Pryhuber K G, Murray K J, Donnelly P, Passo M H, Maksymowych W P, Glass D N, Giannini E H, Colbert R A
William S. Rowe Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
J Rheumatol. 1996 Apr;23(4):747-52.
To determine the potential contribution of the MHC class II region proteasome subunit gene, LMP2, to disease susceptibility, severity, and phenotype in patients with juvenile rheumatoid arthritis (JRA).
A CfoI restriction site polymorphism in the coding region of the LMP2 gene was evaluated in 279 patients with JRA and 107 healthy controls of similar ethnicity. Patients were divided into 5 groups on the basis of clinical presentation; 46% had early onset pauciarticular disease, 10% early onset polyarticular, 10% late onset pauciarticular, 20% late onset polyarticular, and 11% systemic onset arthritis. The influence of this LMP2 polymorphism on susceptibility to disease, clinical subtype of disease at onset (age and number of joints involved), progression and severity of joint disease (pauci to polyarticular course and radiographic changes), and occurrence of inflammatory eye disease was evaluated.
Comparison of genotypes revealed a significantly increased prevalence of homozygosity for the LMP2 B allele (LMP2 BB genotype) in patients who were older (> or = 6 years) at onset of disease (65%, p < 0.05), particularly in those with pauciarticular (71%) involvement at presentation (p < 0.05), compared to controls (51%). The BB genotype was also more prevalent in patients with a polyarticular course, either from onset (63%) or those who progressed from pauciarticular disease (69%), compared with controls, (p = 0.05 and < 0.05, respectively). Stratification for HLA-B27 and DR4, the HLA alleles most frequently associated with late onset pauciarticular and late onset polyarticular JRA, respectively, revealed a persistent effect of LMP2 BB homozygosity on disease susceptibility and phenotype that remained statistically significant in HLA-B27 positive children, and was not due to linkage disequilibrium.
We show that homozygosity of the B allele of the proteasome subunit LMP2 increases susceptibility to certain subgroups of JRA, and influences the phenotype of disease, predisposing to more progressive and severe articular disease.
确定主要组织相容性复合体（MHC）Ⅱ类区域蛋白酶体亚基基因LMP2对青少年类风湿性关节炎（JRA）患者疾病易感性、严重程度及表型的潜在影响。
对279例JRA患者和107例种族相似的健康对照者的LMP2基因编码区CfoI限制性酶切位点多态性进行评估。根据临床表现将患者分为5组；46%为早发型少关节疾病，10%为早发型多关节疾病，10%为晚发型少关节疾病，20%为晚发型多关节疾病，11%为全身型关节炎。评估该LMP2多态性对疾病易感性、发病时疾病的临床亚型（年龄和受累关节数）、关节疾病的进展和严重程度（少关节到多关节病程及影像学改变）以及炎性眼病发生情况的影响。
基因型比较显示，发病年龄较大（≥6岁）的患者中，LMP2 B等位基因纯合子（LMP2 BB基因型）的患病率显著增加（65%，p<0.05），尤其是那些发病时少关节受累（71%）的患者（p<0.05），与对照组（51%）相比。与对照组相比，BB基因型在起病时即为多关节病程的患者（63%）或从少关节疾病进展而来的患者（69%）中也更为常见（分别为p=0.05和<0.05）。对HLA-B27和DR4进行分层分析，这两个HLA等位基因分别最常与晚发型少关节和晚发型多关节JRA相关，结果显示LMP2 BB纯合子对疾病易感性和表型有持续影响，在HLA-B27阳性儿童中仍具有统计学意义，且并非由于连锁不平衡所致。
我们发现蛋白酶体亚基LMP2的B等位基因纯合子增加了对某些JRA亚组的易感性，并影响疾病表型，易导致更进展性和严重的关节疾病。
