Association between a high-expressing interferon-γ allele and a lower frequency of kidney angiomyolipomas in TSC2 patients
Association between a high-expressing interferon-γ allele and a lower frequency of kidney angiomyolipomas in TSC2 patients
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DOI：
10.1086/342718
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发表时间：
2002-10-01
影响因子：
9.8
通讯作者：
Kwiatkowski, DJ
中科院分区：
文献类型：
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作者：
Dabora, SL;Roberts, P;Kwiatkowski, DJ
多发性硬化症（TSC）是一种家族性错构瘤综合征，其中肾脏受累常见，有时危及生命。我们研究了一个非TSC基因对肾脏疾病的潜在影响，在一个队列的172例TSC患者与TSC 2突变。对患者的干扰素-γ（IFN-γ）微卫星多态性进行基因分型，在内含子1内，其中一个常见的等位基因（等位基因2，具有12个CA重复）已被证明具有较高的IFN-γ表达。采用卡方检验分析了IFN-γ等位基因2与TSC 2队列中肾血管平滑肌脂肪瘤（KAML）发生的相关性。由于TSC中KAML的年龄依赖性发展，我们最初关注127名>5岁的患者。进行了额外的亚组分析，以调查年龄和性别的影响。还在该队列的一个亚组（46名先证者）中进行了传递/不平衡检验（TDT），这些先证者的父母和/或兄弟姐妹样本可用于分析。卡方检验和TDT均提示，在已知TSC 2突变的患者中，IFN-γ等位基因2与KAML缺失之间存在关联。在127例>5岁的患者中，95例（75%）存在KAML，32例（25%）缺失。在存在KAML的组中，IFN-γ等位基因2的频率为56%;在不存在KAML的组中，IFN-γ等位基因2的频率显著更高，为78%（P = 0.02，通过卡方检验）。基于家族的TDT分析得出了类似的结果，TDT统计量（TDT chi（2）= 5.45）对应的P值为0.02。亚组分析表明，年龄和性别都可能影响这种关联的影响。虽然这些结果应该在其他人群中与TSC复制，本研究表明，修饰基因在TSC的可变表达中发挥作用，也表明了一种潜在的治疗TSC患者的KAML。
Tuberous sclerosis complex (TSC) is a familial hamartoma syndrome in which renal involvement is common and, at times, life threatening. We have investigated the potential effect of a non-TSC gene on renal disease in a cohort of 172 TSC patients with TSC2 mutations. Patients were genotyped for an interferon-gamma (IFN-gamma) microsatellite polymorphism, within intron 1, for which one common allele (allele 2, with 12 CA repeats) has been shown to have a higher expression of IFN-gamma. A chi(2) analysis was used to examine the association between IFN-gamma allele 2 and the development of kidney angiomyolipomas (KAMLs) in this TSC2 cohort. Because of the age-dependent development of KAMLs in TSC, we initially focused on the 127 patients who were >5 years old. Additional subgroup analyses were done to investigate the influence of age and gender. The transmission/disequilibrium test (TDT) was also performed in a subset of this cohort (46 probands) for whom parent and/or sibling samples were available for analysis. Both chi(2) analysis and TDT suggested an association between IFN-gamma allele 2 and the absence of KAMLs in patients who have known TSC2 mutations. Among the 127 patients who were >5 years old, KAMLs were present in 95 (75%) and were absent in 32 (25%). In the group with KAML present, the frequency of IFN-gamma allele 2 was 56%; in the group with KAML absent, the frequency of IFN-gamma allele 2 was significantly higher, at 78% (P = .02, by chi(2) analysis). The family-based TDT analysis gave similar results, with a TDT statistic (TDT chi(2) = 5.45) corresponding to a P value of .02. Subgroup analyses show that both age and gender may influence the impact of this association. Although these results should be replicated in other populations with TSC, the present study suggests that modifier genes play a role in the variable expression of TSC and also suggests a potential therapy for KAMLs in patients with TSC.