Université de Picardie Jules Verne, UFR de Médecine, INSERM UMR, Amiens, France.
Hum Genet. 2010 Sep;128(3):233-48. doi: 10.1007/s00439-010-0852-1. Epub 2010 Jul 6.
Haemochromatosis is predominantly associated with the HFE p.C282Y homozygous genotype, which is present in approximately 1 in 200 people of Northern European origin. However, not all p.C282Y homozygotes develop clinical features of haemochromatosis, and not all p.C282Y homozygotes even present abnormal iron parameters justifying venesection therapy. This situation was not apparent from initial genotype/phenotype correlation studies as there was a selection bias of patients. Only those patients with a significant iron burden were included in these early studies. It is now largely accepted that the p.C282Y/p.C282Y genotype is necessary for the development of HFE haemochromatosis. However, this genotype provides few clues as to why certain symptoms are associated with the disease. Expression of iron overload in people with this genotype depends on the complex interplay of environmental factors and modifier genes. In this review, we restrict our discussion to work done in humans giving examples of animal models where this has helped clarify our understanding. We discuss penetrance, explaining that this concept normally does not apply to autosomal recessive disorders, and discuss the usefulness of different biochemical markers in ascertaining iron burden. Hepcidin, a peptide synthesized primarily by the liver, has been identified as the central regulator in iron homeostasis. Consequently, understanding its regulation is the key. We conclude that the main goal now is to identify important modifiers that have a significant and unambiguous effect on iron storage.
血色病主要与 HFE p.C282Y 纯合基因型相关,这种基因型在北欧血统人群中约占 1/200。然而,并非所有 p.C282Y 纯合子都会出现血色病的临床特征,也并非所有 p.C282Y 纯合子甚至出现异常铁参数,需要进行静脉放血治疗。这种情况在最初的基因型/表型相关性研究中并不明显,因为存在患者选择偏倚。只有那些铁负荷明显增加的患者才会被纳入这些早期研究。现在人们普遍认为,p.C282Y/p.C282Y 基因型是 HFE 血色病发展的必要条件。然而,这种基因型并不能说明为什么某些症状与该疾病相关。具有这种基因型的人铁过载的表达取决于环境因素和修饰基因的复杂相互作用。在这篇综述中,我们将讨论仅限于在人类中进行的工作,并举例说明动物模型在阐明我们的理解方面的帮助。我们讨论了外显率,指出这个概念通常不适用于常染色体隐性疾病,并讨论了不同生化标志物在确定铁负荷方面的用途。肽激素铁调素主要由肝脏合成,已被确定为铁稳态的中心调节剂。因此,理解其调节机制是关键。我们得出的结论是,现在的主要目标是确定对铁储存有显著和明确影响的重要修饰因子。