Nonalcoholic Fatty Liver Disease Risk Factors Affect Liver-Related Outcomes After Direct-Acting Antiviral Treatment for Hepatitis C

Introduction: In hepatitis C (HCV) patients, obesity and/or diabetes may increase the risk of liver-related outcomes. We aimed to determine whether diabetes and/or obesity are associated with adverse outcomes in direct-acting antiviral (DAA)-treated HCV patients. Methods: We conducted a retrospective study of 33,003 HCV-infected, DAA-treated Veterans between 2013 and 2015. Body mass index was used to categorize patients into underweight (< 18.5 kg/m2), normal weight (18.5 to < 25 kg/m2), overweight (25 to < 30 kg/m2), obesity I (30 to < 35 kg/m2), and obesity II–III (> 35 kg/m2). Diabetes was defined by ICD-9/10 codes in association with hemoglobin A1c > 6.5% or medication prescriptions. Patients were followed from 180 days post-DAA initiation until 2/14/2019 to assess for development of cirrhosis, decompensations, hepatocellular carcinoma (HCC), and death. Multivariable Cox proportional hazards regression models were used to determine the association between diabetes and/or obesity and outcomes. Results: During a mean follow-up of 3 years, 10.1% patients died, 5.0% were newly diagnosed with cirrhosis, 4.7% had a decompensation and 4.0% developed HCC. Diabetes was associated with an increased risk of mortality (AHR = 1.25, 95% CI 1.10–1.42), cirrhosis (AHR = 1.31, 95% CI 1.16–1.48), decompensation (AHR = 1.74, 95% CI 1.31–2.31), and HCC (AHR = 1.32, 95% CI 1.01–1.72) among patients without baseline cirrhosis. Compared to normal-weight persons, obese persons had a higher risk of cirrhosis, but overweight and obese persons had lower risk of mortality and HCC. Conclusions: In this large DAA-treated Veterans cohort, pre-DAA diabetes increases mortality and liver-related events independent of SVR. Continued vigilance is warranted in patients with diabetes despite SVR. Elevated BMI categories appear to have improved outcomes, although further studies are needed to understand those associations

Reverse gene–environment interaction approach to identify variants influencing body-mass index in humans

Identifying gene–environment (G×E) interactions contributing to human cardiometabolic disorders is challenging. Here we apply a reverse G×E candidate search by deriving candidate variants from promoter–enhancer interactions that respond to dietary fatty acid challenge through altered chromatin accessibility in primary human adipocytes. We then test all variants residing in lipid-responsive open chromatin sites in adipocyte promoter–enhancer contacts for interaction effects between genotype and dietary saturated fat intake on body-mass index (BMI) in the UK Biobank. We discover 14 new G×E variants in 12 lipid-responsive promoters, including in well-known lipid-related genes (LIPE, CARM1 and PLIN2) and newly associated genes, such as LDB3, for which we provide further functional and integrative genomic evidence. We further identify 24 G×E variants in enhancers, for a total of 38 new G×E variants for BMI in the UK Biobank, demonstrating that molecular genomics data produced in physiologically relevant contexts can be applied to discover new functional G×E mechanisms in humans

Localization of the murine cholecystokinin A and B receptor genes

We have determined the chromosomal locations of the two cholecystokinin (CCK) receptor genes in the mouse. Genetic localization utilized an interspecific backcross panel formed from the cross (C57BL/6J x Mus spretus ) F 1 x Mus spretus . Genomic DNAs from 94 individuals in the backcross were analyzed by Southern hybridization with rat CCK A and CCK B receptor cDNA probes. Unique map positions were determined by haplotype analysis with 650 previously mapped loci in the mouse backcross. The CCK A receptor gene ( Cckar ) mapped to mouse Chromosome (Chr) 5, in tight linkage with the DNA marker D5Bir8 . The CCK B receptor gene ( Cckbr ) mapped to mouse Chr 7, tightly linked to the β-hemoglobin locus ( Hbb ). This localization places Cckbr in the same region as the mouse obesity mutation tubby ( tub ), which also maps near Hbb (2.4±1.4 cM). Since CCK can function as a satiety factor when administered to rodents, localization of Cckbr near the tub mutation identifies this receptor as a possible candidate gene for this obesity mutation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47021/1/335_2004_Article_BF00352408.pd