CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Rennes, France; Université de Rennes 1, UEB, Biosit, Faculté de Médecine, Rennes, France; CHU Rennes, Service de Génétique Moléculaire et Génomique, Rennes, France.
Inserm, U1043, Toulouse, France; CNRS, U5282, Toulouse, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.
J Hepatol. 2015 Mar;62(3):664-72. doi: 10.1016/j.jhep.2014.10.017. Epub 2014 Oct 18.
BACKGROUND & AIMS: Hereditary hemochromatosis (HH) is the most common form of genetic iron loading disease. It is mainly related to the homozygous C282Y/C282Y mutation in the HFE gene that is, however, a necessary but not a sufficient condition to develop clinical and even biochemical HH. This suggests that modifier genes are likely involved in the expressivity of the disease. Our aim was to identify such modifier genes.
We performed a genome-wide association study (GWAS) using DNA collected from 474 unrelated C282Y homozygotes. Associations were examined for both quantitative iron burden indices and clinical outcomes with 534,213 single nucleotide polymorphisms (SNP) genotypes, with replication analyses in an independent sample of 748 C282Y homozygotes from four different European centres.
One SNP met genome-wide statistical significance for association with transferrin concentration (rs3811647, GWAS p value of 7×10(-9) and replication p value of 5×10(-13)). This SNP, located within intron 11 of the TF gene, had a pleiotropic effect on serum iron (GWAS p value of 4.9×10(-6) and replication p value of 3.2×10(-6)). Both serum transferrin and iron levels were associated with serum ferritin levels, amount of iron removed and global clinical stage (p<0.01). Serum iron levels were also associated with fibrosis stage (p<0.0001).
This GWAS, the largest one performed so far in unselected HFE-associated HH (HFE-HH) patients, identified the rs3811647 polymorphism in the TF gene as the only SNP significantly associated with iron metabolism through serum transferrin and iron levels. Because these two outcomes were clearly associated with the biochemical and clinical expression of the disease, an indirect link between the rs3811647 polymorphism and the phenotypic presentation of HFE-HH is likely.
遗传性血色素沉着症（HH）是最常见的遗传性铁过载疾病。它主要与 HFE 基因中的纯合 C282Y/C282Y 突变相关，但这仅是发生临床甚至生化 HH 的必要而非充分条件。这表明修饰基因可能参与了疾病的表现。我们的目的是鉴定这些修饰基因。
我们对 474 名无血缘关系的 C282Y 纯合子个体的 DNA 进行了全基因组关联研究（GWAS）。使用 534,213 个单核苷酸多态性（SNP）基因型对铁负荷指数和临床结果进行了关联分析，并在来自四个不同欧洲中心的 748 名 C282Y 纯合子个体的独立样本中进行了复制分析。
一个 SNP 与转铁蛋白浓度（rs3811647，GWAS p 值为 7×10(-9)，复制 p 值为 5×10(-13)）显著相关。该 SNP 位于 TF 基因的内含子 11 中，对血清铁具有多效性（GWAS p 值为 4.9×10(-6)，复制 p 值为 3.2×10(-6)）。血清转铁蛋白和铁水平均与血清铁蛋白水平、去除的铁量和总体临床分期相关（p<0.01）。血清铁水平也与纤维化分期相关（p<0.0001）。
这是迄今为止在未选择的 HFE 相关 HH（HFE-HH）患者中进行的最大规模 GWAS，鉴定出 TF 基因中的 rs3811647 多态性是唯一与通过血清转铁蛋白和铁水平影响铁代谢的 SNP。由于这两个结果与疾病的生化和临床表现明显相关，因此 rs3811647 多态性与 HFE-HH 的表型表现之间可能存在间接联系。
