Common variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance
Common variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance
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DOI：
10.1086/520001
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发表时间：
2007-10-01
影响因子：
9.8
通讯作者：
Mosser, Jean
中科院分区：
文献类型：
--
作者：
Milet, Jacqueline;Dehais, Valrie;Mosser, Jean
大多数遗传性血色病（GH）病例与白色人群中的HFE C282 Y/C282 Y（p.Cys282Tyr/p.Cys282Tyr）基因型相关。C282 Y纯合子所表现的症状是非常多变的。只有少数人患有明显的疾病。一些研究表明，除了环境因素，遗传成分可以解释这种表型变异的很大一部分，尽管迄今为止很少有遗传因素被确定。在本研究中，我们在大样本的C282 Y纯合子中，使用治疗前血清铁蛋白水平作为血色病异常的标志物，检测了候选基因中常见变异与血色病异常之间的关联。我们关注两种生物学相关基因类别：参与非HFE GH的基因（TFR 2、HAMP和SLC 40 A1）和参与铁调素表达调控的基因，包括来自骨形态发生蛋白（BMP）调控途径的基因（BMP 2、BMP 4、HJV、SMAD 1、SMAD 4和SMAD 5）和来自炎症介导调控途径的IL 6基因。血清铁蛋白水平与rs 235756（BMP 2基因区常见的单核苷酸多态性（SNP））之间存在显著相关性（P = 4.42 × 10（-5））。校正年龄和性别后，TT基因型的平均铁蛋白水平为655 ng/ml，TC基因型为516 ng/ml，CC基因型为349 ng/ml。我们的研究结果进一步表明BMP 2中rs 235756和HJV中SNP对血清铁蛋白水平的交互作用，BMP 4中SNP具有小的累加效应。BMP途径中的常见变体与铁负荷之间的这种首次报道的关联表明，HFE血色素沉着症的完全表达与铁调素的异常肝脏表达相关，不仅通过HFE功能的损害，而且还通过BMP途径中的功能调节。我们的研究结果还强调了BMP调节途径作为一个很好的候选人，用于识别新的修饰基因。
Most cases of genetic hemochromatosis (GH) are associated with the HFE C282Y/C282Y (p. Cys282Tyr/p. Cys282Tyr) genotype in white populations. The symptoms expressed by C282Y homozygotes are extremely variable. Only a few suffer from an overt disease. Several studies have suggested that, in addition to environmental factors, a genetic component could explain a substantial part of this phenotypic variation, although very few genetic factors have been identified so far. In the present study, we tested the association between common variants in candidate genes and hemochromatosis penetrance, in a large sample of C282Y homozygotes, using pretherapeutic serum ferritin level as marker of hemochromatosis penetrance. We focused on two biologically relevant gene categories: genes involved in non-HFE GH (TFR2, HAMP, and SLC40A1) and genes involved in the regulation of hepcidin expression, including genes from the bone morphogenetic protein (BMP) regulatory pathway (BMP2, BMP4, HJV, SMAD1, SMAD4, and SMAD5) and the IL6 gene from the inflammation- mediated regulation pathway. A significant association was detected between serum ferritin level and rs235756, a common single- nucleotide polymorphism (SNP) in the BMP2 genic region (P = 4.42 x 10(-5)). Mean ferritin level, adjusted for age and sex, is 655 ng/ml among TT genotypes, 516 ng/ml in TC genotypes, and 349 ng/ml in CC genotypes. Our results further suggest an interactive effect on serum ferritin level of rs235756 in BMP2 and a SNP in HJV, with a small additive effect of a SNP in BMP4. This first reported association between common variants in the BMP pathway and iron burden suggests that full expression of HFE hemochromatosis is linked to abnormal liver expression of hepcidin, not only through impairment in the HFE function but also through functional modulation in the BMP pathway. Our results also highlight the BMP regulation pathway as a good candidate for identification of new modifier genes.