Quantitative Trait Loci for CD4:CD8 Lymphocyte Ratio Are Associated with Risk of Type 1 Diabetes and HIV-1 Immune Control
Quantitative Trait Loci for CD4:CD8 Lymphocyte Ratio Are Associated with Risk of Type 1 Diabetes and HIV-1 Immune Control
复制标题
DOI：
10.1016/j.ajhg.2009.12.008
复制
发表时间：
2010-01-08
影响因子：
9.8
通讯作者：
Martin, Nicholas G.
中科院分区：
文献类型：
--
作者：
Ferreira, Manuel A. R.;Mangino, Massimo;Martin, Nicholas G.
特定淋巴细胞亚群的异常扩增或耗竭与临床表现相关，例如 HIV 进展为 AIDS 和自身免疫性疾病。我们试图确定淋巴细胞水平的遗传预测因子，并推断它们可能在免疫相关疾病中发挥作用。我们测试了 230 万个变异体与 5 个淋巴细胞亚群的关联，对普通人群的 2538 名个体进行了测量，包括 CD4+T 细胞、CD8+T 细胞、CD56+ 自然杀伤 (NK) 细胞，以及衍生的 CD4:CD8 比率测量值。我们确定了两个强关联区域。第一个位于主要组织相容性复合体 (MHC) 中，多个 SNP 与 CD4:CD8 比率密切相关 (rs2524054, p = 2.1 x 10(-28))。第二个区域位于 Schlafen 家族基因簇的中心，与 NK 细胞水平相关（rs1838149，p = 6.1 x 10(-14)）。 MHC 与 CD4:CD8 的关联在 988 名个体的独立小组中得到了令人信服的复制 (p 1.4 x 10(-9))。条件分析表明，MHC 区域中有两个主要的独立数量性状位点 (QTL) 调节 CD4:CD8 比率：一个位于 1 类簇中，影响 CD8 水平，而第二个位于 11 类簇中，调节 CD4 水平。两个 QTL 共同解释了 CD4:CD8 比率中 8% 的变异。 I 类变异也与宿主对 HIV 的持久控制密切相关，而 It 类变异与 1 型糖尿病相关，这表明 MFIC 的遗传变异可能部分通过 T 细胞稳态失调而使人易患免疫相关疾病。
Abnormal expansion or depletion of particular lymphocyte subsets is associated with clinical manifestations Such as HIV progression to AIDS and autoimmune disease. We sought to identify genetic predictors of lymphocyte levels and reasoned that these may play a role in immune-related diseases. We tested 2.3 million variants for association with five lymphocyte Subsets, measured in 2538 individuals from the general population, including CD4+T cells, CD8+ T cells, CD56+ natural killer (NK) cells, and the derived measure CD4:CD8 ratio. We identified two regions of strong association. The first was located in the major histocompatibility complex (MHC), with multiple SNPs strongly associated with CD4:CD8 ratio (rs2524054, p = 2.1 x 10(-28)). The second region was centered within a cluster of genes from the Schlafen family and was associated with NK cell levels (rs1838149, p = 6.1 x 10(-14)). The MHC association with CD4:CD8 replicated convincingly (p 1.4 x 10(-9)) in an independent panel of 988 individuals. Conditional analyses indicate that there are two major independent quantitative trait loci (QTL) in the MHC region that regulate CD4:CD8 ratio: one is located in the class 1 cluster and influences CD8 levels, whereas the second is located in the class 11 Cluster and regulates CD4 levels. jointly, both QTL explained 8% of the variance in CD4:CD8 ratio. The class I variants are also strongly associated with durable host control of HIV, and class It variants are associated with type-1 diabetes, suggesting that genetic variation at the MFIC may predispose one to immune-related diseases partly through disregulation of T cell homeostasis.