Body mass index and esophageal and gastric cancer: A pooled analysis of 10 population-based cohort studies in Japan

The effect of body mass index (BMI) on esophageal and gastric carcinogenesis might be heterogeneous, depending on subtype or subsite. However, findings from prospective evaluations of BMI associated with these cancers among Asian populations have been inconsistent and limited, especially for esophageal adenocarcinoma and gastric cardia cancer. We performed a pooled analysis of 10 population-based cohort studies to examine this association in 394,247 Japanese individuals. We used Cox proportional hazards regression to estimate study-specific hazard ratios (HRs) and 95% confidence intervals (CIs), then pooled these estimates to calculate summary HRs with a random effects model. During 5,750,107 person-years of follow-up, 1569 esophageal cancer (1038 squamous cell carcinoma and 86 adenocarcinoma) and 11,095 gastric (728 cardia and 5620 noncardia) cancer incident cases were identified. An inverse association was observed between BMI and esophageal squamous cell carcinoma (HR per 5-kg/m² increase 0.57, 95% CI 0.50–0.65), whereas a positive association was seen in gastric cardia cancer (HR 1.15, 95% CI 1.00–1.32). A nonsignificant and significant positive association for overweight or obese (BMI ≥25 kg/m²) relative to BMI <25 kg/m² was observed with esophageal adenocarcinoma (HR 1.32, 95% CI 0.80–2.17) and gastric cardia cancer (HR 1.24, 95% CI 1.05–1.46), respectively. No clear association with BMI was found for gastric noncardia cancer. This prospective study—the largest in an Asian country—provides a comprehensive quantitative estimate of the association of BMI with upper gastrointestinal cancer and confirms the subtype- or subsite-specific carcinogenic impact of BMI in a Japanese population.     

Genome-wide association study of early ischaemic stroke risk in Brazilian individuals with sickle cell disease implicates ADAMTS2 and CDK18 and uncovers novel loci

Ischaemic stroke is a common complication of sickle cell disease (SCD) and without intervention can affect 11% of children with SCD before the age of 20. Within the Trans-Omics for Precision Medicine (TOPMed), a genome-wide association study (GWAS) of ischaemic stroke was performed on 1333 individuals with SCD from Brazil (178 cases, 1155 controls). Via a novel Cox proportional-hazards analysis, we searched for variants associated with ischaemic stroke occurring at younger ages. Variants at genome-wide significance (p < 5 × 10⁻⁸) include two near genes previously linked to non-SCD early-onset stroke (<65 years): ADAMTS2 (rs147625068, p = 3.70 × 10⁻⁹) and CDK18 (rs12144136, p = 2.38 × 10⁻⁹). Meta-analysis, which included the independent SCD cohorts Walk-PHaSST and PUSH, exhibited consistent association for variants rs1209987 near gene TBC1D32 (p = 3.36 × 10⁻¹⁰), rs188599171 near CUX1 (p = 5.89 × 10⁻¹¹), rs77900855 near BTG1 (p = 4.66 × 10⁻⁸), and rs141674494 near VPS13C (1.68 × 10⁻⁹). Findings from this study support a multivariant model of early ischaemic stroke risk and possibly a shared genetic architecture between SCD individuals and non-SCD individuals younger than 65 years.