Heward J M, Allahabadia A, Sheppard M C, Barnett A H, Franklyn J A, Gough S C
Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
Clin Endocrinol (Oxf). 1999 Jul;51(1):115-8. doi: 10.1046/j.1365-2265.1999.00755.x.
The large multifunctional proteasome (LMP) molecules are over expressed in thyrocytes, the target cells of Graves' disease, and the LMP genes are found within the MHC class II region. The LMP genes may therefore play a role in susceptibility to Graves' disease. The aim of this this study was to determine whether polymorphisms of the LMP genes, LMP 2 and LMP 7 are in linkage disequilibrium with Graves' disease.
Target DNA was amplified using the polymerase chain reaction. The distribution of an Arg-His polymorphism in the LMP 2 gene and a G/T polymorphism in the LMP 7 gene, both of which lead to the presence of an HhaI restriction site, were investigated in a population based case control and family based study in patients with Graves' disease.
We obtained DNA from 306 patients with Graves' disease and 364 control subjects for the population based case-control study. In an independent family based study, DNA was obtained from 129 families including both parents, an affected sibling with Graves' disease and an unaffected sibling. All families, patients and control subjects were white caucasians.
Frequencies of the alleles and genotypes of the LMP 2 and LMP 7 genes were compared between patients and control subjects using the chi2 test. Transmission of alleles from heterozygous parents to affected and unaffected offspring was assessed using the transmission disequilibrium test (TDT).
In the case control study, no difference in allele or genotype frequency was seen between patients and control subjects at the LMP7 locus. At the LMP2 locus the R allele and the RH genotype were increased in subjects with Graves' disease when compared with control subjects (R allele: 36.3% vs. 29.5%, pc = 0. 0164; RH genotype: 56.5% vs. 45%, pc = 0.0102). However, the R allele was in linkage disequilibrium with the associated HLA DRB10304-DQB102-DQA1*0501 haplotype, delta = 0.102. Within the family based study, no preferential allelic transmission was seen from heterozygote parents to offspring at either loci.
These results show that association of the LMP 2 locus with Graves' disease is due to linkage disequilibrium with the associated HLA haplotype DRB10304-DQB102-DQA1*0501.
大型多功能蛋白酶体（LMP）分子在格雷夫斯病的靶细胞甲状腺细胞中过度表达，且LMP基因位于MHCⅡ类区域内。因此，LMP基因可能在格雷夫斯病的易感性中起作用。本研究的目的是确定LMP基因LMP2和LMP7的多态性是否与格雷夫斯病存在连锁不平衡。
使用聚合酶链反应扩增靶DNA。在一项基于人群的病例对照研究和一项基于家系的研究中，对格雷夫斯病患者的LMP2基因中的精氨酸-组氨酸多态性和LMP7基因中的G/T多态性（两者均导致存在HhaI限制性位点）的分布进行了研究。
在基于人群的病例对照研究中，我们从306例格雷夫斯病患者和364名对照受试者中获取了DNA。在一项独立的基于家系的研究中，从129个家庭获取了DNA，这些家庭包括父母、一名患格雷夫斯病的患病同胞和一名未患病的同胞。所有家庭、患者和对照受试者均为白种人。
使用卡方检验比较患者和对照受试者中LMP2和LMP7基因的等位基因和基因型频率。使用传递不平衡检验（TDT）评估等位基因从杂合子父母向患病和未患病后代的传递情况。
在病例对照研究中，在LMP7位点，患者和对照受试者之间的等位基因或基因型频率没有差异。在LMP2位点，与对照受试者相比，格雷夫斯病患者中的R等位基因和RH基因型增加（R等位基因：36.3%对29.5%，pc = 0.0164；RH基因型：56.5%对45%，pc = 0.0102）。然而，R等位基因与相关的HLA DRB10304-DQB102-DQA1*0501单倍型存在连锁不平衡，δ = 0.102。在基于家系的研究中，在两个位点均未观察到等位基因从杂合子父母向后代的优先传递。
这些结果表明，LMP2位点与格雷夫斯病的关联是由于与相关的HLA单倍型DRB10304-DQB102-DQA
