Burke W, Imperatore G, McDonnell S M, Baron R C, Khoury M J
Department of Medical History and Ethics, University of Washington, Seattle, Washington 98195, USA.
Genet Med. 2000 Sep-Oct;2(5):271-7. doi: 10.1097/00125817-200009000-00001.
To determine the contribution of the C282Y and H63D mutations in the HFE gene to clinical expression of hereditary hemochromatosis.
Pooled analysis of 14 case-control studies reporting HFE genotype data, to evaluate the association of different HFE genotypes with iron overload. In addition, we used data from the pooled analysis and published data to estimate the penetrance of the C282Y/C282Y genotype.
Homozygosity for the C282Y mutation carried the largest risk for iron overload (OR = 4383, 95% CI 1374 to >10,000) and accounted for the majority of hemochromatosis cases (attributable fraction (AF) = 0.73). Risks for other genotypes were much smaller: OR = 32 for genotype C282Y/H63D (95% CI 18.5 to 55.4, AF = 0.06); OR = 5.7 for H63D/H63D (95% CI 3.2 to 10.1, AF = 0.01); OR = 4.1 for C282Y heterozygosity (95% CI 2.9 to 5.8, with heterogeneity in study results, making this association uncertain); and OR = 1.6 for H63D heterozygosity (95% CI 1 to 2.6, AF = 0.03). Estimates of penetrance for the C282Y/C282Y genotype were highly sensitive to estimates of the prevalence of iron overload disease. At a prevalence of 2.5 per 1000 or less, penetrance of the C282Y/C282Y genotype is unlikely to exceed 50%. Penetrance of other HFE genotypes is much lower.
C282Y homozygosity confers the highest risk for iron overload but the H63D mutation is also associated with increased risk. Our data indicate a gradient of risk associated with different HFE genotypes and thus suggest the presence of other modifiers, either genetic or environmental, that contribute to the clinical expression of hemochromatosis.
确定HFE基因中C282Y和H63D突变对遗传性血色素沉着症临床表型的影响。
对14项报告HFE基因分型数据的病例对照研究进行汇总分析，以评估不同HFE基因分型与铁过载的相关性。此外，我们使用汇总分析的数据和已发表的数据来估计C282Y/C282Y基因型的外显率。
C282Y突变纯合子发生铁过载的风险最高（OR = 4383，95%CI 1374至>10,000），且占血色素沉着症病例的大多数（归因分数（AF）= 0.73）。其他基因型的风险要小得多：C282Y/H63D基因型的OR = 32（95%CI 18.5至55.4，AF = 0.06）；H63D/H63D的OR = 5.7（95%CI 3.2至10.1，AF = 0.01）；C282Y杂合子的OR = 4.1（95%CI 2.9至5.8，研究结果存在异质性，使得这种相关性不确定）；H63D杂合子的OR = 1.6（95%CI 1至2.6，AF = 0.03）。C282Y/C282Y基因型外显率的估计对铁过载疾病患病率的估计高度敏感。在每1000人患病率为2.5或更低时，C282Y/C282Y基因型的外显率不太可能超过50%。其他HFE基因型的外显率要低得多。
C282Y纯合子导致铁过载的风险最高，但H63D突变也与风险增加有关。我们的数据表明不同HFE基因型存在风险梯度，因此提示存在其他遗传或环境修饰因素，它们影响血色素沉着症的临床表型。
