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Kanwal F.,Baylor College of Medicine | Kanwal F.,Texas Medical Center Digestive Disease Center | Kanwal F.,Michael bakey Veterans Affairs Medical Center | White D.L.,Baylor College of Medicine | And 20 more authors.
Digestive Diseases and Sciences | Year: 2015

Background: Few studies have shown that host interleukin-28B (IL28B) genetic polymorphisms are associated with insulin resistance in patients with chronic hepatitis C virus (HCV) infection. However, the clinical relevance of this relationship is unclear. Aims: We examined the association between IL28B genotype for rs12980275 and risk of type 2 diabetes and diabetes-related complications. Methods: We used a cross-sectional study of prospectively recruited male veterans with chronic HCV. We employed logistic regression analysis and adjusted for patients’ age, race, body mass index, and hepatic fibrosis. Results: A total of 528 participants were recruited (mean age 59.1 years; 38.5 % African-American; 40.3 % advanced fibrosis). Of these, 36.1 % were homozygous for favorable AA allele for rs12980275, 49.0 % were heterozygous (AG), and 14.0 % were homozygous for the unfavorable allele (GG). Prevalence of diabetes was significantly lower in patients with both favorable alleles (AA) than that with at least one unfavorable IL28B G allele (21.1 vs. 30.2 %, p = 0.02). Similarly, patients who were homozygous for the favorable alleles had lower prevalence of diabetes-related complications than patients with any unfavorable IL28B allele (5.7 vs. 12.2 %, p = 0.01). This association did not change after adjusting for sociodemographic characteristics, body mass index, and stage of hepatic fibrosis (adjusted ORdiabetes 0.56, 95 % CI 0.35–0.89; ORdiabetes-related complications 0.47, 95 % CI 0.23–0.96). Conclusions: Patients who have favorable AA IL28B alleles have a lower prevalence of diabetes and related complications compared with patients with unfavorable IL28B rs12980275 genotype. IL28B genotype information may be used to counsel HCV patients regarding their individualized risk of diabetes and diabetes-related complications. © 2015, Springer Science+Business Media New York (Outside the USA).


Mody A.,Texas A&M University | Mody A.,Baylor College of Medicine | Mody A.,Center for Translational Research on Inflammatory Diseases | Whitec D.,Center for Translational Research on Inflammatory Diseases | And 9 more authors.
Cardiovascular Endocrinology | Year: 2015

Nonalcoholic fatty liver disease (NAFLD) is a condition where there is excess accumulation of triglycerides in the liver in the absence of excess alcohol consumption. It ranges from simple steatosis to nonalcoholic steatohepatitis, which can progress to fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD, one of the most common causes of chronic liver disease in Western populations, is the hepatic component of the metabolic syndrome and is associated with increased visceral adipose tissue (VAT), insulin resistance, and dyslipidemia. Studies have also shown that testosterone deficiency is associated with increased VAT and insulin resistance in men, whereas hyperandrogenemia has been associated with increased risk of insulin resistance and VAT in women. Thus, the aims of this review are to discuss the available experimental and epidemiological data evaluating the association between testosterone and NAFLD, to discuss the potential clinical relevance of these data, and to identify gaps in the literature. Cardiovasc Endocrinol 4:83-89. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Duan Z.,Baylor College of Medicine | Duan Z.,Section of Health Services Research IQuESt | Chen G.,University of Kansas Medical Center | Chen L.,Baylor College of Medicine | And 13 more authors.
International Journal of Molecular Epidemiology and Genetics | Year: 2014

The soluble receptor for advanced glycation end-products (sRAGE) is shown to mitigate pro-inflammatory effects triggered by ligation of RAGE with Nε-carboxymethyl-lysine (CML)-AGE or other ligands. We examined the associations among host, lifestyle, and genetic determinants of CML-AGE or sRAGE and risk of pancreatic cancer in the prospective ATBC Study. We obtained baseline exposure information, data on serological and genetic biomarkers from 141 patients with pancreatic cancer and 141 subcohort controls. Stepwise linear and logistic regression models were used for data analysis. Multiple linear regression analyses showed that CML-AGE concentrations were independently inversely correlated with the minor allele of rs640742 of DDOST, physical activity, alcohol consumption, diastolic blood pressure (BP), and positively correlated with heart rate, serum sRAGE and HDL concentrations (P < 0.05). sRAGE concentrations were independently inversely correlated with the 82Ser allele of rs2070600 of RAGE, age, body mass index, heart rate, and serum HDL; and positively correlated with serum CML-AGE, sucrose consumption, and diastolic BP (P < 0.05). The minor allele of rs1035786 of RAGE was associated with reduced risk of pancreatic cancer (any T compared with CC: multivariate OR = 0.61, 95% CI: 0.38-0.98). We identified host metabolic profile, lifestyle and genetic factors that explained approximately 50% of variability of CML-AGE or sRAGE in Finnish men smokers. The association between RAGE SNPs and pancreatic cancer risk warrants further investigation. © 2014, E-Century Publishing Corporation. All rights reserved.


Chen L.,Baylor College of Medicine | Chen L.,Center for Innovations in Quality | Chen L.,Center for Translational Research on Inflammatory Diseases | Duan Z.,Baylor College of Medicine | And 27 more authors.
Cancer Epidemiology | Year: 2016

Objectives: Receptor for advanced glycation end products (RAGE) expressed on adipocytes and immune cells can bind to ligand Nε-(carboxymethyl)-lysine (CML) and trigger dysregulation of adipokines and chronic inflammation. Soluble RAGE (sRAGE) mitigates the detrimental effect of RAGE. We examined the associations between circulating levels of CML-AGE and sRAGE and colorectal cancer (CRC). Methods: In a case-cohort study of the Women's Health Initiative Study, blood levels of CML-AGE and sRAGE were measured using ELISA. We used multivariable Cox regression model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident CRC in relation to quartiles (Q) of biomarker levels. Results: Average follow-up was 7.8 years for 444 cases and 805 subcohort members. In the subcohort, CML-AGE and sRAGE were inversely correlated with BMI (P values < 0.0001). Levels of CML-AGE and sRAGE were not associated with CRC. In BMI-specific analysis, the association between sRAGE and CRC was observed. Among women with BMI ≥ 25 kg/m2, those with highest levels of sRAGE had significantly lower risk for CRC as compared to women with lowest levels of sRAGE (HRQ4 versus Q1: 0.39; 95% CI: 0.17-0.91). This inverse association was not observed among women with BMI <25 kg/m2 (P value for interaction = 0.01). Conclusions: Among postmenopausal women, the RAGE pathway may be involved in obesity-related CRC. © 2016 Elsevier Ltd.


White D.L.,Baylor College of Medicine | White D.L.,Texas Medical Center Digestive Disease Center | White D.L.,Center for Translational Research on Inflammatory Diseases | Liu Y.,Baylor College of Medicine | And 19 more authors.
International Journal of Molecular Epidemiology and Genetics | Year: 2014

Results: Among 466 chronically HCV-infected males, 59% (n = 274) had advanced fibrosis and 54% (n = 252) had advanced inflammation. Nine of 472 SNPs were significantly associated with fibrosis risk; 4 in AKR1C3 (e.g., AKR1C3 rs2186174: ORadj = 2.04, 95% CI 1.38-3.02), 1 each in AKR1C2 and ESR1, and 1 in HSD17B6. Four SNPs were associated with inflammation risk, 2 in SRD5A1 (e.g., SRD5A1 rs248800: ORadj = 1.86, 95% CI 1.20-2.88) and 1 each in AKR1C2 and AKR1C3. MDR analysis identified a single AKR1C3 locus (rs2186174) as the best model for advanced fibrosis; while a 4-locus model with diabetes, AKR1C2 rs12414884, SRD5A1 rs6555406, and SRD5A1 rs248800 was best for inflammation.Methods: We performed a cross-sectional study evaluating single nucleotide polymorphisms (SNPs) in 16 candidate genes involved in androgen and estrogen ligand and receptor synthesis and risk of advanced hepatic fibrosis (F3/F4-F4) and inflammation (A2/A3-A3). We calculated adjusted odds ratios (ORs) using logistic regression and used multifactor dimensionality reduction (MDR) analysis to assess for gene-environment interaction.Conclusions: The consistency of our findings suggests AKR1C isoenzymes 2 and 3, and potentially SRD5A1, may play a role in progression of HCV-related liver disease in males. Future studies are needed to validate these findings and to assess if similar associations exist in females.Background: Males have excess advanced liver disease and cirrhosis risk including from chronic hepatitis C virus (HCV) infection though the reasons are unclear.Goal: To examine the role variants in genes involved in androgen and estrogen biosynthesis and metabolism play in HCV-related liver disease risk in males. © 2014, E-Century Publishing Corporation. All rights reserved.


Natarajan Y.,Baylor College of Medicine | White D.L.,Baylor College of Medicine | White D.L.,Texas Medical Center Digestive Disease Center | White D.L.,Center for Translational Research on Inflammatory Diseases | And 9 more authors.
Digestive Diseases and Sciences | Year: 2016

Background: Medical comorbidities and functional status limitations are determinants of mortality in many chronic diseases. The extent to which survival in the rapidly aging cohort of patients with HCV is affected by these competing causes of mortality remains unclear. Aim: We sought to determine the effect of medical/functional comorbidities on survival after adjusting for liver disease severity in a cohort of patients with HCV infection. Methods: We prospectively recruited consecutive patients from an HCV clinic 2009–2014. We calculated an index of survival (Schonberg Index, SI) based on age, gender, medical comorbidities, and functional status variables. We defined cirrhosis with the FibroSure test (F3/4–F4). We used multivariable Cox modeling to assess association between functional/survival measure and survival after adjustment for severity of liver disease. Results: The cohort consisted of 1052 HCV patients. The average age was 56.8 years; 36 % had cirrhosis. The mean SI was 8.2 (SD = 2.7). During a mean follow-up of 5610 person-years, 102 (9.7 %) patients died. In unadjusted analysis, higher baseline SI predicted mortality (HR 1.17; 95 % CI 1.09–1.25). SI similarly predicted mortality in cirrhotic patients (HR 1.23, 95 % CI 1.13–1.34) and non-cirrhotic patients (HR 1.21, 95 % CI 1.08–1.36). This did not change after adjusting for age, drug use, or coronary artery disease. Discussion: Comorbidities and functional limitations predict higher mortality in patients with HCV; this relationship is independent of cirrhosis. Use of general prognostic indices may help identify HCV patients at high risk for mortality, which could further guide clinical care in a manner not achievable with assessment of liver disease alone. © 2016 Springer Science+Business Media New York (Outside the USA)

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