Temesgen, Zoey B

Abstract Background Increased prevalence of reduced bone mineral density (BMD) is well documented in persons infected with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or both. This study's purpose was to determine if an association exists between dietary calcium intake and BMD in these patients. Methods Participants were individuals with virologically suppressed HIV or untreated HCV monoinfections, those with HIV/HCV coinfection, and noninfected controls. The Hertzler-Frary dietary calcium questionnaire documented calcium intake with calcium amounts based on the US Department of Agriculture nutrient database. BMD was measured at baseline by dual-energy x-ray absorptiometry, and χ2 tests were used to assess the relationship between BMD and infection status. One-way analysis of covariance was used to compare calcium intake data with the prevalence of normal BMD and osteoporosis by infection group. Adjustments were made for race, age, body mass index, and smoking status. Spearman correlation was used to identify relationships between calcium intake from foods/beverages and BMD. Results A total of 452 men were recruited into the study. Osteoporosis and osteopenia were prevalent, but there was no association between infection group and BMD result (χ2(6) = 6.813; P = .34). Only HCV-infected patients with osteoporosis had lower calcium intake than patients with normal BMD (mean difference, 409 mg/d [95% confidence interval, 35–784 mg/d]; P = .03). Conclusions In this study population, dietary calcium intake was correlated with reduced BMD only in patients with HCV monoinfection.

Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.