Cytokine Polymorphisms and Hodgkin Lymphoma Risk

描述(由申请人提供)： 虽然环境因素在青年霍奇金淋巴瘤(HL)的病因中起主要作用，但遗传因素也很重要。原本健康的年轻成年HL患者的同卵双胞胎患病风险是非同卵双胞胎患者的99倍。我们假设遗传因素与细胞因子分泌的调节有关，因为未经治疗的HL患者循环中某些细胞因子(Th2型)水平较高，而细胞免疫功能(Th1型细胞因子的标志)较低。我们先前比较了50例年轻成人HL病例(代孕病例)中未受影响的同卵双胞胎的细胞因子水平与匹配的对照组。与对照组相比，未受影响的双胞胎的IL-6和IL-8水平显著高于对照组，但IL-12水平低于对照组。我们随后发现，与对照组相比，双胞胎病例携带低分泌IL-6等位基因的可能性较小(OR=0.29，95%CI=0.1-0.87)(Cozen，2004)。我们还发现，病例更有可能携带低分泌的IL-12等位基因。我们建议通过扩大原始研究和招募更多的双胞胎对和对照(增加66对双胞胎和对照，总共154对病例-双胞胎、未受影响的双胞胎和对照)来证实这些结果，并评估其他细胞因子基因型(IL-5、IL-9、IL-10、IL-13、IL-18、肿瘤坏死因子-α)在青年HL病因中的作用。我们将使用Illumina来识别384个已知的功能SNPs和建议的细胞因子基因中的额外SNPs，以获得最大的信息并避免遗漏未知的调控位点。单倍型将从原始的SNP数据中开发出来，单倍型的风险将通过单SNP和单倍型配对(双胞胎病例与对照，未受影响的双胞胎与对照)进行多变量条件Logistic回归分析。未受影响的同卵双胞胎作为双胞胎病例的基因型的质量控制，在双胞胎病例死亡的情况下，可以替换同卵双胞胎的基因型。在这个样本量下，如果次要等位基因频率分别为30%和15%(大多数已知细胞因子次要等位基因的范围)，我们将有80%检测到1.6和1.8的优势比。这项研究很重要，因为它可能导致对病因遗传因素的识别，这可能会提供替代的治疗策略或预防。

DESCRIPTION (provided by applicant): Although environmental factors play a major role in the etiology of young adult Hodgkin lymphoma (HL), genetic factors are also important. Originally healthy identical twins of young adult HL patients have a 99-fold increased risk of disease compared to no excess among fraternal twins of patients. We hypothesized that heritable factors were related to regulation of cytokine secretion because untreated HL patients have high circulating levels of certain cytokines (Th2 type) and depressed cellular immunity (a marker for Thl type cytokines). We previously compared cytokine levels in 50 unaffected identical twins of young adult HL cases (surrogate cases) to those of matched controls. Unaffected twins had statistically significantly higher levels of IL-6 and IL-8, but lower levels of IL-12, compared to controls. We then found that case-twins were less likely to carry the low-secreting IL-6 allele compared to controls (OR= 0.29, 95% CI = 0.1-0.87) (Cozen, 2004). We also found that cases were more likely to carry the low-secreting IL-12 allele. We propose to confirm these results and evaluate the role of other cytokine genotypes (IL-5, IL-9, IL-10, IL-13, IL-18, TNF-alpha) in young adult HL etiology by expanding the original study and recruiting more twin pairs and controls (to add 66 additional twin pairs plus a control for a total of 154 trios of case-twin, unaffected twin and control). We will use Illumina to identify 384 known functional and additional SNPs in the proposed cytokine genes in order to obtain maximum information and avoid missing unknown regulatory sites. Haplotypes will be developed from the raw SNP data and risk by single SNPs and haplotypes will be assessed in matched pairs (case-twin vs. control, and unaffected twin vs. control) using multivariate conditional logistic regression. The unaffected identical twin serves as a quality control for the genotype of the case-twin, and in situations where the case-twin is deceased, the identical twins' genotype can be substituted. With this sample size we will have 80% to detect an odds ratio of 1.6 and 1.8 if the minor allele frequency is 30% and 15%, respectively (the range of most of the known cytokine minor alleles). This study is important since it may will lead to identification of causal genetic factors which may offer alternative therapeutic strategies or prevention.