McTernan C L, Stewart L C, Mijovic C H, Barnett A H
Department of Medicine, Birmingham University, UK.
Diabet Med. 2000 Sep;17(9):661-6. doi: 10.1046/j.1464-5491.2000.00358.x.
Whilst HLA-DRB1 and HLA-DQ alleles contribute to IDDM1, the major determinant of genetic susceptibility to Type 1 diabetes mellitus, other major histocompatibility complex (MHC)-encoded genes may also be involved. The LMP7 (large multifunctional proteasome 7) gene is a potential candidate. The aim of this study was to assess whether LMP7 confers susceptibility to Type 1 diabetes independently of linkage disequilibrium with HLA-DRB1 and HLA-DQ.
The diallelic LMP7 polymorphism (LMP7*A or *B) was determined in 142 multiplex families from the British Diabetic Association Warren Repository. At least one parent was heterozygous for LMP7 in 112 families and these were informative for calculation of the statistic Tsp. This gives a valid chi2 test of the null hypothesis of no association or no linkage.
An excess of transmissions of LMP7A was observed from parents to affected offspring and the Tsp statistic was significant for association in the presence of linkage. LMP7A was in positive, and LMP7B in negative, linkage disequilibrium with the HLA-DRB103-DQ2, DRB104-DQ8 (group of all DRB104 subtypes), DRB10401-DQ8 and DRB10404-DQ8 haplotypes, although the linkage disequilibrium coefficient (delta) value was not statistically significant for DRB1*0404-DQ8. Analysis of HLA-DR-DQ-LMP7 haplotypes and Tsp analysis of HLA-matched-homozygous parents showed no association between LMP7 alleles and Type I diabetes independent of linkage disequilibrium with HLA-DR-DQ haplotypes associated with increased risk of disease. A contribution of LMP7 alleles to susceptibility to Type 1 diabetes in subjects with low-risk HLA-DR-DQ haplotypes could not be excluded.
LMP7 alleles do not contribute to genetic susceptibility to Type 1 diabetes in subjects with high-risk-associated HLA-DR-DQ haplotypes.
虽然HLA - DRB1和HLA - DQ等位基因是1型糖尿病（IDDM1）遗传易感性的主要决定因素，但其他主要组织相容性复合体（MHC）编码的基因也可能参与其中。LMP7（大的多功能蛋白酶体7）基因是一个潜在的候选基因。本研究的目的是评估LMP7是否独立于与HLA - DRB1和HLA - DQ的连锁不平衡而赋予1型糖尿病易感性。
在英国糖尿病协会沃伦储存库的142个多重家庭中确定了双等位基因LMP7多态性（LMP7A或B）。在112个家庭中至少有一位父母是LMP7杂合子，这些家庭可用于计算统计量Tsp。这给出了一个有效的卡方检验，用于检验无关联或无连锁的零假设。
观察到从父母向受影响后代过度传递LMP7A，并且在存在连锁的情况下Tsp统计量对于关联是显著的。LMP7A与HLA - DRB103 - DQ2、DRB104 - DQ8（所有DRB104亚型的组）、DRB10401 - DQ8和DRB10404 - DQ8单倍型呈正连锁不平衡，而LMP7B与这些单倍型呈负连锁不平衡，尽管DRB1*0404 - DQ8的连锁不平衡系数（δ）值无统计学意义。对HLA - DR - DQ - LMP7单倍型的分析以及对HLA匹配的纯合子父母的Tsp分析表明，LMP7等位基因与1型糖尿病之间不存在独立于与疾病风险增加相关的HLA - DR - DQ单倍型的连锁不平衡的关联。不能排除LMP7等位基因对具有低风险HLA - DR - DQ单倍型的个体的1型糖尿病易感性有贡献。
LMP7等位基因对具有高风险相关HLA - DR - DQ单倍型的个体的1型糖尿病遗传易感性没有贡献。
