Barbesino G, Tomer Y, Concepcion E S, Davies T F, Greenberg D A
Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
J Clin Endocrinol Metab. 1998 Sep;83(9):3290-5. doi: 10.1210/jcem.83.9.5091.
Hashimoto's thyroiditis (HT) and Graves' disease (GD) are autoimmune thyroid diseases (AITD) in which multiple genetic factors are suspected to play an important role. Until now, only a few minor risk factors for these diseases have been identified. Susceptibility seems to be stronger in women, pointing toward a possible role for genes related to sex steroid action or mechanisms related to genes on the X-chromosome. We have studied a total of 45 multiplex families, each containing at least 2 members affected with either GD (55 patients) or HT (72 patients), and used linkage analysis to target as candidate susceptibility loci genes involved in estrogen activity, such as the estrogen receptor alpha and beta and the aromatase genes. We then screened the entire X-chromosome using a set of polymorphic microsatellite markers spanning the whole chromosome. We found a region of the X-chromosome (Xq21.33-22) giving positive logarithm of odds (LOD) scores and then reanalyzed this area with dense markers in a multipoint analysis. Our results excluded linkage to the estrogen receptor alpha and aromatase genes when either the patients with GD only, those with HT only, or those with any AITD were considered as affected. Linkage to the estrogen receptor beta could not be totally ruled out, partly due to incomplete mapping information for the gene itself at this time. The X-chromosome data revealed consistently positive LOD scores (maximum of 1.88 for marker DXS8020 and GD patients) when either definition of affectedness was considered. Analysis of the family data using a multipoint analysis with eight closely linked markers generated LOD scores suggestive of linkage to GD in a chromosomal area (Xq21.33-22) extending for about 6 cM and encompassing four markers. The maximum LOD score (2.5) occurred at DXS8020. In conclusion, we ruled out a major role for estrogen receptor alpha and the aromatase genes in the genetic predisposition to AITD. Estrogen receptor beta remains a candidate locus. We found a locus on Xq21.33-22 linked to GD that may help to explain the female predisposition to GD. Confirmation of these data in HT may require study of an extended number of families because of possible heterogeneity.
桥本甲状腺炎（HT）和格雷夫斯病（GD）是自身免疫性甲状腺疾病（AITD），其中多种遗传因素被怀疑发挥重要作用。到目前为止，仅确定了这些疾病的少数次要危险因素。女性的易感性似乎更强，这表明与性类固醇作用相关的基因或与X染色体上基因相关的机制可能发挥作用。我们共研究了45个多重家庭，每个家庭至少有2名受GD（55例患者）或HT（72例患者）影响的成员，并使用连锁分析来确定参与雌激素活性的候选易感基因座基因，如雌激素受体α和β以及芳香化酶基因。然后，我们使用一组跨越整个染色体的多态性微卫星标记对整个X染色体进行筛选。我们发现X染色体的一个区域（Xq21.33 - 22）给出了正的对数优势（LOD）分数，然后在多点分析中用密集标记对该区域进行重新分析。当仅考虑GD患者、仅考虑HT患者或考虑任何AITD患者时，我们的结果排除了与雌激素受体α和芳香化酶基因的连锁。与雌激素受体β的连锁不能完全排除，部分原因是此时该基因本身的定位信息不完整。当考虑任何一种受累定义时，X染色体数据始终显示出正的LOD分数（标记DXS8020对GD患者的最大值为1.88）。使用八个紧密连锁的标记进行多点分析对家庭数据进行分析，产生的LOD分数表明在一个延伸约6厘摩并包含四个标记的染色体区域（Xq21.33 - 22）与GD连锁。最大LOD分数（2.5）出现在DXS8020处。总之，我们排除了雌激素受体α和芳香化酶基因在AITD遗传易感性中的主要作用。雌激素受体β仍然是一个候选基因座。我们在Xq21.33 - 22上发现了一个与GD连锁的基因座，这可能有助于解释女性对GD的易感性。由于可能存在异质性，在HT中确认这些数据可能需要研究更多的家庭。
