Genome-wide Association Study Reveals Multiple Nasopharyngeal Carcinoma-Associated Loci within the HLA Region at Chromosome 6p21.3
Genome-wide Association Study Reveals Multiple Nasopharyngeal Carcinoma-Associated Loci within the HLA Region at Chromosome 6p21.3
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DOI：
10.1016/j.ajhg.2009.07.007
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发表时间：
2009-08-14
影响因子：
9.8
通讯作者：
Shugart, Yin Yao
中科院分区：
文献类型：
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作者：
Tse, Ka-Po;Su, Wen-Hui;Shugart, Yin Yao
鼻咽癌是一种与遗传因素和eb病毒感染密切相关的多因素恶性肿瘤。为了确定与鼻窦炎易感性相关的常见遗传变异，我们对277名鼻窦炎患者和285名健康对照进行了全基因组关联研究（GWAS），分析了480,365个单核苷酸多态性（SNPS）。鉴定出12个具有统计学意义的snp，并将其定位到染色体6p21 .3。关联在两组独立的病例对照样本中得到了重复。两个最显著的snp （rs2517713和rs2975042； P-combined = 3.9 X 10（-20）和1.6 X 10(-19)）位于HLA-A基因。此外，我们还发现了NPC与两个基因之间的显著相关性：具体来说，伽马氨基丁酸b受体1 (GABBR1) （rs29232； p -联合= 8.9 7 X 10(-17)）和HLA-F （rs3129055和rs92S8122； p -联合= 7.36 X 10（-11）和3.33 X 10(-10)）。值得注意的是，在调整年龄、性别和hla相关snp后，rs29232的相关性仍然显著（残差p < 5 × 10(-4)）。此外，在鼻咽癌活检中，与相邻上皮细胞相比，肿瘤细胞中GABA(B)受体1的表达水平更高（p < 0.001），这意味着GABBR1在鼻咽癌发生中的生物学作用。据我们所知，这是首次在GWAS报告中发现染色体6p21.3内多个位点（HLA-A、HLA-F和GABBR1）与NPC相关。虽然其中一些关系可能归因于基因座之间的连锁不平衡，但研究结果显然为鼻咽癌的发展研究提供了新的方向。
Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy closely associated with genetic factors and Epstein-Barr virus infection. To identify the common genetic variants linked to NPC susceptibility, we conducted a genome-wide association study (GWAS) in 277 NPC patients and 285 healthy controls within the Taiwanese population, analyzing 480,365 single-nucleotide polymorphisms (SNPS). Twelve statistically significant SNPs were identified and mapped to chromosome 6p2l.3. Associations were replicated in two independent sets of case-control samples. Two of the most significant SNPs (rs2517713 and rs2975042; P-combined = 3.9 X 10(-20) and 1.6 x 10(-19), respectively) were located in the HLA-A gene. Moreover, we detected significant associations between NPC and two genes: specifically, gamma aminobutyric acid b receptor 1 (GABBR1) (rs29232; P-combined = 8.9 7 X 10(-17)) and HLA-F (rs3129055 and rs92S8122; P-combined = 7.36 x 10(-11) and 3.33 x 10(-10), respectively). Notably, the association of rs29232 remained significant (residual p < 5 X 10(-4)) after adjustment for age, gender, and HLA-related SNPs. Furthermore, higher GABA(B) receptor 1 expression levels can be found in the tumor cells in comparison to the adjacent epithelial cells (p < 0.001) in NPC biopsies, implying a biological role of GABBR1 in NPC carcinogenesis. To our knowledge, it is the first GWAS report of NPC showing that multiple loci (HLA-A, HLA-F, and GABBR1) within chromosome 6p21.3 are associated with NPC. Although some of these relationships may be attributed to linkage disequilibrium between the loci, the findings clearly provide a fresh direction for the study of NPC development.