Genetic polymorphisms and asthma: findings from a case - control study in the Madeira island population

BACKGROUND: Asthma is a complex disease influenced by multiple genetic and environmental factors. While Madeira has the highest prevalence of asthma in Portugal (14.6%), the effect of both genetic and environmental factors in this population has never been assessed. We categorized 98 asthma patients according to the Global Initiative for Asthma (GINA) guidelines, established their sensitization profile, and measured their forced expiratory volume in 1second (FEV1) and forced vital capacity (FVC) indexes. Selected single nucleotide polymorphisms (SNPs) were analysed as potential markers for asthma susceptibility and severity in the interleukin 4 (IL4), interleukin 13 (IL13), beta-2-adrenergic receptor (ADRB2), a disintegrin and metalloprotease 33 (ADAM33), gasdermin-like (GSDML) and the signal transducer and activator of transcription 6 (STAT6) genes comparatively to a population reference set. RESULTS: Although mites are the major source of allergic sensitization, no significant difference was found amongst asthma severity categories. IL4-590*CT/TT and IL4-RP2*253183/183183 were found to predict the risk (2-fold) and severity (3 to 4-fold) of asthma and were associated with a lower FEV1 index. ADRB2-c.16*AG is a risk factor (3.5-fold), while genotype GSDML-236*TT was protective (4-fold) for moderate-severe asthma. ADAM33-V4*C was associated to asthma and mild asthma by the transmission disequilibrium test (TDT). Finally, ADAM33-V4*CC and STAT6-21*TT were associated with higher sensitization (mean wheal size ≥10mm) to house dust (1.4-fold) and storage mite (7.8-fold). CONCLUSION: In Madeira, IL4-590C/T, IL4-RP2 253/183, GSDML-236C/T and ADAM33-V4C/G SNPs are important risk factors for asthma susceptibility and severity, with implications for asthma healthcare management.

Associação de polimorfismos e expressão gênica de marcadores de apoptose ligados carcinogênese cervical induzida pelo hpv em mulheres infectadas ou não pelo HIV / Association of polymorphisms and gene expression of apoptosis markers linked cervical carcinogenesis induced hpv in women infected with HIV or not

A frequência observada desses SNPs estavam em equilíbrio de Hardy–Weinberg nos casos e controles. Nenhuma diferença estatística na frequência genotípica e alélica do polimorfismo de BCL-2 (-938C>A) foi observada entre casos e controles. Contudo, uma forte associação foi identificada na freqüência do genótipo GG de BAX (-248G>A) entre os casos e controles. Quando os grupos de LSIL e HSIL foram comparados, nenhuma diferença estatística foi observada, indicando que o genótipo GG pode influenciar no aparecimento de lesões cervicais, mas não na gravidade da doença. Analisamos a expressão de RNAm de genes associados a apoptose (BAX, BCL2, p53 e pRb) e citotoxicidade (perforina e Fas). Quando a expressão de RNAm de Perforina e Fas foram avaliadas, diferença estatística foi observadas em pacientes portadoras de NIC III e câncerObservamos diferença estatística entre os controles e todos os casos, quando analisamos a expressão de RNAm de p53, mas não de pRb, sendo observada diferença apenas nos controles e NIC II e III. Na analise de RNAm de BCL2, notamos uma baixa expressão no grupo de câncer quando comparado com NIC II, III e controle. Em conclusão, a infecção pelo HIV pode induzir redução na degranulação de células inflamatórias, corroborando para a progressão de infecção pelo HPV, e que carreadoras do alelo G na região promotora de BAX (-248G>A) pode estar associado ao desenvolvimento de NIC quando comparado com as carreadoras do alelo A, possuindo papel protetor; contudo o alelo G não está correlacionado com a gravidade da doença...

Cell-mediated cytotoxicity plays an important role in the regulation of HPVinfection, and in tumor formation. Apoptosis is regulated by different pathways involving a number of genes that either promote (BAX gene)or inhibit (BCL2 gene) the cell death. We evaluated the presence of cervical inflammatory cells, apoptotic (Bax, Bcl-2, FasL, NOS2, perforin) markers and the degranulating expressing cell marker (CD107a) from HPV and HPV/HIV women. Higher per centage of cervical CD4 + and CD8 + T cells were observed in both groups, with lower CD4+ T cells count observed in HPV/HIV women. There were few FasL, Bax and Bcl - 2 inflammatory cervical expressing cells in both groups. NOS2 expression was present especially in the epithelium basal layer on keratinocytes in both groups. Perforin was identified in few cervical cells. However, CD107a was detected in the epithelium basal layer and stroma, meanly on HPV women. We determined whether the SNPs of BCL2(-938C>A) and BAX ( - 248G>A) promoters are associated with risk of cervical intraepithelial neoplasia (CIN) outcome. The observed genotype frequencies of these SNPs were in agreement with Hardy – Weinberg equilibrium in cases and controlgroups. No statistical difference in genotype and allelic frequency ofBCL - 2 ( - 938C>A) polymorphism was observed between all cases and control groups. However, a strong association was identified in GG genotype frequency of BAX ( - 248G>A) polymorphism between cases and controls. When LSIL an d HSILgroups were compared, no statistical difference was observed, indicating thatGG genotype may influence the risk of CIN but not the lesion severity. Weanalyzed the mRNA expression of apoptosis - associated genes (BAX, BCL2, p53 and pRb ) and cytotoxicity -related genes (perforin and Fas). When Fas and Perforin mRNA expressions were evaluated, the statistical difference betweenCIN III and cancer was seen...

Immune response in cervical dysplasia induced by human papillomavirus: the influence of human immunodeficiency virus-1 co-infection - review

Human immunodeficiency virus (HIV-1) has become an important risk factor for human papillomavirus (HPV) infection and the development of HPV associated lesions in the female genital tract. HIV-1 may also increase the oncogenicity of high risk HPV types and the activation of low risk types. The Center for Disease Control and Prevention declared invasive cervical cancer an acquired immunodeficience virus (AIDS) defining illness in HIV positive women. Furthermore, cervical cancer happens to be the second most common female cancer worldwide. The host's local immune response plays a critical factor in controlling these conditions, as well as in changes in the number of professional antigen-presenting cells, cytokine, and MHC molecules expression. Also, the production of cytokines may determine which arm of the immune response will be stimulated and may influence the magnitude of immune protection. Although there are many studies describing the inflammatory response in HPV infection, few data are available to demonstrate the influence of the HIV infection and several questions regarding the cervical immune response are still unknown. In this review we present a brief account of the current understanding of HIV/HPV co-infection, emphasizing cervical immune response.