Genetic association between germline JAK2 polymorphisms and myeloproliferative neoplasms in Hong Kong Chinese population: a case-control study.
Genetic association between germline JAK2 polymorphisms and myeloproliferative neoplasms in Hong Kong Chinese population: a case-control study.
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DOI：
10.1186/s12863-014-0147-y
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发表时间：
2014-12-20
期刊：
影响因子：
2.9
通讯作者：
Yung BY
中科院分区：
文献类型：
--
作者：
Koh SP;Yip SP;Lee KK;Chan CC;Lau SM;Kho CS;Lau CK;Lin SY;Lau YM;Wong LG;Au KL;Wong KF;Chu RW;Yu PH;Chow EY;Leung KF;Tsoi WC;Yung BY
骨髓增生性肿瘤(MPN)是一组以体细胞突变(JAK2V617F)为特征的血液系统恶性肿瘤。这种突变会导致骨髓产生过多的血细胞，并在真性红细胞增多症(~95%)、原发性血小板增多症和原发性骨髓纤维化(均为~50%)中发现。它被认为是导致这些MPN发展的主要遗传因素。到目前为止，还没有关于MPN在香港人群中的遗传相关性的研究报告。在这里，我们调查了胚系JAK2基因多态性与香港中国人MPN的关系，以寻找导致MPN发生的因果变异。我们分析了172名MPN患者和470名健康对照JAK2基因座上的19个标签单核苷酸多态(SNPs)。这19个SNP中有3个定义了已报道的JAK2 46/1单倍型：rs10974944、rs12343867和rs12340895。采用Logistic回归对性别和年龄进行校正，比较患者和对照组之间的等位基因和单倍型频率。采用排列检验对多重比较进行校正。根据19个SNP的重要发现，我们随后通过与来自1000基因组计划的SNP数据的推算，检查了JAK2 148.7 kb区域的另外76个SNP。在单标记分析中，有15个SNPs与JAK2V617F阳性的MPN相关(N MPN128)，其中8个是新发现的与 = 相关的SNPs。详尽的可变大小滑动窗单倍型分析确定了184个单倍型，即使在多重测试校正后，患者和对照组之间的频率也显示出显著差异(P <； 0.05)。然而，单标记等位基因与V617F阳性MPN的相关性最强。在香港本地华人中，rs12342421表现出最强的关联信号：渐近P = 3.76 × 10−15，经验P = 2.00 × 10−5对50,000个排列，或 = 3.55对次等位基因C，95%CI，2.59-4.87。条件Logistic回归也表明rs12342421在显著的单倍型窗口中具有独立效应，即使增加了76个SNP，这种独立效应也没有改变。未发现V617F阴性MPN与JAK2 SNPs显著相关。在大样本的情况下，我们报道了JAK2V617F阳性MPN与15个标签JAK2 SNP之间的关联，以及rs12342421与JAK2 46/1单倍型无关的关联。本文的在线版本(doi：10.1186/s12863-0147.0147-y)包含补充材料，授权用户可以使用。
Myeloproliferative neoplasms (MPNs) are a group of haematological malignancies that can be characterised by a somatic mutation (JAK2V617F). This mutation causes the bone marrow to produce excessive blood cells and is found in polycythaemia vera (~95%), essential thrombocythaemia and primary myelofibrosis (both ~50%). It is considered as a major genetic factor contributing to the development of these MPNs. No genetic association study of MPN in the Hong Kong population has so far been reported. Here, we investigated the relationship between germline JAK2 polymorphisms and MPNs in Hong Kong Chinese to find causal variants that contribute to MPN development. We analysed 19 tag single nucleotide polymorphisms (SNPs) within the JAK2 locus in 172 MPN patients and 470 healthy controls. Three of these 19 SNPs defined the reported JAK2 46/1 haplotype: rs10974944, rs12343867 and rs12340895. Allele and haplotype frequencies were compared between patients and controls by logistic regression adjusted for sex and age. Permutation test was used to correct for multiple comparisons. With significant findings from the 19 SNPs, we then examined 76 additional SNPs across the 148.7-kb region of JAK2 via imputation with the SNP data from the 1000 Genomes Project. In single-marker analysis, 15 SNPs showed association with JAK2V617F-positive MPNs (n = 128), and 8 of these were novel MPN-associated SNPs not previously reported. Exhaustive variable-sized sliding-window haplotype analysis identified 184 haplotypes showing significant differences (P < 0.05) in frequencies between patients and controls even after multiple-testing correction. However, single-marker alleles exhibited the strongest association with V617F-positive MPNs. In local Hong Kong Chinese, rs12342421 showed the strongest association signal: asymptotic P = 3.76 × 10−15, empirical P = 2.00 × 10−5 for 50,000 permutations, OR = 3.55 for the minor allele C, and 95% CI, 2.59-4.87. Conditional logistic regression also signified an independent effect of rs12342421 in significant haplotype windows, and this independent effect remained unchanged even with the imputation of additional 76 SNPs. No significant association was found between V617F-negative MPNs and JAK2 SNPs. With a large sample size, we reported the association between JAK2V617F-positive MPNs and 15 tag JAK2 SNPs and the association of rs12342421 being independent of the JAK2 46/1 haplotype in Hong Kong Chinese population. The online version of this article (doi:10.1186/s12863-014-0147-y) contains supplementary material, which is available to authorized users.