RESUMO
A variant upstream of human leukocyte antigen C (HLA-C) shows the most significant genome-wide effect on HIV control in European Americans and is also associated with the level of HLA-C expression. We characterized the differential cell surface expression levels of all common HLA-C allotypes and tested directly for effects of HLA-C expression on outcomes of HIV infection in 5243 individuals. Increasing HLA-C expression was associated with protection against multiple outcomes independently of individual HLA allelic effects in both African and European Americans, regardless of their distinct HLA-C frequencies and linkage relationships with HLA-B and HLA-A. Higher HLA-C expression was correlated with increased likelihood of cytotoxic T lymphocyte responses and frequency of viral escape mutation. In contrast, high HLA-C expression had a deleterious effect in Crohn's disease, suggesting a broader influence of HLA expression levels in human disease.
Assuntos
Regulação da Expressão Gênica , Infecções por HIV/genética , Infecções por HIV/imunologia , HIV/imunologia , Antígenos HLA-C/genética , Linfócitos T Citotóxicos/imunologia , Negro ou Afro-Americano/genética , Alelos , Sequência de Aminoácidos , Antirretrovirais/uso terapêutico , Doença de Crohn/genética , Doença de Crohn/imunologia , HIV/genética , Infecções por HIV/tratamento farmacológico , Humanos , Epitopos Imunodominantes/genética , Dados de Sequência Molecular , Mutação , Fragmentos de Peptídeos/imunologia , Polimorfismo de Nucleotídeo Único , Carga Viral/genéticaRESUMO
Variants near the HLA-DP gene show the strongest genome-wide association with chronic hepatitis B virus (HBV) infection and HBV recovery/persistence in Asians. To test the effect of the HLA-DP region on outcomes to HBV infection, we sequenced the polymorphic HLA-DPB1 and DPA1 coding exons and the corresponding 3' untranslated regions (3'UTRs) in 662 individuals of European-American and African-American ancestry. The genome-wide association study (GWAS) variant (rs9277535; 550A/G) in the 3'UTR of the HLA-DPB1 gene that associated most significantly with chronic hepatitis B and outcomes to HBV infection in Asians had a marginal effect on HBV recovery in our European- and African-American samples (odds ratio [OR] = 0.39, P = 0.01, combined ethnic groups). However, we identified a novel variant in the HLA-DPB1 3'UTR region, 496A/G (rs9277534), which associated very significantly with HBV recovery in both European and African-American populations (OR = 0.37, P = 0.0001, combined ethnic groups). The 496A/G variant distinguishes the most protective HLA-DPB1 allele (DPB1*04:01) from the most susceptible (DPB1*01:01), whereas 550A/G does not. 496A/G has a stronger effect than any individual HLA-DPB1 or DPA1 allele and any other HLA alleles that showed an association with HBV recovery in our European-American cohort. The 496GG genotype, which confers recessive susceptibility to HBV persistence, also associates in a recessive manner with significantly higher levels of HLA-DP surface protein and transcript level expression in healthy donors, suggesting that differences in expression of HLA-DP may increase the risk of persistent HBV infection.
Assuntos
Cadeias alfa de HLA-DP/genética , Cadeias beta de HLA-DP/genética , Vírus da Hepatite B/fisiologia , Hepatite B/genética , Grupos Raciais/genética , Estudos de Coortes , Variação Genética , Estudo de Associação Genômica Ampla , HumanosRESUMO
Combination lipid-reducing therapy is increasingly used, particularly for the management of severe or combined dyslipidemia in patients at high risk for coronary heart disease. To assess the potential additive effects of combining the cholesterol absorption inhibitor ezetimibe with a bile acid resin (BAR), a prospective chart review was performed of 40 patients in whom ezetimibe 10 mg/day was added to a stable regimen that included a BAR. At an average follow-up of 107 +/- 57 days, ezetimibe coadministration significantly reduced total cholesterol by 18%, triglycerides by 14%, and low-density lipoprotein cholesterol by 19% (all p < or =0.03), without significantly changing high-density lipoprotein cholesterol, and the combination was well tolerated.
