Physical Activity, Sedentary Behavior, and Pancreatic Cancer Risk: A Mendelian Randomization Study.

Pancreatic cancer is currently the seventh leading cause of cancer death worldwide. Understanding whether modifiable factors increase or decrease the risk of this disease is central to facilitating primary prevention. Several epidemiological studies have described the benefits of physical activity, and the risks associated with sedentary behavior, in relation to cancer. This study aimed to assess evidence of causal effects of physical activity and sedentary behavior on pancreatic cancer risk. We conducted a two-sample Mendelian randomization study using publicly available data for genetic variants associated with physical activity and sedentary behavior traits and genetic data from the Pancreatic Cancer Cohort Consortium (PanScan), the Pancreatic Cancer Case-Control Consortium (PanC4), and the FinnGen study for a total of 10 018 pancreatic cancer cases and 266 638 controls. We also investigated the role of body mass index (BMI) as a possible mediator between physical activity and sedentary traits and risk of developing pancreatic cancer. We found evidence of a causal association between genetically determined hours spent watching television (hours per day) and increased risk of pancreatic cancer for each hour increment (PanScan-PanC4 odds ratio = 1.52, 95% confidence interval 1.17-1.98, P = .002). Additionally, mediation analysis showed that genetically determined television-watching time was strongly associated with BMI, and the estimated proportion of the effect of television-watching time on pancreatic cancer risk mediated by BMI was 54%. This study reports the first Mendelian randomization-based evidence of a causal association between a measure of sedentary behavior (television-watching time) and risk of pancreatic cancer and that this is strongly mediated by BMI. Summary: Pancreatic cancer is a deadly disease that is predicted to become the second leading cause of cancer-related deaths by 2030. Physical activity and sedentary behaviors have been linked to cancer risk and survival. However, there is limited research on their correlation with pancreatic cancer. To investigate this, we used a Mendelian randomization approach to examine the genetic predisposition to physical activity and sedentariness and their relation to pancreatic cancer risk, while excluding external confounders. Our findings revealed a causal link between the time spent watching television and an increased risk of pancreatic cancer. Additionally, we determined that over half of the effect of watching television on pancreatic risk is mediated by the individual's BMI.

The local environment and germline genetic variation predict cancer risk in the UK Biobank prospective cohort.

BACKGROUND: There is a growing body of evidence on the effect of the local environment exposure on cancer susceptibility. Nonetheless, several of the associations remain controversial. Moreover, our understanding of the possible interaction between the local environment and the genetic variability is still very limited. OBJECTIVE: The aim of this study was to clarify the role of the local environment and its possible interplay with genetics on common cancers development. METHODS: Using the UK Biobank (UKBB) prospective cohort, we selected 12 local environment exposures: nitrogen oxides, nitrogen dioxides, particulate matter (10 and 2.5 µm), noise pollution, urban traffic, living distance from the coast, percentage of greenspace, natural environment, water, and domestic garden within 1000 m from the residential coordinates of each participant. All these exposures were tested for association with 17 different types of cancer for a total of 53,270 cases and 302,645 controls. Additionally, a polygenic score (PGS) was computed for each cancer, to test possible gene-environment interactions. Finally, mediation analyses were carried out. RESULTS: Thirty-six statistically significant associations considering multiple testing (p < 2.19 × 10-4) were observed. Among the novel associations we observed that individuals living farther from the coast had a higher risk of developing prostate cancer (OR = 1.13, CI95% = 1.06-1.20, P = 1.98 × 10-4). This association was partially mediated by physical activity (indirect effect (IE) = -8.48 × 10-7) and the time spent outdoor (IE = 9.07 × 10-6). All PGSs showed statistically significant associations. Finally, genome-environment interaction analysis showed that local environment and genetic variability affect cancer risk independently. DISCUSSION: Living close to the coast and air pollution were associated with a decreased risk of prostate cancer and skin melanoma, respectively. These findings from the UKBB support the role of the local environment on cancer development, which is independent from genetics and may be mediated by several lifestyle factors.

The genetic variant SLC2A1 -rs1105297 is associated with the differential analgesic response to a glucose-based treatment in newborns.

ABSTRACT: Neonatal pain is a critical issue in clinical practice. The oral administration of glucose-based solutions is currently one of the most common and effective nonpharmacologic strategies for neonatal pain relief in daily minor procedures. However, a varying degree of analgesic efficacy has been reported for this treatment. Environmental, maternal, and genetic factors may explain this variability and potentially allow for a personalized analgesic approach, maximizing therapeutic efficacy and preventing side effects. We investigated the exposome (ie, the set of clinical and anthropometric variables potentially affecting the response to the therapy) and the genetic variability of the noradrenaline transporter gene (solute carrier family 6 member 2 [ SLC6A2 ]) and 2 glucose transporter genes (solute carrier family 2 member 1 [ SLC2A1 ] and 2 [ SLC2A2 ]) in relation to the neonatal analgesic efficacy of a 33% glucose solution. The study population consisted in a homogeneous sample of more than 1400 healthy term newborns. No association for the exposome was observed, whereas a statistically significant association between the G allele of SLC2A1 -rs1105297 and a fourfold decreased probability of responding to the therapy was identified after multiple-testing correction (odds ratio of 3.98, 95% confidence interval 1.95-9.17; P = 4.05 × 10 -4 ). This allele decreases the expression of SLC2A1-AS1 , causing the upregulation of SLC2A1 in the dorsal striatum, which has been suggested to be involved in reward-related processes through the binding of opioids to the striatal mu-opioid receptors. Altogether, these results suggest the involvement of SLC2A1 in the analgesic process and highlight the importance of host genetics for defining personalized analgesic treatments.

Long or short? Telomere length and pancreatic cancer and its precursor lesions, a narrative review.

Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal form of pancreatic cancer, with a survival approaching only 11% at five years after diagnosis. In the last 15 years, telomere length measured in leukocyte (LTL) has been studied in relation to PDAC risk. The majority of the studies reported an association between short LTL and increased PDAC risk, but the results are heterogeneous. Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) in the telomerase reverse transcriptase (TERT) gene as susceptibility loci for PDAC. Polygenic risk scores (PRS) computed using SNPs associated with LTL have been tested in relation to PDAC susceptibility with various methods and giving contrasting results. The aim of this review is to analyze all publications carried out specifically on LTL, considering LTL measured with qPCR and with genetic proxies, and PDAC risk. Additionally, we will give an overview of the most relevant associations between SNPs in telomere associated genes and PDAC, to answer the question shorter or longer? Which one of the two is associated with PDAC risk?

Analysis of exposome and genetic variability suggests stress as a major contributor for development of pancreatic ductal adenocarcinoma.

BACKGROUND: The current knowledge on pancreatic ductal adenocarcinoma (PDAC) risk factors is limited and no study has comprehensively tested the exposome in combination with the genetic variability in relation to the disease susceptibility. AIM: The aim of this study was to analyze the exposome and its interaction with known genetic susceptibility loci, in relation to PDAC risk. METHODS: A case-control study nested in UK Biobank cohort was conducted on 816 PDAC cases and 302,645 controls. A total of 347 exposure variables, and a polygenic risk score (PRS) were analyzed through logistic regression. Gene-environment interaction analyses were conducted. RESULTS: A total of 52 associations under the Bonferroni corrected threshold of p < 1.46 × 10-4 were observed. Known risk factors such as smoking, pancreatitis, diabetes, PRS, heavy alcohol drinking and overweight were replicated in this study. As for novel associations, a clear indication for length and intensity of mobile phone use and the stress-related factors and stressful events with increase of PDAC risk was observed. Although the PRS was associated with PDAC risk (P = 2.09 × 10-9), statistically significant gene-exposome interactions were not identified. CONCLUSION: In conclusion, our results suggest that a stressful lifestyle and sedentary behaviors may play a major role in PDAC susceptibility independently from the genetic background.

A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma.

Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P = 2.46 × 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P = 1.53 × 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data.

Role of pancreatic ductal adenocarcinoma risk factors in intraductal papillary mucinous neoplasm progression.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is lethal due to its late diagnosis and lack of successful treatments. A possible strategy to reduce its death burden is prevention. Intraductal papillary mucinous neoplasms (IPMNs) are precursors of PDAC. It is difficult to estimate the incidence of IPMNs because they are asymptomatic. Two recent studies reported pancreatic cysts in 3% and 13% of scanned subjects. The possibility of identifying a subgroup of IPMN patients with a higher probability of progression into cancer could be instrumental in increasing the survival rate. In this study, genetic and non-genetic PDAC risk factors were tested in a group of IPMN patients under surveillance. Methods: A retrospective study was conducted on 354 IPMN patients enrolled in two Italian centres with an average follow-up of 64 months. With the use of DNA extracted from blood, collected at IPMN diagnosis, all patients were genotyped for 30 known PDAC risk loci. The polymorphisms were analysed individually and grouped in an unweighted polygenic score (PGS) in relation to IPMN progression. The ABO blood group and non-genetic PDAC risk factors were also analysed. IPMN progression was defined based on the development of worrisome features and/or high-risk stigmata during follow-up. Results: Two genetic variants (rs1517037 and rs10094872) showed suggestive associations with an increment of IPMN progression. After correction for multiple testing, using the Bonferroni correction, none of the variants showed a statistically significant association. However, associations were observed for the non-genetic variables, such as smoking status, comparing heavy smokers with light smokers (HR = 3.81, 95% 1.43-10.09, p = 0.007), and obesity (HR = 2.46, 95% CI 1.22-4.95, p = 0.012). Conclusion: In conclusion, this study is the first attempt to investigate the presence of shared genetic background between PDAC risk and IPMN progression; however, the results suggest that the 30 established PDAC susceptibility polymorphisms are not associated with clinical IPMN progression in a sample of 354 patients. However, we observed indications of cigarette smoking and body mass index (BMI) involvement in IPMN progression. The biological mechanism that could link these two risk factors to progression could be chronic inflammation, of which both smoking and obesity are strong promoters.

The PANcreatic Disease ReseArch (PANDoRA) consortium: Ten years' experience of association studies to understand the genetic architecture of pancreatic cancer.

Pancreatic cancer has an incidence that almost matches its mortality. Only a small number of risk factors and 33 susceptibility loci have been identified. so Moreover, the relative rarity of pancreatic cancer poses significant hurdles for research aimed at increasing our knowledge of the genetic mechanisms contributing to the disease. Additionally, the inability to adequately power research questions prevents small monocentric studies from being successful. Several consortia have been established to pursue a better understanding of the genetic architecture of pancreatic cancers. The Pancreatic disease research (PANDoRA) consortium is the largest in Europe. PANDoRA is spread across 12 European countries, Brazil and Japan, bringing together 29 basic and clinical research groups. In the last ten years, PANDoRA has contributed to the discovery of 25 susceptibility loci, a feat that will be instrumental in stratifying the population by risk and optimizing preventive strategies.

Association between a polymorphic variant in the CDKN2B-AS1/ANRIL gene and pancreatic cancer risk.

Genes carrying high-penetrance germline mutations may also be associated with cancer susceptibility through common low-penetrance genetic variants. To increase the knowledge on genetic pancreatic ductal adenocarcinoma (PDAC) aetiology, the common genetic variability of PDAC familial genes was analysed in our study. We conducted a multiphase study analysing 7745 single nucleotide polymorphisms (SNPs) from 29 genes reported to harbour a high-penetrance PDAC-associated mutation in at least one published study. To assess the effect of the SNPs on PDAC risk, a total of 14 666 PDAC cases and 221 897 controls across five different studies were analysed. The T allele of the rs1412832 polymorphism, that is situated in the CDKN2B-AS1/ANRIL, showed a genome-wide significant association with increased risk of developing PDAC (OR = 1.11, 95% CI = 1.07-1.15, P = 5.25 × 10-9 ). CDKN2B-AS1/ANRIL is a long noncoding RNA, situated in 9p21.3, and regulates many target genes, among which CDKN2A (p16) that frequently shows deleterious somatic and germline mutations and deregulation in PDAC. Our results strongly support the role of the genetic variability of the 9p21.3 region in PDAC aetiopathogenesis and highlight the importance of secondary analysis as a tool for discovering new risk loci in complex human diseases.

Maternal anthropometric variables and clinical factors shape neonatal microbiome.

Recent studies indicate the existence of a complex microbiome in the meconium of newborns that plays a key role in regulating many host health-related conditions. However, a high variability between studies has been observed so far. In the present study, the meconium microbiome composition and the predicted microbial metabolic pathways were analysed in a consecutive cohort of 96 full-term newborns. The effect of maternal epidemiological variables on meconium diversity was analysed using regression analysis and PERMANOVA. Meconium microbiome composition mainly included Proteobacteria (30.95%), Bacteroidetes (23.17%) and Firmicutes (17.13%), while for predicted metabolic pathways, the most abundant genes belonged to the class "metabolism". We observed a significant effect of maternal Rh factor on Shannon and Inverse Simpson indexes (p = 0.045 and p = 0.049 respectively) and a significant effect of delivery mode and maternal antibiotic exposure on Jaccard and Bray-Curtis dissimilarities (p = 0.001 and 0.002 respectively), while gestational age was associated with observed richness and Shannon indexes (p = 0.018 and 0.037 respectively), and Jaccard and Bray-Curtis dissimilarities (p = 0.014 and 0.013 respectively). The association involving maternal Rh phenotype suggests a role for host genetics in shaping meconium microbiome prior to the exposition to the most well-known environmental variables, which will influence microbiome maturation in the newborn.

Polymorphic variants in Sweet and Umami taste receptor genes and birthweight.

The first thousand days of life from conception have a significant impact on the health status with short, and long-term effects. Among several anthropometric and maternal lifestyle parameters birth weight plays a crucial role on the growth and neurological development of infants. Recent genome wide association studies (GWAS) have demonstrated a robust foetal and maternal genetic background of birth weight, however only a small proportion of the genetic hereditability has been already identified. Considering the extensive number of phenotypes on which they are involved, we focused on identifying the possible effect of genetic variants belonging to taste receptor genes and birthweight. In the human genome there are two taste receptors family the bitter receptors (TAS2Rs) and the sweet and umami receptors (TAS1Rs). In particular sweet perception is due to a heterodimeric receptor encoded by the TAS1R2 and the TAS1R3 gene, while the umami taste receptor is encoded by the TAS1R1 and the TAS1R3 genes. We observed that carriers of the T allele of the TAS1R1-rs4908932 SNPs showed an increase in birthweight compared to GG homozygotes Coeff: 87.40 (35.13-139.68) p-value = 0.001. The association remained significant after correction for multiple testing. TAS1R1-rs4908932 is a potentially functional SNP and is in linkage disequilibrium with another polymorphism that has been associated with BMI in adults showing the importance of this variant from the early stages of conception through all the adult life.

Role of OPRM1, clinical and anthropometric variants in neonatal pain reduction.

An increased awareness on neonatal pain-associated complications has led to the development of pain scales adequate to assess the level of pain experienced by newborns such as the ABC score. A commonly used analgesic procedure is to administer a 33% oral dextrose solution to newborns prior to the painful intervention. Although this procedure is very successful, not in all subjects it reaches complete efficacy. A possible explanation for the different response to the treatment could be genetic variability. We have investigated the genetic variability of the OPRM1 gene in 1077 newborns in relation to non-pharmacologic pain relief treatment. We observed that the procedure was successful in 966 individuals and there was no association between the genotypes and the analgesic efficacy when comparing individuals that had an ABC score = 0 and ABC score >0. However, considering only the individuals with ABC score>0, we found that the homozygous carriers of the G allele of the missense variant SNP rs1799971 (A118G) showed an interesting association with higher ABC score. We also observed that individuals fed with formula milk were more likely to not respond to the analgesic treatment compared to those that had been breastfed.