Cytokine Polymorphisms and Hodgkin Lymphoma Risk

描述（由申请人提供）： 虽然环境因素在年轻成人霍奇金淋巴瘤（HL）的病因中起主要作用，但遗传因素也很重要。年轻成人HL患者的原本健康的同卵双胞胎与患者的异卵双胞胎相比，疾病风险增加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患者具有高循环水平的某些细胞因子（Th 2型）和抑制的细胞免疫（Th 1型细胞因子的标志物）。我们先前比较了50例未受影响的年轻成人HL病例（替代病例）的同卵双胞胎与匹配对照组的细胞因子水平。与对照组相比，未受影响的双胞胎具有统计学显著较高的IL-6和IL-8水平，但较低的IL-12水平。然后我们发现，与对照组相比，病例双胞胎携带低分泌IL-6等位基因的可能性更低（OR= 0.29，95% CI = 0.1-0.87）（Cozen，2004）。我们还发现病例更可能携带低分泌IL-12等位基因。我们建议通过扩大原始研究并招募更多的双胞胎对和对照组（增加66对额外的双胞胎对加上对照组，共154个病例双胞胎、未受影响双胞胎和对照组的三联体）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、TNF-α）在年轻成人HL病因中的作用。我们将使用Illumina来识别所提出的细胞因子基因中的384个已知的功能性和额外的SNP，以获得最大的信息并避免遗漏未知的调控位点。将从原始SNP数据开发单倍型，并使用多变量条件logistic回归在匹配对（病例双胞胎与对照，未受影响双胞胎与对照）中评估单个SNP和单倍型的风险。未受影响的同卵双胞胎作为病例双胞胎基因型的质量控制，在病例双胞胎死亡的情况下，同卵双胞胎的基因型可以被替换。在此样本量下，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），则我们将有80%的样本检测到比值比为1.6和1.8。这项研究是重要的，因为它可能会导致确定的因果遗传因素，可能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.