A meta-analysis of reflux genome-wide association studies in 6750 Northern Europeans from the general population.

BACKGROUND: Gastroesophageal reflux disease (GERD), the regurgitation of gastric acids often accompanied by heartburn, affects up to 20% of the general population. Genetic predisposition is suspected from twin and family studies but gene-hunting efforts have so far been scarce and no conclusive genome-wide study has been reported. We exploited data available from general population samples, and studied self-reported reflux symptoms in relation to genome-wide single nucleotide polymorphism (SNP) genotypes. METHODS: We performed a GWAS meta-analysis of three independent population-based cohorts from Sweden, Finland, and UK. GERD cases (n=2247) and asymptomatic controls (n=4503) were identified using questionnaire-derived symptom data. Upon stringent quality controls, genotype data for more than 2.5M markers were used for association testing. Bioinformatic characterization of genomic regions associated with GERD included gene-set enrichment analysis (GSEA), in silico prediction of genetic risk effects on gene expression, and computational analysis of drug-induced gene expression signatures using Connectivity Map (cMap). KEY RESULTS: We identified 30 GERD suggestive risk loci (P≤5×10-5 ), with concordant risk effects in all cohorts, and predicted functional effects on gene expression in relevant tissues. GSEA revealed involvement of GERD risk genes in biological processes associated with the regulation of ion channel and cell adhesion. From cMap analysis, omeprazole had significant effects on GERD risk gene expression, while antituberculosis and anti-inflammatory drugs scored highest among the repurposed compounds. CONCLUSIONS: We report a large-scale genetic study of GERD, and highlight genes and pathways that contribute to further our understanding of its pathogenesis and therapeutic opportunities.

Gallstones and cholecystectomy in relation to risk of intra- and extrahepatic cholangiocarcinoma.

BACKGROUND: Cholangiocarcinomas are highly lethal tumours of the intrahepatic or extrahepatic biliary tract. The aetiology is largely unknown, and the potential roles of gallstones and gall bladder removal (cholecystectomy) need to be addressed in a large study with a long follow-up. METHODS: A population-based nationwide Swedish cohort study was carried out, in which patients hospitalised for gallstone diagnosis with or without gallbladder removal (cholecystectomy) between 1965 and 2008 were identified in the Swedish Patient Registry. The cohort was followed up for cancer in the Swedish Cancer Registry. The observed numbers of intra- and extrahepatic cholangiocarcinomas that developed after one year of follow-up were compared with the expected numbers, calculated from the corresponding background population, and the relative risks were estimated by standardised incidence ratios (SIRs) and 95% confidence intervals (CIs). RESULTS: Among the 192,960 non-cholecystectomised individuals with gallstones, there was a more than two-fold overall increased risk of both intra- and extra- hepatic cholangiocarcinomas, which remained stable over the follow-up period (SIR 2.77, 95% CI 2.17-3.49, and SIR 2.58, 95% CI 2.21-3.00, respectively). In the cholecystectomy cohort, including 345,251 people and 4,854,969 person-years, 325 incident cholangiocarcinomas were identified, of which 98 (30%) were intrahepatic and 227 (70%) were extrahepatic. Initially (1-4 years after surgery), the risk was increased for both intrahepatic cholangiocarcinoma (SIR 1.80, 95% CI 1.19-2.62) and extrahepatic cholangiocarcinoma (SIR 2.29, 95% CI 1.83-2.82), but no increase remained after 10 years of follow-up or more (SIR 1.10, 95% CI 0.79-1.48, and SIR 0.87, 95% CI 0.70-1.07, respectively). INTERPRETATION: Gallstones seem to increase the risk of both intra- and extrahepatic cholangiocarcinoma. However, this risk seems to decline to the level of the background population with time after cholecystectomy.

Increased risk of hepatocellular carcinoma after cholecystectomy.

BACKGROUND: The association between gall bladder removal (cholecystectomy) and hepatocellular carcinoma warrants investigation. An increased intrahepatic bile duct pressure following cholecystectomy might cause chronic inflammation in the surrounding liver tissue, which might induce cancer development. METHODS: A nationwide Swedish population-based cohort study in 1965-2008 included 345,251 patients undergoing cholecystectomy because of gallstone. The number of observed hepatocellular carcinoma cases was divided by the expected number, calculated from the corresponding background Swedish population, thus providing standardised incidence ratios (SIRs) with 95% confidence intervals (CIs). RESULTS: During follow-up of 4,854,969 person-years, 333 new cases of hepatocellular carcinoma were identified, rendering an overall increased risk (SIR 1.24, 95% CI: 1.11-1.38). The risk increased with longer follow-up (P for trend=0.003). Among patients who underwent cholecystectomy 30-43 years earlier, SIR was 2.00 (95% CI: 1.32-2.87). The results were similar after exclusion of 15,634 patients with any recorded risk factor, that is, diabetes, obesity, hepatitis, liver cirrhosis, alcoholism, or blood transfusion. CONCLUSION: Cholecystectomy might be associated with a long-term increased risk of hepatocellular carcinoma.

Sex-specific exposure prevalence of established risk factors for oesophageal adenocarcinoma.

BACKGROUND: There is an unexplained male predominance in the incidence of oesophageal adenocarcinoma, and the sex-specific distribution of its risk factors in the general population is not known. METHODS: A random sample of Swedish citizens aged 40-79 years completed a questionnaire for assessment of the prevalence of five risk factors for oesophageal adenocarcinoma: reflux symptoms, body mass index, tobacco smoking habits, socioeconomic status, and use of non-steroidal anti-inflammatory drugs (NSAIDs). Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) to evaluate the association of these risk factors, separately and combined, with male sex, with women as reference. RESULTS: Among 6969 invited people, 4906 (70.4%) completed the questionnaire. Adjusted prevalence estimates showed a negative association with male sex with regard to reflux disease (OR=0.70, 95% CI=0.58-0.84), whereas overweight (OR=1.98, 95% CI=1.72-2.27) and obesity (OR=1.22, 95% CI=1.01-1.47), previous smoking (OR=1.50, 95% CI=1.30-1.72), and no NSAID use (OR=1.35, 95% CI=1.15-1.49) were positively associated. CONCLUSIONS: Exposure to some but not all established risk factors for oesophageal adenocarcinoma seems to be more common in men than in women, but the differences are small and unlikely to explain the male predominance of this tumour.

Severe symptoms of gastro-oesophageal reflux disease are associated with cardiovascular disease and other gastrointestinal symptoms, but not diabetes: a population-based study.

BACKGROUND: Few population-based studies have examined comorbidity in relation to gastro-oesophageal reflux disease (GERD). AIM: To study the association between cardiovascular disease, diabetes, gastrointestinal symptoms and GERD. METHODS: Population-based, cross-sectional, case-control study based on a large Norwegian health survey conducted in 1995-97. Among 65,333 participants, 3153 persons reporting severe reflux symptoms were defined as cases, and 40,210 persons without such symptoms were defined as controls. Data on cardiovascular disease, diabetes, gastrointestinal symptoms and potential confounders were collected through questionnaires. Odds ratios (OR) with 95% confidence intervals (CI) were estimated using unconditional logistic regression, in crude and adjusted models. RESULTS: In the crude models, positive associations were observed between myocardial infarction (OR 1.7, 95% CI 1.4-2.1), angina pectoris (OR 2.5, 95% CI 2.1-2.9) and stroke (OR 1.6, 95% CI 1.2-2.1) and risk of GERD. The associations were attenuated in the adjusted models, but remained significant for angina pectoris (OR 1.9, 95% CI 1.6-2.2). No association was observed between diabetes and GERD. Strong positive associations were seen between all studied gastrointestinal symptoms, i.e. nausea, diarrhoea and constipation, and risk of GERD. CONCLUSIONS: This population-based study indicates that myocardial infarction, angina pectoris, stroke and symptoms of nausea, diarrhoea and constipation are associated with GERD.

Severe gastro-oesophageal reflux symptoms in relation to anxiety, depression and coping in a population-based study.

BACKGROUND: The association between psychiatric disorders and gastro-oesophageal reflux symptoms is uncertain, and few population-based studies are available. AIM: To examine the association between psychiatric and psychological factors and reflux symptoms. METHODS: Population-based, cross-sectional, case-control study based on two health surveys conducted in the Norwegian county Nord-Trondelag in 1984-1986 and 1995-1997. Reflux symptoms were assessed in the second survey, including 65,333 participants (70% of the county's adult population). 3153 subjects reporting severe reflux symptoms were defined as cases and 40,210 subjects without symptoms were defined as controls. Data were collected in questionnaires. Odds ratio with 95% confidence intervals were estimated using unconditional logistic regression, in adjusted models. RESULTS: Subjects reporting anxiety without depression had a 3.2-fold (95% CI: 2.7-3.8) increased risk of reflux, subjects with depression without anxiety had a 1.7-fold (95% CI: 1.4-2.1) increased risk and subjects with both anxiety and depression had a 2.8-fold (95% CI: 2.4-3.2) increased risk, compared to subjects without anxiety/depression. We observed a weak inverse association between one measure of covert coping and risk of reflux and a weak positive association between another coping measure and risk of reflux. CONCLUSIONS: This population-based study indicates that anxiety and depression are strongly associated with reflux symptoms, while no consistent association regarding coping and reflux was found.