Gene-Environment Interactions and the Risk of Barrett's Esophagus in Three US Cohorts
American Journal of Gastroenterology. 114(6):893-899, June 2019.
Several single-nucleotide polymorphisms (SNPs) have been associated with Barrett's esophagus (BE) risk. In addition, environmental factors including smoking, alcohol consumption, and heartburn increase BE risk. However, data on potential interactions between these genetic and environmental factors on BE risk are scant. Understanding how genes and environmental risk factors interact may provide key insight into the pathophysiology of BE, and potentially identify opportunities for targeted prevention and treatment. The objectives of this study were to examine the main effects and the potential effect modification between known genetic loci (SNPs) and established environmental risk factors for BE.
METHODS:
We performed a nested case-control study using data on 401 incident BE cases and 436 age-matched controls from the Nurses' Health Study, Nurses' Health Study II, and Health Professionals Follow-up Study cohorts, who gave blood and completed biennial questionnaires. Overall, we genotyped 46 SNPs identified in previous BE genome-wide association studies as well as SNPs in candidate genes related to BE susceptibility (i.e., related to excess body fat, fat distribution, factors associated with insulin resistance, and inflammatory mediators). A genetic risk score (GRS) was constructed to evaluate the combined effect of the selected SNPs on BE risk. Interactions between SNPs and BE risk factors were also assessed.
RESULTS:
We observed a suggestive, but not statistically significant, association between our GRS and BE risk: a one-allele increase in the unweighted GRS increased the risk of BE by a factor of 1.20 (95% confidence interval = 1.00–1.44; P = 0.057). We did not observe any meaningful multiplicative interactions between smoking, alcohol consumption, or heartburn duration and BE genotypes. When we assessed the joint effect of weighted GRS and BE risk factors, we did not observe any significant interaction with alcohol and heartburn duration, whereas smoking showed a significant multiplicative interaction ( P = 0.016).
CONCLUSIONS:
Our results suggest that SNPs associated with BE at genome-wide significant levels can be combined into a GRS with a potential positive association with BE risk.
- SDC
Impact of Previous Exposure to Macrolide Antibiotics on Helicobacter pylori Infection Treatment Outcomes
American Journal of Gastroenterology. 114(6):900-906, June 2019.
Helicobacter pylori ( H. pylori ) guidelines, including the recent ACG clinical guideline, recommend avoiding clarithromycin-based triple therapy (TT-C) among patients with past macrolide exposure. Data to support this recommendation are scarce, and the impact of macrolide exposure on quadruple therapies is unclear. We aimed to determine the impact of macrolide exposure on the efficacy of H. pylori treatment in our region.
Methods:
We searched the Clalit Health Services database to identify subjects aged 25–60 years who underwent the first-ever 13 C-urea breath test between 2010 and 2015. Patients who underwent a previous H. pyloristool antigen test or gastroscopy were excluded. Pharmacy dispensation data were retrieved.
Results:
We identified 7,842 subjects (36.1% male individuals, age: 40.3 ± 10.5 years), including 3,062 (39.0%) with previous macrolide exposure. The efficacy of TT-C was 74.3% and 82.4% among subjects with and without macrolide exposure, respectively (odds ratio (OR), 0.62; 95% confidence interval (CI), 0.55–0.70; P < 0.0001). TT success was adversely affected by exposure to clarithromycin (55.5%; OR, 0.31; 95% CI, 0.24–0.39; P < 0.0001), roxythromycin (74.4%; OR, 0.65; 95% CI, 0.58–0.74; P < 0.0001), and erythromycin (73.9%; OR, 0.72; 95% CI, 0.57–0.89; P < 0.01) but not by exposure to azithromycin. A greater time elapsed because exposure to clarithromycin and roxythromycin was associated with higher eradication (OR, 1.007; 95% CI, 1.002–1.012; P < 0.01 and OR, 1.004; 95% CI, 1.002–1.006; P < 0.0001). A higher dose of clarithromycin and roxythromycin was associated with a lower likelihood of successful eradication (OR, 0.99988; 95% CI, 0.99982–0.99996; P < 0.01 and OR, 0.99981; 95% CI, 0.99971–0.99992; P < 0.001). The efficacies of sequential and concomitant therapies were 82.7% and 81.3%, respectively, and were not significantly affected by macrolide exposure.
Conclusions:
TT-C is adversely affected by previous exposure to macrolide antibiotics. Sequential, concomitant, and bismuth-based treatment may be preferred in this setting.
Physical Activity, Fatty Liver, and Glucose Metabolism Over the Life Course: The Lifelines Cohort
American Journal of Gastroenterology. 114(6):907-915, June 2019.
We examined the dose-dependent association of habitual moderate-to-vigorous physical activity (MVPA) with the biochemical markers for nonalcoholic fatty liver disease (NAFLD) and whether this association changes with age and degree of impaired glucose metabolism. We also investigated whether the associations depend on the domain of MVPA.
METHODS:
In this study, using data from the population-based Lifelines cohort (N = 42,661), MVPA was self-reported on the short questionnaire to assess health-enhancing physical activity. NAFLD was defined as a fatty liver index value of >60, based on body mass index, waist circumference, plasma triglycerides, and gamma-glutamyltransferase. Glucose metabolism was defined as normal (NGM), impaired (IGM), and type 2 diabetes mellitus (T2DM). Exclusion criteria were previously diagnosed hepatitis or cirrhosis and excessive alcohol use. All analyses were adjusted for age, sex, and education.
RESULTS:
Higher MVPA was dose dependently associated with a lower risk of having NAFLD: compared with “No MVPA,” the odds ratios (ORs) (95% confidence intervals) for MVPA quintiles were 0.78 (0.71–0.86), 0.64 (0.58–0.70), 0.53 (0.48–0.59), 0.51 (0.46–0.56), and 0.45 (0.41–0.50) for the highest level of MVPA. The association between MVPA and NAFLD was stronger for more impaired glucose status (ORNGM = 0.49 (0.42–0.57), OR IGM = 0.46 (0.40–0.54), OR T2DM = 0.42 (0.27–0.66)) and for older age (OR20-40 years = 0.51 (0.42–0.62), OR 60-80 years = 0.37 (0.29–0.48)) with the highest level of MVPA, relative to No MVPA. No favorable association was observed for occupational MVPA. With regard to MVPA and fibrosis, associations with fibrosis markers showed contradictory results.
CONCLUSIONS:
Higher MVPA levels are dose dependently associated with a lower NAFLD risk. This association is stronger in people with diabetes and older adults.
- SDC
Impact of Obesity and Alanine Aminotransferase Levels on the Diagnostic Accuracy for Advanced Liver Fibrosis of Noninvasive Tools in Patients With Nonalcoholic Fatty Liver Disease
American Journal of Gastroenterology. 114(6):916-928, June 2019.
Some evidence suggests an interference of obesity and alanine aminotransferase (ALT) levels on the diagnostic accuracy for advanced fibrosis of noninvasive tools such as liver stiffness measurement (LSM) by FibroScan, Fibrosis-4 (FIB-4), and nonalcoholic fatty liver disease fibrosis score (NFS). We assessed whether the diagnostic accuracy of LSM, Fibrosis-4 (FIB-4), and NFS and strategies based on the combination of these tools is affected by obesity and/or ALT levels.
METHODS:
We analyzed data from 968 patients with a histological diagnosis of nonalcoholic fatty liver disease. FIB-4, NFS, and LSM by FibroScan were measured.
RESULTS:
LSM was better than both FIB-4 and NFS for staging F3-F4 fibrosis area under the receiver operating characteristic curve test (AUC) 0.863, 0.777, and 0.765, respectively; P < 0.001 for both), showing higher accuracy and higher negative predictive value (NPV), but lower positive predictive value (PPV). LSM worked less well in high ALT (>100 IU) (AUC 0.811 vs 0.877, P = 0.04; PPV 57.5% vs 62.4%; NPV 90.7% vs 94%) or obese patients (AUC 0.786 vs 0.902, P < 0.001; PPV 58.7% vs 64.8%; NPV 88.3% vs 95.2%), the latter not being affected by the M or XL probe. Consistently, LSM worked better in terms of AUC and accuracy compared with both FIB-4 and NFS only in nonobese or high ALT patients, even with always keeping a slightly lower PPV. A serial combination of FIB-4 or NFS with LSM as the second test in patients in the gray area of the first test retained—in most scenarios—similar PPV and NPV compared with LSM alone. These strategies also increased the diagnostic accuracy of about 20% in all groups of patients, even if with a lower overall accuracy in obese patients (71.3% and 67.1% for FIB-4 and NFS as the first test, respectively) compared to nonobese patients (81.9% and 82.4% for FIB-4 and NFS as the first test, respectively).
CONCLUSIONS:
All tested noninvasive tools have overall better NPV than PPV. LSM has a better diagnostic accuracy for advanced fibrosis than both FIB-4 and NFS only in nonobese and/or low ALT patients. Serial combination strategies are better than a single tool strategy, regardless of obesity and ALT levels, although the accuracy is lower in obese patients.
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