Figlioli Gisella, Chen Bowang, Elisei Rossella, Romei Cristina, Campo Chiara, Cipollini Monica, Cristaudo Alfonso, Bambi Franco, Paolicchi Elisa, Hoffmann Per, Herms Stefan, Kalemba Michał, Kula Dorota, Pastor Susana, Marcos Ricard, Velázquez Antonia, Jarząb Barbara, Landi Stefano, Hemminki Kari, Gemignani Federica, Försti Asta
1] Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany [2] Department of Biology, University of Pisa, Pisa, Italy.
Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Sci Rep. 2015 Mar 10;5:8922. doi: 10.1038/srep08922.
A genome-wide association study (GWAS) performed on a high-incidence Italian population followed by replications on low-incidence cohorts suggested a strong association of differentiated thyroid cancer (DTC) with single nucleotide polymorphisms (SNPs) at 9q22.33, 2q35, 20q11.22-q12 and 14q24.3. Moreover, six additional susceptibility loci were associated with the disease only among Italians. The present study had two aims, first to identify loci involved in DTC risk and then to assess the cumulative effect of the SNPs identified so far in the Italian population. The combined analysis of the previous GWAS and the present Italian study provided evidence of association with rs7935113 (GALNTL4, OR = 1.36, 95%CI 1.20-1.53, p-value = 7.41 × 10(-7)) and rs1203952 (FOXA2, OR = 1.29, 95%CI 1.16-1.44, p-value = 4.42 × 10(-6)). Experimental ENCODE and eQTL data suggested that both SNPs may influence the closest genes expression through a differential recruitment of transcription factors. The assessment of the cumulative risk of eleven SNPs showed that DTC risk increases with an increasing number of risk alleles (p-trend = 3.13 × 10(-47)). Nonetheless, only a small fraction (about 4% on the disease liability scale) of DTC is explained by these SNPs. These data are consistent with a polygenic model of DTC predisposition and highlight the importance of association studies in the discovery of the disease hereditability.
在一个高发病率的意大利人群中进行的全基因组关联研究（GWAS），随后在低发病率队列中进行重复验证，结果表明分化型甲状腺癌（DTC）与9q22.33、2q35、20q11.22 - q12和14q24.3处的单核苷酸多态性（SNP）存在强关联。此外，另外六个易感位点仅在意大利人群中与该疾病相关。本研究有两个目的，一是确定与DTC风险相关的位点，二是评估目前在意大利人群中已鉴定出的SNP的累积效应。先前GWAS与本意大利研究的联合分析提供了与rs7935113（GALNTL4，比值比=1.36，95%置信区间1.20 - 1.53，p值=7.41×10⁻⁷）和rs1203952（FOXA2，比值比=1.29，95%置信区间1.16 - 1.44，p值=4.42×10⁻⁶）关联的证据。实验性的ENCODE和eQTL数据表明，这两个SNP可能通过转录因子的差异募集影响最接近基因的表达。对11个SNP累积风险的评估表明，DTC风险随着风险等位基因数量的增加而增加（p趋势=3.13×10⁻⁴⁷）。尽管如此，这些SNP仅解释了一小部分（疾病易感性量表上约4%）的DTC。这些数据与DTC易感性的多基因模型一致，并突出了关联研究在发现疾病遗传易感性方面的重要性。
