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BACKGROUND & AIMS Individuals with Barrett’s esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EA). Obesity contributes to development of BE and its progression to cancer. We investigated the roles of obesity-induced hyperinsulinemia and dysregulation of adipokines in these processes. METHODS We measured fasting levels of glucose, insulin, leptin, and adiponectin in 392 patients enrolled in the Seattle BE Study. We calculated homeostatic model assessment (HOMA) scores (a measure of insulin sensitivity) and identified subjects with metabolic syndrome. We evaluated the association between these measures and risk of EA using Cox regression models adjusted for known risk factors. RESULTS Increasing HOMA scores were associated with increasing risk for EA; the strongest association was observed within the first 3 years after participants entered the study (hazard ratio (HR)=2.45; 95% confidence interval [CI], 1.43–4.1; Ptrend=.001). Leptin level was also significantly associated with increased risk of EA within 3 y (HR=2.51; 95% CI 1.09–5.81; Ptrend =0.03) and 6 y (HR=2.07; 95% CI 1.01–4.26; Ptrend=0.048) of baseline. The level of high molecular weight adiponectin had a non-linear inverse association with risk of EA; the strongest associations were observed in the second tertile (HR=0.34; 95% CI, 0.14–0.82). Metabolic syndrome was not associated with risk of EA. CONCLUSIONS Among patients with BE, increased levels of leptin and insulin resistance are associated with increased risk for EA, whereas increased level of high molecular weight adiponectin is inversely associated with EA. These biomarkers might be used to determine cancer risk among patients with BE.

Background & AimsBarrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations.MethodsWe performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls.ResultsWe identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09–1.18; P = 1.8 × 10−11) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86–0.93; P = 7.5 × 10−9). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87–0.93; P = 3.72 × 10−9).ConclusionsWe identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

People with a high genetic propensity to obesity have higher risks of esophageal metaplasia and neoplasia than people with low genetic propensity. These analyses provide the strongest evidence to date that obesity is independently associated with BE and EAC, and is not due to confounding or bias inherent in conventional epidemiologic analyses.

BackgroundEsophageal adenocarcinoma (EA) incidence in many developed countries has increased dramatically over four decades, while survival remains poor. Persons with Barrett's esophagus (BE), who experience substantially elevated EA risk, are typically followed in surveillance involving periodic endoscopy with biopsies, although few progress to EA. No medical, surgical or lifestyle interventions have been proven to safely lower EA risk.DesignWe investigated whether smoking, obesity or alcohol could predict progression to EA in a prospective cohort of 411 BE patients. Data were collected during personal interview. Adjusted hazard ratios (HR) were estimated using Cox regression.Results39% had body mass index (BMI) over 30 and 64% had smoked cigarettes. Main analyses focused on those with at least 5 months of follow-up (33,635 person-months), in whom 45 developed EA. Risk increased by 3% per year of age (trend p-value 0.02), with approximate doubling of risk among males. EA risk increased with smoking pack-years (trend p-value 0.04) and duration (p-value 0.05). Compared to never-smokers, the HR for those in the highest pack-year tertile was 2.29 (95%CI 1.04–5.07). No association was found with alcohol or BMI, whereas a suggestion of increased risk was observed in those with higher waist-hip ratio, especially among males.ConclusionEA risk significantly increased with increasing age and cigarette exposure. Abdominal obesity, but not BMI, was associated with a modest increased risk. Continued follow-up of this and other cohorts is needed to precisely define these relationships so as to inform risk stratification and preventive interventions.

These results indicate that the TSH reference range should be narrowed and support a value of approximately 4.0 as the upper-reference limit.

Context Approximately 740000 Ci (2.73 ϫ 10 16 Bq) of iodine 131 (131 I) were released to the atmosphere from the Hanford Nuclear Site in Washington State from 1944 through 1957. The risk of thyroid disease resulting from prolonged environmental 131 I exposure is poorly understood. Objective The Hanford Thyroid Disease Study (HTDS) was conducted to determine if thyroid disease is increased among persons exposed as children to atmospheric releases of 131 I from Hanford. Design Retrospective cohort study. Exposure could have occurred from December 1944 through 1957. Follow-up occurred until the time of the HTDS examination (December 1992-September 1997). Participants' thyroid radiation doses from Hanford's 131 I releases were estimated from interview data regarding residence and dietary histories. Setting The cohort included a sample of all births from 1940 through 1946 to mothers with usual residence in 1 of 7 counties in eastern Washington State. Participants Of 5199 individuals identified, 4350 were located alive and 3440 were evaluable; ie, had sufficient data for dose estimation and received an HTDS evaluation for thyroid disease, including a thyroid ultrasound, physical examination, and fine needle biopsy if required to evaluate thyroid nodularity. Main Outcome Measures Thyroid cancer, benign thyroid nodules, total neoplasia, any thyroid nodules, autoimmune thyroiditis, and hypothyroidism. Results There was no evidence of a relationship between Hanford radiation dose and the cumulative incidence of any of the outcomes. These results remained unchanged after taking into account several factors that might confound the relationship between radiation dose and the outcomes of interest. Conclusion These results do not support the hypothesis that exposure during infancy and childhood to 131 I at the dose levels (median, 97 mGy; mean, 174 mGy) and exposure circumstances experienced by our study participants increases the risk of the forms of thyroid disease evaluated in this study.

We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases.