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Lymphoid neoplasms (LNs) are heterogeneous malignancies arising from lymphoid cells, displaying diverse clinical and molecular features. Although LNs are collectively frequent, individual subtypes are rare, posing challenges for genetic association studies. Indeed, genome-wide association studies (GWAS) explained only a fraction of the heritability. Shared genetic susceptibility and overlapping risk factors suggest a partially common etiology across subtypes. We employed a multi-trait GWAS strategy to improve discovery power by leveraging pleiotropy among LN subtypes. We defined LN phenoclusters based on cell of origin, somatic mutation profiles, and approved therapeutic agents. Using data from three large cohorts—the UK Biobank, Million Veteran Program, and FinnGen—we analyzed 31,937 LN cases and 1.2 million controls across 8 individual subtypes and 7 phenoclusters. We replicated the novel associations in two independent cohorts (All of Us and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) with 2892 LN cases and 165,791 controls. We identified 76 genome-wide significant loci for individual subtypes or subtype clusters, including 20 novel associations. We identified the subtypes contributing to each locus, putative candidate causal variants, and genes underlying the associations, and found enrichment of specific cell types, biological processes, and drugs associated with LN risk genes. Overall, this study identified new LN genetic risk loci and candidate genes, providing insights that may inform novel therapeutic approaches.

Helicobacter pylori (HP) colonizes the human stomach and induces acute gastritis, peptic ulcer disease, atrophic gastritis, and gastric adenocarcinoma. Increased virulence in HP isolates derives from harboring the cag (cytotoxin-associated genes) pathogenicity island ( cag PAI). We analyzed the microvariants in cag PAI genes with the hypothesis that they may play an important role in determining HP virulence. We tested DNAs from cagA positive patients HP isolates; a total of 74 patients with chronic gastritis (CG, N = 37), intestinal metaplasia (IM, N = 21) or gastric cancer (GC, N = 16) from Mexico and Colombia. We selected 520 non-synonymous variants with at least 7.5% frequency in the original sequence outputs or with a minimum of 5 isolates with minor allele. After adjustment for multiple comparisons, no variants were statistically significantly associated with IM or GC. However, 19 non-synonymous showed conventional P-values < 0.05 comparing the frequency of the alleles between the isolates from subjects with gastritis and isolates from subjects with IM or GC; 12 of these showed a significant correlation with the severity of the disease. The present study revealed that several cag PAI genes from Latin American Western HP strains contains a number of non-synonymous variants in relatively high frequencies which could influence on the clinical outcome. However, none of the associations remained statistically significant after adjustment for multiple comparison.

Pancreatic ductal adenocarcinoma (PDAC) has high mortality and rising incidence rates. Recent data indicate that the gut microbiome and associated metabolites may play a role in the development of PDAC. To complement and inform observational studies, we investigated associations of genetically predicted abundances of individual gut bacteria and genetically predicted circulating concentrations of microbiome-associated metabolites with PDAC using Mendelian randomisation (MR). Gut microbiome-associated metabolites were identified through a comprehensive search of Pubmed, Exposome Explorer and Human Metabolome Database. Single Nucleotide Polymorphisms (SNPs) associated by Genome-Wide Association Studies (GWAS) with circulating levels of 109 of these metabolites were collated from Pubmed and the GWAS catalogue. SNPs for 119 taxonomically defined gut genera were selected from a meta-analysis performed by the MiBioGen consortium. Two-sample MR was conducted using GWAS summary statistics from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including a total of 8,769 cases and 7,055 controls. Inverse variance-weighted MR analyses were performed along with sensitivity analyses to assess potential violations of MR assumptions. Nominally significant associations were noted for genetically predicted circulating concentrations of mannitol (odds ratio per standard deviation [OR SD ] = 0.97; 95% confidence interval [CI]: 0.95–0.99, p  = 0.006), methionine (OR SD = 0.97; 95%CI: 0.94-1.00, p  = 0.031), stearic acid (OR SD = 0.93; 95%CI: 0.87–0.99, p  = 0.027), carnitine = (OR SD =1.01; 95% CI: 1.00-1.03, p  = 0.027), hippuric acid (OR SD = 1.02; 95%CI: 1.00-1.04, p  = 0.038) and 3-methylhistidine (OR SD = 1.05; 95%CI: 1.01–1.10, p  = 0.02). Two gut microbiome genera were associated with reduced PDAC risk; Clostridium sensu stricto 1 (OR: 0.88; 95%CI: 0.78–0.99, p  = 0.027) and Romboutsia (OR: 0.87; 95%CI: 0.80–0.96, p  = 0.004). These results, though based only on genetically predicted gut microbiome characteristics and circulating bacteria-related metabolite concentrations, provide evidence for causal associations with pancreatic carcinogenesis.

(HP) infection has been linked to nearly 90 different health conditions, including gastric malignant and premalignant lesions. Recently, Mendelian randomization (MR) has gained popularity to overcome limitations in observational studies. This review aims to compile MR studies on the causal relationship between HP infection and health outcomes, systematically assess the quality of individual studies, evaluate the overall evidence in comparison with other existing data, and identify common strengths and weaknesses in order to guide future research directions on HP-associated health outcomes. Eligible studies were identified from the two major biomedical literature databases, PubMed and Embase. After removing overlaps, we found 33 unique records published by July 10, 2024. Among those, 16 were qualified for full-text review as original research papers presenting MR analysis with HP infection as the primary exposure of interest. Among the 16 studies, one was one-sample MR study and the rest 2-sample MR studies. All except one were conducted on individuals of European descent. Health outcomes studied include four metabolic conditions, four cardiovascular diseases (CVDs), five gastrointestinal conditions, and three other miscellaneous conditions. All used genome-wide association study (GWAS) data on HP serology to select instrumental variants, ranging from 1 to 84. Nine out of 16 studies concluded that HP had a causal association with the disease of their interest. However, not all papers fully examined whether MR key assumptions were met and there are inaccurate descriptions and misinterpretations in many papers. In addition, there are inconsistencies between studies, depending on the choice of exposure GWAS from which instrumental variants were chosen. Overall, published MR studies concerning HP infection and various health outcomes to date are limited in their quality/integrity. The results from HP eradication trials completed or in progress may help address the causality of some of the health outcomes with high incidence rates. In addition, MR studies in non-European populations with higher HP prevalence are warranted.

In a genome-wide association study to identify loci associated with colorectal cancer (CRC) risk, we genotyped 555,510 SNPs in 1,012 early-onset Scottish CRC cases and 1,012 controls (phase 1). In phase 2, we genotyped the 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. We then genotyped the five highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from seven populations, and identified a previously unreported association, rs3802842 on 11q23 (OR = 1.1; P = 5.8 × 10 −10 ), showing population differences in risk. We also replicated and fine-mapped associations at 8q24 (rs7014346; OR = 1.19; P = 8.6 × 10 −26 ) and 18q21 (rs4939827; OR = 1.2; P = 7.8 × 10 −28 ). Risk was greater for rectal than for colon cancer for rs3802842 ( P < 0.008) and rs4939827 ( P < 0.009). Carrying all six possible risk alleles yielded OR = 2.6 (95% CI = 1.75–3.89) for CRC. These findings extend our understanding of the role of common genetic variation in CRC etiology.

We developed an absolute risk model to identify individuals in the general population at elevated risk of pancreatic cancer. Using data on 3,349 cases and 3,654 controls from the PanScan Consortium, we developed a relative risk model for men and women of European ancestry based on non-genetic and genetic risk factors for pancreatic cancer. We estimated absolute risks based on these relative risks and population incidence rates. Our risk model included current smoking (multivariable adjusted odds ratio (OR) and 95% confidence interval: 2.20 [1.84-2.62]), heavy alcohol use (>3 drinks/day) (OR: 1.45 [1.19-1.76]), obesity (body mass index >30 kg/m(2)) (OR: 1.26 [1.09-1.45]), diabetes >3 years (nested case-control OR: 1.57 [1.13-2.18], case-control OR: 1.80 [1.40-2.32]), family history of pancreatic cancer (OR: 1.60 [1.20-2.12]), non-O ABO genotype (AO vs. OO genotype) (OR: 1.23 [1.10-1.37]) to (BB vs. OO genotype) (OR 1.58 [0.97-2.59]), rs3790844(chr1q32.1) (OR: 1.29 [1.19-1.40]), rs401681(5p15.33) (OR: 1.18 [1.10-1.26]) and rs9543325(13q22.1) (OR: 1.27 [1.18-1.36]). The areas under the ROC curve for risk models including only non-genetic factors, only genetic factors, and both non-genetic and genetic factors were 58%, 57% and 61%, respectively. We estimate that fewer than 3/1,000 U.S. non-Hispanic whites have more than a 5% predicted lifetime absolute risk. Although absolute risk modeling using established risk factors may help to identify a group of individuals at higher than average risk of pancreatic cancer, the immediate clinical utility of our model is limited. However, a risk model can increase awareness of the various risk factors for pancreatic cancer, including modifiable behaviors.

The incidence of pancreatic ductal adenocarcinoma (PDAC) is different among males and females. This disparity cannot be fully explained by the difference in terms of exposure to known risk factors; therefore, the lower incidence in women could be attributed to sex-specific hormones. A two-phase association study was conducted in 12,387 female subjects (5436 PDAC cases and 6951 controls) to assess the effect on risk of developing PDAC of single nucleotide polymorphisms (SNPs) in 208 genes involved in oestrogen and pregnenolone biosynthesis and oestrogen-mediated signalling. In the discovery phase 14 polymorphisms showed a statistically significant association (P < 0.05). In the replication none of the findings were validated. In addition, a gene-based analysis was performed on the 208 selected genes. Four genes ( NR5A2 , MED1 , NCOA2 and RUNX1 ) were associated with PDAC risk, but only NR5A2 showed an association (P = 4.08 × 10 −5 ) below the Bonferroni-corrected threshold of statistical significance. In conclusion, despite differences in incidence between males and females, our study did not identify an effect of common polymorphisms in the oestrogen and pregnenolone pathways in relation to PDAC susceptibility. However, we validated the previously reported association between NR5A2 gene variants and PDAC risk.