), p = 0.11]). We also did not find any evidence for an association with prostate cancer [1.00 (0.94-1.05), p = 0.93] or advanced subtype [0.97 (0.90-1.05), p = 0.46]. Sensitivity analyses did not reveal directional pleiotropy. CONCLUSION: Our study does not support a causal effect of allergic disease on the risk of breast or prostate cancer. Future studies may be conducted to focus on understanding the causal role of allergic disease in cancer prognosis or drug responses (e.g., immunotherapy).

Mendelian randomization does not support serum calcium in prostate cancer risk.

PURPOSE: Observational studies suggest that dietary and serum calcium are risk factors for prostate cancer. However, such studies suffer from residual confounding (due to unmeasured or imprecisely measured confounders), undermining causal inference. Mendelian randomization uses randomly assigned (hence unconfounded and pre-disease onset) germline genetic variation to proxy for phenotypes and strengthen causal inference in observational studies. We tested the hypothesis that serum calcium is associated with an increased risk of overall and advanced prostate cancer. METHODS: A genetic instrument was constructed using five single-nucleotide polymorphisms robustly associated with serum calcium in a genome-wide association study (n ≤ 61,079). This instrument was then used to test the effect of a 0.5 mg/dL increase (1 standard deviation, SD) in serum calcium on risk of prostate cancer in 72,729 men in the PRACTICAL (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome) Consortium (44,825 cases, 27,904 controls) and risk of advanced prostate cancer in 33,498 men (6,263 cases, 27,235 controls). RESULTS: We found weak evidence for a protective effect of serum calcium on prostate cancer risk (odds ratio [OR] per 0.5 mg/dL increase in calcium: 0.83, 95% CI 0.63-1.08; p = 0.12). We did not find strong evidence for an effect of serum calcium on advanced prostate cancer (OR per 0.5 mg/dL increase in calcium: 0.98, 95% CI 0.57-1.70; p = 0.93). CONCLUSIONS: Our Mendelian randomization analysis does not support the hypothesis that serum calcium increases risk of overall or advanced prostate cancer.

Mitochondrial DNA Haplogroups and Breast Cancer Risk Factors in the Avon Longitudinal Study of Parents and Children (ALSPAC).

The relationship between mitochondrial DNA (mtDNA) and breast cancer has been frequently examined, particularly in European populations. However, studies reporting associations between mtDNA haplogroups and breast cancer risk have had a few shortcomings including small sample sizes, failure to account for population stratification and performing inadequate statistical tests. In this study we investigated the association of mtDNA haplogroups of European origin with several breast cancer risk factors in mothers and children of the Avon Longitudinal Study of Parents and Children (ALSPAC), a birth cohort that enrolled over 14,000 pregnant women in the Southwest region of the UK. Risk factor data were obtained from questionnaires, clinic visits and blood measurements. Information on over 40 independent breast cancer risk factor-related variables was available for up to 7781 mothers and children with mtDNA haplogroup data in ALSPAC. Linear and logistic regression models adjusted for age, sex and population stratification principal components were evaluated. After correction for multiple testing we found no evidence of association of European mtDNA haplogroups with any of the breast cancer risk factors analysed. Mitochondrial DNA haplogroups are unlikely to underlie susceptibility to breast cancer that occurs via the risk factors examined in this study of a population of European ancestry.

Reassessing the Association between Circulating Vitamin D and IGFBP-3: Observational and Mendelian Randomization Estimates from Independent Sources.

BACKGROUND: Circulating insulin-like growth factor binding protein 3 (IGFBP-3) has been associated with prostate cancer. Preclinical studies found that vitamin D regulates IGFBP-3 expression, although evidence from epidemiologic studies is conflicting. METHODS: Mendelian randomization analyses (MR) were conducted to reassess associations between IGFBP-3 and prostate cancer risk and advanced prostate cancer using summary statistics from the PRACTICAL consortium (44,825 cases; 27,904 controls). Observational and MR analyses were conducted to assess the relationship between inactive vitamin D [25(OH)D] and IGFBP-3 using data from the ProtecT study (1,366 cases;1,071 controls) and summary statistics from the CHARGE consortium (n = 18,995). RESULTS: The OR for prostate cancer per SD unit increase in circulating IGFBP-3 was 1.14 [95% confidence interval (CI), 1.02-1.28]. The OR for advanced prostate cancer per SD unit increase in IGFBP-3 was 1.22 (95% CI, 1.07-1.40). Observationally, a SD increase in 25(OH)D was associated with a 0.1SD (95% CI, 0.05-0.14) increase in IGFBP-3. MR analyses found little evidence for a causal relationship between circulating 25(OH)D and IGFBP-3 in the circulation. CONCLUSIONS: This study provided confirmatory evidence that IGFBP-3 is a risk factor for prostate cancer risk and progression. Observationally, there was evidence that 25(OH)D is associated with IGFBP-3, but MR analyses suggested that these findings were unlikely to be causal. Findings may be limited by the nature of instrumentation of 25(OH)D and IGFBP-3 and the utility of circulating measures. 25(OH)D appears unlikely to be causally related to IGFBP-3 in the circulation, however, our findings do not preclude causal associations at the tissue level. IMPACT: IGFBP-3 is a prostate cancer risk factor but 25(OH)D are unlikely to be causally related to IGFBP-3 in the circulation.