Badenhoop K, Schwarz G, Schleusener H, Weetman A P, Recks S, Peters H, Bottazzo G F, Usadel K H
II. Medizinische Klinik, Klinikum Mannheim der Universität, Heidelberg, Germany.
J Clin Endocrinol Metab. 1992 Feb;74(2):287-91. doi: 10.1210/jcem.74.2.1346144.
The physical mapping of tumor necrosis factor alpha (TNF alpha) and lymphotoxin (TNF beta) genes to the short arm of chromosome 6 in man between the loci for histocompatibility leucocyte antigens (HLA)-B and the complement system focused attention to this genetic region that controls immune responses in many ways. It also holds susceptibility genes for a variety of autoimmune disorders that are linked to specific alleles of loci in the HLA D subregion. We have recently identified a TNF restriction fragment length polymorphism with the enzyme NcoI (K. Badenhoop, G. Schwarz, J. Trowsdale, et al. Diabetologia. 1989;32:445-8). The less frequent fragment of 5.5 kilobase (kb) is in strong linkage disequilibrium with the HLA haplotype A1B8DR3. Since Graves' disease is linked to A1B8DR3, we analyzed TNF gene polymorphisms in a large group of Graves' disease patients and normal controls derived from four Centers. We show here a significant association of TNF beta polymorphisms with Graves' disease. The patients have less homozygotes for the 10.5 kb band (60 of 174, 34%) and more heterozygotes 10.5/5.5 kb (96 of 174, 55%), than 173 controls (49% homozygotes 10.5 kb and 42% heterozygotes; chi 2 = 7.45, P less than 0.03). When DR3+ patients and controls were analyzed separately, heterozygotes were still significantly increased in DR3+ Graves' disease patients (54 of 77, 70%) compared to DR3+ controls (21 of 45, 47%; chi 2 = 6.6, P less than 0.04). Furthermore, TNF fragment heterozygotes were found predominantly in patients, who had TSH-receptor antibodies (29/45, 64%, P less than 0.007), implying that these patients might represent an immunogenetic subset of the disease. Although TNF beta polymorphisms are linked to A1B8DR3, these results suggest that they represent an additional susceptibility marker in Graves' disease.
肿瘤坏死因子α（TNFα）和淋巴毒素（TNFβ）基因在人类第6号染色体短臂上的物理定位，位于组织相容性白细胞抗原（HLA）-B位点和补体系统位点之间，这使得人们将注意力集中到这个以多种方式控制免疫反应的基因区域。该区域还包含与HLA D亚区中特定基因座等位基因相关的多种自身免疫性疾病的易感基因。我们最近利用NcoI酶鉴定出一种TNF限制性片段长度多态性（K. Badenhoop、G. Schwarz、J. Trowsdale等人，《糖尿病学》，1989年；32:445 - 448）。频率较低的5.5千碱基（kb）片段与HLA单倍型A1B8DR3处于强连锁不平衡状态。由于格雷夫斯病与A1B8DR3相关联，我们分析了来自四个中心的一大组格雷夫斯病患者和正常对照的TNF基因多态性。我们在此表明TNFβ多态性与格雷夫斯病存在显著关联。与173名对照（49%为10.5 kb纯合子，42%为杂合子；χ2 = 7.45，P < 0.03）相比，患者中10.5 kb条带的纯合子较少（174名中有60名，34%），10.5/5.5 kb杂合子较多（174名中有96名，55%）。当分别分析DR3 +患者和对照时，与DR3 +对照（45名中有21名，47%；χ2 = 6.6，P < 0.04）相比，DR3 +格雷夫斯病患者中的杂合子仍然显著增加。此外，TNF片段杂合子主要在患有促甲状腺激素受体抗体的患者中发现（45名中有29名，64%，P < 0.007），这意味着这些患者可能代表该疾病的一个免疫遗传亚组。尽管TNFβ多态性与A1B8DR3相关联，但这些结果表明它们是格雷夫斯病中一个额外的易感标志物。
