Citations

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.

Summary Evidence for an association between insulin‐like growth factors (IGF) and multiple myeloma (MM) is inconsistent. We examined total IGF‐I concentrations and risk of MM by combining baseline serological data among UK Biobank participants ( n = 444 187; 732 incident MM) with a two‐sample Mendelian randomisation (MR) analysis using identified genetic variants associated with circulating total IGF‐I and IGF‐binding protein 3 (IGFBP‐3) in the InterLymph consortium (2434 MM and their 2567 controls). Finally, additional lymphoid neoplasm (LN) subtypes were included for comparison with the main hypothesis. Circulating IGF‐I level was positively associated with MM risk Hazard ratio‐HR‐per one standard deviation‐SD‐increase (HR 1‐SD = 1.11, 95% confidence interval [CI]: 1.01–1.22; p ‐value = 0.03), especially closer to diagnosis. Genetically inferred IGF‐I levels were associated with increased MM risk (odds ratio [OR] = 1.27, 95% CI: 1.05–1.54) but not with any other LNs. Genetically inferred IGFBP‐3 levels showed no associations with any LN evaluated. Corroborating previous findings, in a secondary analysis, IGF‐I levels were associated with the risk of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) in males with higher body mass index (HR 1‐SD in obese male = 1.36, 95% CI: 1.14–1.61). Our serological and MR analyses suggest a contributing role of IGF‐I in the susceptibility of MM; the CLL/SLL findings warrant further investigation considering sex‐specific adiposity.

Background/Objectives: Overall survival in patients with amyotrophic lateral sclerosis (ALS) is linked to the rate of predicted respiratory vital capacity (PVC) loss. The objective of this study was to test whether changes in quantitative PVC measures over time linked to survival would define an immunopathogenic subset of ALS responsive to NP001, a regulator of innate immunity. Methods: In a retrospective study, data from intent-to-treat (ITT) population of two phase 2 trials of NP001 were evaluated for over time changes in PVC, time-to-event (TTE) loss of 15% PVC and PVC change from baseline, as linked to survival outcomes in patients treated with NP001 vs placebo. Results: Treatment with NP001 was associated with a significantly lower risk compared to placebo in the loss of 15% PVC over six months (p = 0.01; HR = 0.60, 95% CI: 0.39, 0.90). Data from the two trials were subsequently divided by a disease progression rate (DPR) value of 0.50 units of ALSFRS-R score lost per month for analysis of slow vs. rapid disease. In ALS patients with slowly progressive disease (DPR < 0.50), TTE PVC changes from baseline were slowed (p < 0.0005) and overall survival extended significantly (18.5 months) in NP001-treated vs. placebo groups. The rapidly progressive ALS patients (DPR ≥ 0.50) treated with NP001 showed no significant difference in PVC change or survival from the placebo group. Conclusions: These hypothesis-generating observations suggest that inflammation might play a significant role in the loss of respiratory function in a major subset of ALS patients.

Abstract Background The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood. Methods We investigated associations of genetic susceptibility to type 2 diabetes (T2D), 8 T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242 283 cases, 1 569 734 controls), T1D (18 942 cases, 501 638 controls), and PDAC (10 244 cases and 360 535 controls) in individuals of European ancestry. Results Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI = 1.05 to 1.15), particularly the T2D obesity (OR = 1.28; 95% CI = 1.15 to 1.42) and lipodystrophy (OR = 1.25; 95% CI = 1.03 to 1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI = 0.99 to 1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10−8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10−4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions. Conclusions Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.

Abstract Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome‐wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co‐development with hepatitis C virus‐negative (HCV‐negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV‐negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale heritability of each trait at 0.02 to ensure reliable inferences with adequate study power. Next, we observed significant positive genetic correlations between HCV‐negative HCC and blood‐based biomarkers of liver injury (ALT, GGT) and allostatic load (including glycated hemoglobin, blood pressure, and total albumin). We also identified a positive genetic correlation between HCV‐negative HCC and diseases associated with metabolic dysfunction‐associated steatotic liver disease (MASLD), including diabetes, hypertension, chronic ischemic heart disease, and others. Taken together, our results help to identify polygenic and pleiotropic signals related to different phenotypic traits associated with HCC and support further exploration of the predictive power of blood‐based biomarkers identified in this study for inferring HCC development among HCV‐negative individuals.

Abstract Obesity has been associated with non‐Hodgkin lymphoma (NHL), but the evidence is inconclusive. We examined the association between genetically determined adiposity and four common NHL subtypes: diffuse large B‐cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, and marginal zone lymphoma, using eight genome‐wide association studies of European ancestry ( N = 10,629 cases, 9505 controls) and constructing polygenic scores for body mass index (BMI), waist‐to‐hip ratio (WHR), and waist‐to‐hip ratio adjusted for BMI (WHRadjBMI). Higher genetically determined BMI was associated with an increased risk of DLBCL [odds ratio (OR) per standard deviation (SD) = 1.18, 95% confidence interval (95% CI): 1.05–1.33, p = .005]. This finding was consistent with Mendelian randomization analyses, which demonstrated a similar increased risk of DLBCL with higher genetically determined BMI (OR per SD = 1.12, 95% CI: 1.02–1.23, p = .03). No significant associations were observed with other NHL subtypes. Our study demonstrates a positive link between a genetically determined BMI and an increased risk of DLBCL, providing additional support for increased adiposity as a risk factor for DLBCL.

Abstract Background: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. Methods: We conducted a genome-wide interaction analysis of single-nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than three drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies. Our analysis included 3,707 cases and 4,167 controls from case–control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed-effect meta-analyses were conducted. Results: A potential novel region of association on 10p11.22, lead SNP rs7898449 (interaction P value (Pinteraction) = 5.1 × 10−8 in the meta-analysis; Pinteraction = 2.1 × 10−9 in the case–control studies; Pinteraction = 0.91 in the cohort studies), was identified. An SNP correlated with this lead SNP is an expression quantitative trait locus for the neuropilin 1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004). Conclusions: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an expression quantitative trait locus for neuropilin 1, a protein that plays an important role in the development and progression of pancreatic cancer. Impact: This work can provide insights into the etiology of pancreatic cancer, particularly in heavy drinkers.

Background and Aims: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). Approach and Results: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP, rs9842969, (0.51, [0.40–0.65]); 5p15.33, TERT, rs2242652, (0.70, (0.62–0.79]); 19q13.11, TM6SF2, rs58542926, (1.49, [1.29–1.72]); 19p13.11 MAU2, rs58489806, (1.53, (1.33–1.75]); and 22q13.31, PNPLA3, rs738409, (1.66, [1.51–1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74–0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. Conclusions: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

Abstract Background: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. Methods: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. Results: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88–1.22; MR-Egger OR, 0.89; 95% CI, 0.65–1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90–1.27; MR-Egger OR, 0.93; 95% CI, 0.67–1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample. Conclusions: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. Impact: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.

AbstractNon‐Hodgkin lymphoma (NHL) is composed of a heterogeneous collection of subtypes with considerable differences in genetics, biology and aetiology. Studies to date on physical activity and NHL risk have not had sufficient sample size to evaluate whether associations differ by subtype. We pooled data from nine case‐control studies to examine the association between moderate‐to‐vigorous intensity physical activity (MVPA) and risk of NHL overall and by subtype (diffuse large B‐cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia/small lymphocytic lymphoma, marginal zone lymphoma and mature T‐cell lymphoma). A total of 5653 cases and 9115 controls were included in the pooled analysis. Physical activity was harmonised across nine studies and modelled as study‐specific tertiles. Multinomial logistic regression was used to estimate the association between physical activity and NHL, adjusting for confounders. The overall odds of NHL was 13% lower among participants in the most active tertile of MVPA compared to the least active tertile (adjusted odds ratio = 0.87, 95% CI = 0.80, 0.95). Similar decreases were observed across NHL subtypes. In summary, in this pooled analysis of case‐control studies, physical activity was associated with a modest risk reduction for each NHL subtype examined and with overall NHL.