The expression of genes in top obesity-associated loci is enriched in insula and substantia nigra brain regions involved in addiction and reward.

BACKGROUND: Genome-wide association studies (GWAS) have identified more than 250 loci associated with body mass index (BMI) and obesity. However, post-GWAS functional genomic investigations have been inadequate for understanding how these genetic loci physiologically impact disease development. METHODS: We performed a PCR-free expression assay targeting genes located nearby the GWAS-identified SNPs associated with BMI/obesity in a large panel of human tissues. Furthermore, we analyzed several genetic risk scores (GRS) summing GWAS-identified alleles associated with increased BMI in 4236 individuals. RESULTS: We found that the expression of BMI/obesity susceptibility genes was strongly enriched in the brain, especially in the insula (p = 4.7 × 10-9) and substantia nigra (p = 6.8 × 10-7), which are two brain regions involved in addiction and reward. Inversely, we found that top obesity/BMI-associated loci, including FTO, showed the strongest gene expression enrichment in the two brain regions. CONCLUSIONS: Our data suggest for the first time that the susceptibility genes for common obesity may have an effect on eating addiction and reward behaviors through their high expression in substantia nigra and insula, i.e., a different pattern from monogenic obesity genes that act in the hypothalamus and cause hyperphagia. Further epidemiological studies with relevant food behavior phenotypes are necessary to confirm these findings.

Impact of Highly Active Antiretroviral Therapy on Chronic Hepatitis B Serological Markers among Senegalese HIV Co-infected Children.

BACKGROUND: Coinfection with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) causes complex interactions. The aim of this study was to evaluate the seroprevalence and HBV evolution among HIV coinfected children receiving highly active antiretroviral therapy (HAART). METHODS: A descriptive cross-sectional study was carried out among 252 HIV infected children enrolled in the Hôpital d'enfants Albert Royer, Dakar, Senegal, from April 2013 to March 2015. Clinical characteristics, immuno-virological status, alanine aminotransferase (ALT) levels, and HBV serological marker were taken from the patients' medical records. RESULTS: Overall, 7 children were HBsAg positive with a determinate prevalence rate of 2.8%. Median age at HIV diagnosis was 3.5 years (1.3-14.4 years). According to World Health Organization (WHO) staging, 40.1% of children were stage 4 and 25.8% were stage 3. Of the 7 HIV/HBV-co-infected children, 6 (86%) received lamivudine alone at initiation of treatment, and only one child received tenofovir associated with emtricitabine. Overall median HAART duration treatment including lamivudine alone or tenofovir+lamivudine (or emtricitabine) was 7.7 years (3.3-11.3). Only the two children (29%) receiving lamivudine during follow-up had high HBV DNA load despite having good immuno-virological status. Suppression of HBV DNA replication was achieved in 5 (71.4%) of 7 children. CONCLUSION AND GLOBAL HEALTH IMPLICATION: HIV/HBV coinfection prevalence was low in our study. HBsAg and HBeAg loss were low while suppression of HBV DNA replication was still higher on tenofovir. Screening and monitoring HBV infection among all HIV infected children are required to direct treatment in order to improve children HBV/HIV coinfected outcome.

Expression and functional assessment of candidate type 2 diabetes susceptibility genes identify four new genes contributing to human insulin secretion.

OBJECTIVES: Genome-wide association studies (GWAS) have identified >100 loci independently contributing to type 2 diabetes (T2D) risk. However, translational implications for precision medicine and for the development of novel treatments have been disappointing, due to poor knowledge of how these loci impact T2D pathophysiology. Here, we aimed to measure the expression of genes located nearby T2D associated signals and to assess their effect on insulin secretion from pancreatic beta cells. METHODS: The expression of 104 candidate T2D susceptibility genes was measured in a human multi-tissue panel, through PCR-free expression assay. The effects of the knockdown of beta-cell enriched genes were next investigated on insulin secretion from the human EndoC-ßH1 beta-cell line. Finally, we performed RNA-sequencing (RNA-seq) so as to assess the pathways affected by the knockdown of the new genes impacting insulin secretion from EndoC-ßH1, and we analyzed the expression of the new genes in mouse models with altered pancreatic beta-cell function. RESULTS: We found that the candidate T2D susceptibility genes' expression is significantly enriched in pancreatic beta cells obtained by laser capture microdissection or sorted by flow cytometry and in EndoC-ßH1 cells, but not in insulin sensitive tissues. Furthermore, the knockdown of seven T2D-susceptibility genes (CDKN2A, GCK, HNF4A, KCNK16, SLC30A8, TBC1D4, and TCF19) with already known expression and/or function in beta cells changed insulin secretion, supporting our functional approach. We showed first evidence for a role in insulin secretion of four candidate T2D-susceptibility genes (PRC1, SRR, ZFAND3, and ZFAND6) with no previous knowledge of presence and function in beta cells. RNA-seq in EndoC-ßH1 cells with decreased expression of PRC1, SRR, ZFAND6, or ZFAND3 identified specific gene networks related to T2D pathophysiology. Finally, a positive correlation between the expression of Ins2 and the expression of Prc1, Srr, Zfand6, and Zfand3 was found in mouse pancreatic islets with altered beta-cell function. CONCLUSIONS: This study showed the ability of post-GWAS functional studies to identify new genes and pathways involved in human pancreatic beta-cell function and in T2D pathophysiology.