Eivind Ness-Jensen

Antibodies against HPV proteins can provide pre‐diagnostic information about cancer development. We described the prevalence of antibodies to proteins of oncogenic HPV types prior to diagnosis of HPV‐related cancers. We analysed pre‐diagnostic blood from 1700 participants with incident HPV‐related cancers (anal = 387, cervical = 274, oropharyngeal = 788, penile = 168, vaginal = 83) and 6221 controls from nine prospective cohorts in Europe, North America and Australia in the HPV Cancer Cohort Consortium. We measured antibodies against E6, E7 and L1 proteins for 6 HPV types, and additionally against E1, E2, E4, E6, E7 and L1 proteins of HPV16 and 18. We described seroprevalence by lead time from blood draw to cancer diagnosis (range: 0–43 years). We found that among oropharyngeal cancers, seroprevalence increased approaching diagnosis for HPV16 E1, E2, E4, E6, E7, L1 and HPV18 E1, E2, L1 (HPV16‐E6: from 10.4% at > 20 years to 35.8% at 0–5 years, vs. 0.3% in controls). Anal cancer showed similar patterns for HPV16 E1, E2, E4, E6 and L1 and HPV18 E2 (HPV16‐E6: from 3.8% at > 20 years to 29.8% at 0–5 years). No trends were observed for cervical, penile, or vaginal cancers. In a multivariable model fit among cases, HPV16‐E6 seropositivity was higher at shorter lead times and more recent calendar periods, lower among US non‐Hispanic Blacks, and varied by cancer type (highest in oropharyngeal followed by anal, vaginal, penile and cervical) (all p < 0.03). In conclusion, pre‐diagnostic HPV antibody responses vary by cancer type, with seroprevalence of 6–9 HPV proteins increasing approaching diagnosis for oropharyngeal and anal cancers, but not cervical, penile or vaginal cancers.

Background: Irritable bowel syndrome (IBS) is a complex disorder of gut-brain interaction, with heterogeneous symptoms, no available biomarkers and limited pathogenetic insight. Objective: To identify genetic risk factors and actionable mechanisms for future clinical translation in IBS. Design: We conducted a genome-wide association study (GWAS) meta-analysis of IBS in 2 775 539 individuals from 22 biobanks. IBS genetics was studied across multiple ancestries, different case definitions and symptom-related subtypes. Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships. GWAS data were functionally annotated and fine-mapped to prioritise tissues, cell types, pathways, candidate genes, specific mechanisms and druggable targets. Results: Significant heritability was only detected in individuals of European ancestry, with near-identical genetic architecture across case definitions. Genetic correlations with GI, psychiatric and cardiometabolic traits were observed, including causal relationships with triglyceride (TG) levels. Functional annotation of IBS risk loci highlighted cell types and pathways relevant to brain, enteric neuro-glial and cardiometabolic domains, as well as actionable targets like GCKR, a regulator of TG metabolism. Druggability analyses converged on cardiometabolic mechanisms, including TG modulation. IBS polygenic risk scores were derived and showed a significant association with case status in an independent case-control dataset, supporting further evaluation in external population-based and clinically ascertained cohorts. Conclusions: This study provides the most comprehensive assessment of IBS genetics to date, demonstrating reproducible polygenic inheritance. We link IBS risk to convergent neurogastrointestinal and novel cardiometabolic mechanisms, highlight specific biological pathways and actionable mechanisms and outline translational opportunities emerging from integrated computational analyses.

Polymorphisms of human leukocyte antigen (HLA) genes confer risks for human diseases. Predisposing effects related to T cell receptor (TCR) recognition of peptide–HLA can be selection of TCR repertoire and/or preferential presentation of disease-driving epitopes. In celiac disease (CeD), HLA-DQ2.5 predisposes by presenting gluten peptides to CD4 ⁺ T cells that typically employ stereotyped TCRs. Here, we analyzed whether genetic variants within the HLA and TR loci shape the naive TCR repertoire. We sequenced the αβ TCR repertoires of naive CD4 ⁺ T cells of 103 CeD subjects and 103 controls and performed gene usage quantitative trait loci analyses. The naive CD4 ⁺ TCR repertoire was significantly affected by TRA, TRB, and in particular HLA polymorphisms. The presence of HLA-DQ2.5 influenced the TCR repertoire, resulting in significant enrichment of TCR genes being involved in recognition of gluten epitopes in the repertoires of CeD subjects versus controls. HLA thus affects disease risk by selection of a disease-relevant TCR repertoire.

Objectives: Proton pump inhibitors (PPI) might mask gastric cancer symptoms, leading to delayed diagnosis and worse oncological outcomes. However, current evidence is sparse and underpowered. This study aimed to elucidate if PPI-use influences oncological outcomes of gastric cancer in a well-powered study. Methods: This population-based cohort study included individuals with gastric non-cardia adenocarcinoma from the five Nordic nations. Multiple nationwide registries provided prospectively collected data. The individuals were grouped into non-users, light users, or heavy PPI-users during the 2-year period before diagnosis. The outcomes 5-year disease-specific mortality (primary) and 5-year all-cause mortality were analyzed using Cox regression, providing hazard ratios (HR) with 95% confidence intervals (CI). The outcomes metastatic disease and advanced tumor stage at diagnosis were analyzed using logistic regression, providing odds ratios (OR) with 95% CI. The risk estimates were adjusted for age, sex, country, year, comorbidity, and Helicobacter pylori treatment. Results: Among 21,433 individuals with gastric non-cardia adenocarcinoma, there were 9,736 users and 11,697 non-users. Heavy and light PPI use were both associated with reduced risk of 5-year disease-specific mortality (adjusted HR=0.90, 95% CI 0.86-0.94 and HR=0.87, 95% CI 0.84-0.91, respectively), with similar results for 5-year all-cause mortality. Heavy PPI-use was associated with decreased risks of presenting with metastatic disease (adjusted OR=0.70, 95% CI 0.64-0.76) or advanced tumor stage (adjusted OR=0.71, 95% CI 0.56-0.89). Conclusion: PPI-use before gastric non-cardia adenocarcinoma diagnosis may not be associated with an increased risk of advanced disease at presentation or of increased mortality.

Ulcerative colitis (UC) is an idiopathic chronic inflammatory bowel disease (IBD) involving the mucosal lining of the colon. The disease causes bloody diarrhea and abdominal pain, leading to impair...

Background: The incidence of esophago-gastric cancer has an age-dependent male predominance mirroring the physiological sex differences in sex hormonal levels. Some research suggests that menopausal hormone therapy counteracts these tumors to occur, but larger studies with longer follow-up are needed, which prompted this study. Methods: This population-based case-control study included women aged 45 years and older in the 5 Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) between 1995 and 2020. Prospectively collected data came from national registries for medications, cancer, diagnoses, total populations, and death. Menopausal hormone therapy use was categorized as nonuse (referent) and 3 equal-sized groups (tertiles) of defined daily doses (DDDs). Esophago-gastric cancer was divided into esophageal or cardia adenocarcinoma, esophageal squamous cell carcinoma, and gastric adenocarcinoma. Multivariable logistic regression provided odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for multiple confounders. Results: The study included 19 518 esophago-gastric cancer patients and 195 094 control participants matched for age, calendar year, and country. Compared with nonuse, the adjusted odds ratios of esophageal or cardia adenocarcinoma were 0.74 (95% CI = 0.67 to 0.81) for low menopausal hormone therapy use (848 DDDs). The corresponding odds ratios were 0.69 (95% CI = 0.62 to 0.77), 0.70 (95% CI = 0.62 to 0.77), and 0.71 (95% CI = 0.64 to 0.79) for esophageal squamous cell carcinoma and 0.90 (95% CI = 0.84 to 0.96), 0.85 (95% CI = 0.79 to 0.91), and 0.80 (95% CI = 0.74 to 0.86) for gastric adenocarcinoma, respectively. Conclusion: Menopausal hormone therapy users seem to have lower odds of developing esophago-gastric cancer.

Genetic variation in the loci encoding immunoglobulin genes (IGH, IGK and IGL) affects the repertoire of B-cell receptors (BCRs). Such effects were previously demonstrated for total peripheral blood B cells, but so far have not been investigated at scale for isolated naïve B cells. As B cells are implicated in the pathogenesis of autoimmune diseases, genetically encoded features of the naïve BCR repertoire may affect disease risk, for instance in celiac disease (CeD) which is hallmarked by stereotyped disease-specific antibodies that recognize antigen in their germline configuration. Here we have characterized the BCR repertoire of naïve B cells in 102 individuals with CeD and 102 control subjects by undertaking gene usage quantitative trait loci analyses based on repertoire sequencing and single nucleotide polymorphism genotyping. Variants within each of the loci had significant effects on the naïve BCR repertoires, with the usage of 80% of IGH genes, 54% of IGK genes and 84% of IGL genes being significantly affected by gene polymorphisms. Effects of genetic polymorphisms on BCR usage were observed for genes implicated in stereotypic responses previously associated with CeD, yet no strong evidence for CeD predisposing effects of polymorphisms within the IGH, IGK and IGL loci was uncovered.

The gut microbiota is associated with human health and disease. Here we conducted a genome-wide association study of host genetic factors influencing gut microbiota composition in 12,652 individuals from the Trøndelag Health Study (HUNT), with replication in Nordic cohorts ( n = 16,017–21,976). We identified 12 reproducible SNP–species associations across six genomic loci, including known ( LCT , ABO ) and novel ( HLA-DQB1 , MUC12 , SLC37A2 , FUT2 ) regions. Additionally, we detected genetic signals associated with gut microbiota functional modules at three loci ( LCT , ABO , FUT2 ). Follow-up analyses suggest that these host–microbiota associations are linked to the pathogenesis of celiac disease and hemorrhoidal disease. Mendelian randomization analyses provided evidence supporting a causal effect of body mass index on gut microbiota composition. These findings highlight the interplay between host genetics and gut microbiota for human health and disease.

INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) induce weight loss, and have been associated with an overall decreased risk of esophageal cancer. Obesity is strongly associated with esophageal adenocarcinoma and substantial weight loss may decrease the risk of this malignancy, whereas weight loss does not decrease the risk of esophageal squamous cell carcinoma. We examined the hypothesis that GLP-1RA treatment decreases the risk of esophageal adenocarcinoma. METHODS: This multinational population-based case-control study included all cases of esophageal adenocarcinoma and esophageal squamous cell carcinoma in adults who had dispensed medication for type 2 diabetes in Denmark (2007–2020), Finland (2011–2018), Iceland (2009–2019), Norway (2007–2019), or Sweden (2007–2020). For each case participant, >10 control participants who had dispensed medication for type 2 diabetes were randomly sampled from the general populations. Data came from nationwide health-data registries. Multivariable logistic regression provided odds ratios (OR) with 95% confidence intervals (CI), adjusted for sex, age, calendar year, country, comorbidity, gastroesophageal reflux disease, obesity, alcohol overconsumption, and tobacco smoking. RESULTS: This study included 2,909 case participants with esophageal adenocarcinoma, 670 case participants with esophageal squamous cell carcinoma, and 55,408 control participants. The risk of esophageal adenocarcinoma was not decreased in GLP-1RA users compared with nonusers (adjusted OR 1.3, 95% CI 1.1–1.5). Instead, the risk of esophageal squamous cell carcinoma was decreased (adjusted OR 0.5, 95% CI 0.3–0.8). DISCUSSION: Standard GLP-1RA treatment in patients with type 2 diabetes might not decrease the risk of esophageal adenocarcinoma. The validity of the observed decreased risk of esophageal squamous cell carcinoma is uncertain.