HEMOCHROMATOSIS--GENETIC PREVALENCE AND PENETRANCE

血色病——遗传患病率和外显率

• 批准号: 6390110
• 负责人: PRADYUMNA D PHATAK
• 金额: $ 33.22万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390110
• 关键词: clinical research; epidemiology; gene expression; gene frequency; genetic screening; hereditary hemochromatosis; human genetic material tag; human population genetics; human subject

Hereditary hemochromatosis (HH) is the most common inherited disorder among Caucasians with an estimated frequency as high as 8 per 1000. Affected individuals absorb excessive amounts of dietary iron and develop progressive accumulation of tissue iron stores with consequent organ dysfunction including hepatic cirrhosis, diabetes mellitus, congestive heart failure, arthropathy and impotence. Early diagnosis and institution of phlebotomy treatments will prevent disease manifestations and normalize life expectancy. HH is therefore a natural target for the development of a routine screening strategy. Our group has demonstrated the favorable cost-effectiveness ratio of adopting such a screening strategy (1) and has screened 16,031 primary care patients using serum transferrin saturation (TS) levels to confirm the prevalence of undiagnosed HH in this setting and to demonstrate the feasibility of screening. (2) The recent description of HFE gene mutations in individuals with HH has made genetic testing for HH possible and may increase the attractiveness of general screening. However, several important questions about genetic prevalence and penetrance remain to be addressed before such a recommendation can be made. Our large screened sample provides us a unique opportunity to address several of these important issues. First, we will obtain population-based estimates of the prevalence of HFE gene mutations. Second, we will determine the sensitivity of serum TS testing for detecting these mutations. Third, the comparison of genotype and phenotype will allow us to draw useful inferences about disease penetrance. The results will enable us to propose an optimal screening strategy for HH and to determine the place of genetic testing in the diagnostic algorithm. This strategy may vary depending on age, sex and race. The answers to these questions will enable us to determine with greater confidence the relative effectiveness of a screening strategy for HH and will clarify for primary care practitioners which of their patients should be screened for this disorder. These questions have recently been identified as a priority by the Centers for Disease Control and Prevention and by the National Heart Lung and Blood Insitute.

Hereditary hemochromatosis (HH) is the most common inherited disorder among Caucasians with an estimated frequency as high as 8 per 1000. Affected individuals absorb excessive amounts of dietary iron and develop progressive accumulation of tissue iron stores with consequent organ dysfunction including hepatic cirrhosis, diabetes mellitus, congestive heart failure, arthropathy and impotence. 早期诊断和制度的静脉切开术治疗将预防疾病表现并使预期寿命正常化。 因此，HH是制定常规筛选策略的自然目标。 我们的小组已经证明了采用这种筛查策略（1）的成本效益比，并使用血清转移蛋白饱和度（TS）水平筛选了16,031名初级保健患者，以确认在这种情况下未诊断HH的流行率并证明了筛查的可行性。 （2）HH患者中HFE基因突变的最新描述使HH的基因测试成为可能，并可能提高一般筛查的吸引力。 但是，在提出这样的建议之前，有关遗传流行和渗透率的几个重要问题仍有待解决。 我们的大型筛选样本为我们提供了一个独特的机会，可以解决其中几个重要问题。 首先，我们将获得基于人群的HFE基因突变患病率的估计值。 其次，我们将确定血清TS测试检测这些突变的敏感性。 第三，基因型和表型的比较将使我们能够对疾病渗透率进行有用的推论。 结果将使我们能够为HH提出最佳的筛选策略，并确定基因检测的位置在诊断算法中。 该策略可能会因年龄，性别和种族而异。 这些问题的答案将使我们能够更有信心确定HH筛查策略的相对有效性，并将澄清初级保健从业人员应筛查哪些患者的这种疾病。 这些问题最近被疾病控制和预防中心以及国家心脏肺和血液中心确定为优先事项。