Medications that relax the lower oesophageal sphincter and risk of oesophageal cancer : An analysis of two independent population-based databases

Acknowledgements We acknowledge collaboration with the Research Applications and Data Management Team lead by Ms Katie Wilde, University of Aberdeen in conducting our study. This research has been conducted using the UK Bio-bank Resource under application number 34374.Peer reviewedPostprin

Shared genetic risk between major orofacial cleft phenotypes in an African population

Nonsyndromic orofacial clefts (NSOFCs) represent a large proportion (70%–80%) of all OFCs. They can be broadly categorized into nonsyndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO). Although NSCL/P and NSCPO are considered etiologically distinct, recent evidence suggests the presence of shared genetic risks. Thus, we investigated the genetic overlap between NSCL/P and NSCPO using African genome-wide association study (GWAS) data on NSOFCs. These data consist of 814 NSCL/P, 205 NSCPO cases, and 2159 unrelated controls. We generated common single-nucleotide variants (SNVs) association summary statistics separately for each phenotype (NSCL/P and NSCPO) under an additive genetic model. Subsequently, we employed the pleiotropic analysis under the composite null (PLACO) method to test for genetic overlap. Our analysis identified two loci with genome-wide significance (rs181737795 [p = 2.58E−08] and rs2221169 [p = 4.5E−08]) and one locus with marginal significance (rs187523265 [p = 5.22E−08]). Using mouse transcriptomics data and information from genetic phenotype databases, we identified MDN1, MAP3k7, KMT2A, ARCN1, and VADC2 as top candidate genes for the associated SNVs. These findings enhance our understanding of genetic variants associated with NSOFCs and identify potential candidate genes for further exploration.</p

Pancreatic cancer risk in relation to lifetime smoking patterns, tobacco type, and dose-response relationships.

BACKGROUND: Despite smoking being a well-established risk factor for pancreatic cancer (PC), there is a need to further characterize PC risk according to lifespan smoking patterns and other smoking features. Our aim was to deeply investigate them within a large European case-control study. METHODS: Tobacco smoking habits and other relevant information was obtained from 2,009 cases and 1,532 controls recruited in the PanGenEU study using standardized tools. Multivariate logistic regression analysis was performed to evaluate PC risk by smoking characteristics and interactions with other PC risk factors. Fractional polynomials and restricted cubic splines were used to test for non-linearity of the dose-response relationships and to analyse their shape. RESULTS: Relative to never-smokers, current smokers (OR=1.72, 95%CI: 1.39-2.12), those inhaling into the throat (OR=1.48, 95%CI: 1.11-1.99), chest (OR=1.33, 95%CI: 1.12-1.58), or using non-filtered cigarettes (OR=1.69, 95%CI: 1.10-2.61), were all at an increased PC risk. PC risk was highest in current black tobacco smokers (OR=2.09, 95%CI: 1.31-3.41), followed by blond tobacco smokers (OR=1.43, 95%CI: 1.01-2.04). Childhood exposure to tobacco smoke relative to parental smoking was also associated with increased PC risk (OR=1.24, 95%CI: 1.03-1.49). Dose-response relationships for smoking duration, intensity, cumulative dose, and smoking cessation were non-linear and showed different shapes by tobacco type. Effect modification by family history of PC and diabetes was likely. CONCLUSIONS: This study reveals differences in PC risk by tobacco type and other habit characteristics, as well as non-linear risk associations. IMPACT: This characterization of smoking-related PC risk profiles may help in defining PC high-risk populations

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer

Funder: Fundación Científica Asociación Española Contra el Cáncer (ES)Funder: Cancer Focus Northern Ireland and Department for Employment and LearningFunder: Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USAAbstract: Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E−06 in 1D approach and a Local Moran’s Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8—a lncRNA associated with pancreatic carcinogenesis—with a lowest p value = 6.91E−05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1—a major regulator of the ER stress and unfolded protein responses in acinar cells—identified by 3D; all of them with a strong in silico functional support. Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases

Built environment correlates of physical activity in low- and middle-income countries: A systematic review

Insufficient physical activity (PA) is the fourth major risk factor for many non-communicable diseases and premature mortality worldwide. Features of the built environment (BE) play a considerable role in determining population PA behaviors. The majority of evidence for PA-BE relationships comes from high-income countries and may not be generalizable to low- and middle-income countries (LMICs). We aim to systematically review the literature and assess the associations between perceived and/or objective BE characteristics and PA domains in LMICs. This review adopted a systematic search strategy for English language articles published between January 2000 and June 2019 from four electronic databases-Medline, Embase, Web of Science and PubMed-adhering to the PRISMA guidelines. Studies addressing the associations between self-reported and/or objective BE and PA were only included if they were conducted in LMICs, according to the World Bank classification list. Articles investigating PA-BE relationships across any age groups were included, and all study designs were eligible, except for qualitative studies and reviews. Thirty-three studies were included for evidence synthesis. Cross-sectional studies were the most prevailing study design (97%), revealing a notable gap in longitudinal PA-BE research in LMICs. A majority of the BE factors were not associated with different PA domains while others (e.g., density, proximity to services, aesthetics) exhibited an inconsistent association. Land-use mix diversity was positively associated with transport PA and the presence of recreation facilities resulted in an increase in PA during leisure-time. Increased safety from crime at night consistently increased total PA and walking levels. Research exploring the associations between BE attributes and PA behaviors in LMICs appears to be limited and is primarily cross-sectional. Longitudinal research studies with objective measures are needed for inferring well-grounded PA-BE causal relationships and informing the design of evidence-based environmental interventions for increasing PA levels in LMICs

Evaluation of a worksite cervical screening initiative to increase Pap smear uptake in Malaysia:a cluster randomized controlled trial

Background. Despite the significant burden of cervical cancer, Malaysia like many middle-income countries relies on opportunistic cervical screening as opposed to a more organized population-based program. The aim of this study was to ascertain the effectiveness of a worksite screening initiative upon Papanicolaou smear test (Pap test) uptake among educated working women in Malaysia. Methods. 403 female teachers who never or infrequently attended for a Pap test from 40 public secondary schools in Kuala Lumpur were recruited into a cluster randomized trial conducted between January and November 2010. The intervention group participated in a worksite cervical screening initiative whilst the control group received usual care from the existing cervical screening program. Multivariate logistic regression was performed to determine the impact of the intervention program on Pap smear uptake after 24 weeks of followup. Results. The proportion of women attending for a Pap test was significantly higher in the intervention than in the control group (18.1% versus 10.1%, P value < 0.05) with the worksite screening initiative doubling the Pap smear uptake, adjusted odds ratio 2.44 (95% CI: 1.29–4.62). Conclusion. Worksite health promotion interventions can effectively increase cervical smear uptake rates among eligible workers in middle-income countries. Policy makers and health care providers in these countries should include such interventions in strategies for reducing cervical cancer burden. This trial is registered with IRCT201103186088N1