Genetic Epidemiology of HPV Infection Outcome in Men

描述(由研究人员提供)：持续感染人乳头瘤病毒(HPV)基本上会导致男性和女性的癌前病变和癌症损害，也可能影响HPV在性伴侣中的传播，因此是一种重要的“中间表型”。到目前为止，HPV的病因学研究大多集中在女性身上。鉴于男性在将HPV传播给女性性伴侣以及生殖器疣和几种癌症的公共卫生负担方面起着重要作用，了解男性HPV的自然历史将使男性和女性都受益。这项研究的目的是检验宿主基因差异影响男性HPV持久性的假设。尽管HPV持续存在的机制尚不清楚，但有几项研究涉及免疫逃避，涉及宿主免疫反应的遗传介导性决定因素。HPV对女性的遗传影响已有报道，我们建议在男性背景下检验这一假设。我们与UAB和莫菲特癌症中心和研究所的研究人员合作的团队拥有丰富的经验和专业知识，为评估男性HPV感染结果的遗传影响提供了独特的机会。在这项新的调查中，我们将利用500名高加索男性在男性HPV感染(HIM)中嵌套的数据，这是唯一一项针对男性的多国前瞻性研究，由4299名参与者组成，他们居住在美国佛罗里达州南部、巴西圣保罗和墨西哥库尔纳瓦卡。我们将确定250名在感染后6个月内清除HPV16的人，以及另一组250名HPV16持续存在超过12个月的人，并使用免疫芯片(从传染病和自身免疫性疾病的关联研究汇编的~200,000个SNP)对免疫相关基因的变异进行基因分型。我们将执行Logistic回归类型的遗传模型来检查两组中基因多态的不同分布，将多重联合感染与每种HPV类型作为单独结果的相关性考虑在内。这项研究的三个具体目标是：1)从登记访问时收集的250名持续性(e 12个月)生殖器HPV 16型感染者和250名暂时性(仅1x检测)生殖器HPV16型男性的登记全血中提取基因组DNA；2)使用免疫芯片阵列对所有500个样本进行基因分型；以及3)进行统计分析，以确定与生殖器HPV16DNA清除和持久性相关的遗传变异，这将是迄今为止第一次对男性HPV感染结局的免疫遗传学研究。这项研究的任何信息性数据都将填补男性HPV发病机制与免疫学效应之间的空白，并可能有助于确定男性及其伴侣适用于特定治疗方法的分子特征。

DESCRIPTION (provided by investigator): Persistent infection with human papillomavirus (HPV) causes essentially pre-cancerous and cancer lesions in both men and women and also likely influences HPV transmission within sexual partners and thus is an important "intermediate phenotype." To date, most efforts in etiological research of HPV have focused in women. Given that men are important in transmitting HPV to their female sexual partners along with the public health burden of genital warts and several cancers, understanding the natural history of HPV in men would benefit both men and women. The purpose of this study is to test the hypothesis that differences in host genes influence HPV persistence in men. Although the mechanism for HPV persistence is unknown, several studies implicate immune evasion, involving genetically mediated determinants of the host immune response. Genetic influences of HPV in women have been reported and we propose test this hypothesis in the context of men. Our collaborative team with investigators from UAB and Moffitt Cancer Center and Research Institute has the experience and expertise that provides a unique opportunity to evaluate the genetic effects with well- documented HPV infection outcomes in men. For this new investigation, we will draw upon data from 500 Caucasian men nested within the HPV infection in Men (HIM), the only multi-national prospective study of men, which consists of 4299 participants, 18-70 years residing in southern Florida, USA, Sao Paulo, Brazil and Cuernavaca, Mexico. We will identify 250 individuals who cleared HPV16 within 6 months after acquisition and another set of 250 individuals in whom HPV16 has persisted for over 12 months and perform genotyping of variants in immune-related genes using the ImmunoChip ((~200,000 SNPs compiled from association studies of infectious and autoimmune diseases). We will perform a logistic regression type of genetic models to examine differential distribution of the genetic polymorphisms in the two groups, accounting for correlations of multiple co-infections with each HPV type as an individual outcome. Three specific aims of the study are: 1) Extract genomic DNA from archived whole blood collected at the enrollment visit among 250 men with persistent (e 12 months) genital HPV 16 infection and 250 with transient (1x detection only) genital HPV 16; 2) Genotype all 500 samples using the ImmunoChip array; and 3) Conduct statistical analyses to identify genetic variants associated with genital HPV 16 DNA clearance and persistence To our knowledge, this would be the first immunogenetic study of HPV infection outcome among men, to date. Any informative data from this study would fill in the gap of immunological effects with HPV pathogenesis in men and may help identify molecular signatures amenable to specific therapeutic approaches in men and their partners.