Contribution of different HFE genotypes to iron overload disease: a pooled analysis
Contribution of different HFE genotypes to iron overload disease: a pooled analysis
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DOI：
10.1097/00125817-200009000-00001
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发表时间：
2000-09-01
影响因子：
8.8
通讯作者：
Khoury, MJ
中科院分区：
文献类型：
--
作者：
Burke, W;Imperatore, G;Khoury, MJ
目的：探讨HFE基因C282 Y和H63 D突变对遗传性血色病临床表现的影响。研究方法：对14项报告HFE基因型数据的病例对照研究进行汇总分析，以评估不同HFE基因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C282 Y/C282 Y基因型的多态性。结果如下：C282 Y突变的纯合性携带铁过载的最大风险（OR = 4383，95%CI 1374至> 10，000），并占血色病病例的大多数（归因分数（AF）= 0.73）。其他基因型的风险要小得多：基因型C282 Y/H63 D的OR = 32（95% CI 18.5 - 55.4，AF = 0.06）; H63D/H63D的OR = 5.7（95% CI 3.2 - 10.1，AF = 0.01）; C282 Y杂合性OR = 4.1（95% CI 2.9 - 5.8，研究结果具有异质性，使得这种关联不确定）; H63 D杂合性OR = 1.6（95% CI 1 ~ 2.6，AF = 0.03）。C282 Y/C282 Y基因型的估计值对估计铁超载疾病的患病率高度敏感。在2.5/1000或更低的患病率下，C282 Y/C282 Y基因型的突变率不太可能超过50%。其他HFE基因型的外显率要低得多。结论：C282 Y纯合性赋予铁超载的风险最高，但H63 D突变也与增加的风险。我们的数据表明与不同的HFE基因型相关的风险梯度，从而表明存在其他修饰，无论是遗传或环境，有助于血色素沉着症的临床表现。
Purpose: To determine the contribution of the C282Y and H63D mutations in the HFE gene to clinical expression of hereditary hemochromatosis. Methods: 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. Results: 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. Conclusions: 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.