Penetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA
Penetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA
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DOI：
10.1016/s0140-6736(02)07447-0
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发表时间：
2002-01-19
期刊：
影响因子：
168.9
通讯作者：
Gelbart, T
中科院分区：
文献类型：
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作者：
Beutler, E;Felitti, VJ;Gelbart, T
背景人们对筛查人群中与疾病相关的突变很感兴趣。最受欢迎的候选基因是HFE基因，该基因的突变是欧洲人血色素沉着症的最常见原因。每1000人中约有5人是845G->；A突变的纯合子，但有多少人有突变引起的临床表现尚不清楚。方法我们对41038名在美国健康评估诊所就诊的人进行845G-->；A和187C；>；GHFE突变的筛查，并分析了实验室数据和调查问卷引发的血色病体征和症状的数据。结果发现，在152名已确认的纯合子中，最常见的血色病症状并不比对照组更常见，包括一般健康状况不佳、糖尿病、关节疾病、心律失常、阳萎和皮肤色素沉着。纯合子和复合杂合子的年龄分布与对照组没有显著差异：在人口老龄化过程中，没有可测量到的此类个体的损失。然而，随着血清天冬氨酸氨基转移酶和IV型胶原浓度的增加，纯合子中肝炎或肝病病史的患病率显著增加；这些变化与铁负荷或年龄无关。在152名纯合子中，只有一人的体征和症状提示血色病的诊断。根据血色病基因携带者的正常年龄分布，以及所有年龄段的患者都没有症状，表明遗传性血色病的外显率比通常认为的要低得多。疾病的临床外显性是筛查遗传病的一个基本考虑因素；低外显性的疾病比高外显性的疾病的筛查对象更昂贵。我们最好的估计是，只有不到1%的纯合子会发展成明显的临床血色病。
Background There has been much interest in screening populations for disease-associated mutations. A favoured candidate has been the HFE gene, mutations of which are the most common cause of haemochromatosis in the European population. About five people in 1000 are homozygotes for the 845G-->A mutation, but little is known of how many have mutation-caused clinical manifestations.Methods We screened 41038 individuals attending a health appraisal clinic in the USA for the 845G-->A and 187C-->G HFE mutations, and analysed laboratory data and data on signs and symptoms of haemochromatosis as elicited by questionnaire.Findings The most common symptoms of haemochromatosis, including poor general health, diabetes, arthropathies, arrhythmias, impotence, and skin pigmentation were no more prevalent among the 152 identified homozygotes than among the controls. The age distribution of homozygotes and compound heterozygotes did not differ significantly from that of controls: there was no measurable loss of such individuals from the population during ageing. However, there was a significantly increased prevalence of a history of hepatitis or "liver trouble" among homozygotes and in the proportion of homozygotes with increased concentrations of serum aspartate aminotransferase and collagen IV; these changes were not related to iron burden or to age. Only one of the 152 homozygotes had signs and symptoms that would suggest a diagnosis of haemochromatosis.Interpretation The normal age distribution of people with the haemochromatosis genotype, and the lack of symptoms in patients of all ages, indicate that the penetrance of hereditary haemochromatosis is much lower than generally thought. The clinical penetrance of a disorder is an essential consideration in screening for genetic disease; disorders with low penetrance are more expensive candidates for screening than disorders with high penetrance. Our best estimate is that less than 1% of homozygotes develop frank clinical haemochromatosis.