Conte W J, Rotter J I
Am J Hum Genet. 1984 Jan;36(1):152-66.
The study of genetic markers linked and associated with disease has provided important evidence of a genetic contribution to numerous diseases and has helped to establish their modes of inheritance. However, this information has not been fully utilized in counseling individuals at risk for these disorders. In the case of recessive, marker-linked diseases, such as idiopathic hemochromatosis linked to HLA in family studies and associated with specific HLA alleles in population surveys, the only current clinical application has been to identify siblings who share both HLA-marker haplotypes with the affected proband. They are considered to be presymptomatically affected, and more definitive invasive investigations are considered appropriate. All other relatives, including parents, offspring, and other siblings, who share only one marker with the proband, have been counseled only that their risk is equivalent to the gene frequency of the disease allele, for example, 3%-6% for hemochromatosis. We have developed a generally applicable method to utilize population association data to derive more specific and accurate risk figures for these other relatives of patients with marker-linked and associated diseases. We have applied this method to idiopathic hemochromatosis. If the offspring of a patient with hemochromatosis lacks A3, B7, and B14, the risk to that offspring for developing hemochromatosis is less than 2%. On the other hand, if they receive HLA A3 from their unaffected parent, their risk climbs to 9%-10%; if they receive an A3-B14 haplotype, their risk increases to virtually 100%. As demonstrated by our example, the application of association data to family members already at a basal increased risk for marker-linked disease can significantly refine the disease risk estimates given to those relatives. This information can be utilized to select individuals in whom invasive diagnostic testing or preventative intervention is indicated.
对与疾病相关联的遗传标记的研究，为众多疾病的遗传因素提供了重要证据，并有助于确定其遗传模式。然而，这些信息在为有这些疾病风险的个体提供咨询时并未得到充分利用。在隐性的、与标记相关的疾病中，如在家族研究中与HLA相关联且在人群调查中与特定HLA等位基因相关的特发性血色素沉着症，目前唯一的临床应用是识别与患病先证者共享两个HLA标记单倍型的兄弟姐妹。他们被认为处于症状前受影响状态，更确定性的侵入性检查被认为是合适的。所有其他亲属，包括父母、子女和其他兄弟姐妹，若仅与先证者共享一个标记，则仅被告知其风险等同于疾病等位基因的基因频率，例如，血色素沉着症的风险为3%-6%。我们开发了一种普遍适用的方法，利用人群关联数据为这些与标记相关且有关联疾病患者的其他亲属得出更具体、准确的风险数字。我们已将此方法应用于特发性血色素沉着症。如果血色素沉着症患者的后代缺乏A3、B7和B14，那么该后代患血色素沉着症的风险小于2%。另一方面，如果他们从未受影响的父母那里获得HLA A3，其风险会升至9%-10%；如果他们获得A3-B14单倍型，其风险几乎会增至100%。如我们的例子所示，将关联数据应用于已经因与标记相关疾病而处于基础风险增加状态的家庭成员，可以显著细化给予这些亲属的疾病风险估计。此信息可用于选择需要进行侵入性诊断测试或预防性干预的个体。
