儿童系统性红斑狼疮与HLA基因单倍型和基因型的相关性及家系分析

目的 探讨HLA基因连锁不平衡情况对儿童SLE发病的影响,以期发现HLA基因在SLE发病中的作用。方法 53例SLE患儿,其中40例有父母资料,35例HLA-DRB*15阳性的SLE患儿,其中有父母资料者27例,78名健康对照儿童,43名有父母资料,及1个SLE大家系作为研究对象,应用微量淋巴毒实验,序列特异性引物聚合酶链反应方法,分析了研究对象的HLA-I类抗原A、B位点,HLA-Ⅱ类基因。DRBI位点的多态性。根据实测的单倍型及基因型情况与正常对比,分析了SLE患儿与HLA-A、B、DR单倍型及基因型的相关性,并分析了DRB1*15阳性的SLE患儿其DRB1*15基因来自父母的垂直传递情况。结果 (1)患儿比正常对照单倍型种类少,患儿与对照共有单倍型较少。单倍型A9B40DRB1*15频率在SLE患儿中较对照高,SLE大家系的研究中,也恰恰表现为A9B40DRB1*15单倍型与患病相连锁。(2)SLE患儿基因型以DRB1*09／DRB1*15及DRB1*03／。DRB1*15多见。(3)在父母携带DRB1*15基因相同的情况下,SLE患儿的DRB1*15基因来源于父亲者较正常对照多。结论 SLE发病不仅与单个HLA基因有关,而且与HLA的某些基因组合相关,由此可见SLE多发位点的致病作用有叠加性。SLE患儿DRB1*15来自父亲者较对照组多,其机理及意义尚不清楚,可能与HLA的遗传模式有关。

Association of HLA-A, B, and DR haplotypes with genotype in Chinese children with systemic lupus erythematosus

OBJECTIVE: Development of systemic lupus erythematosus (SLE) is not only associated with single loci of HLA gene, but also possibly related to certain haplotypes and genotypes of MHC. In the present study the authors explored association of HLA-A, B, DR haplotype and genotype with SLE in Chinese children, analyzed a large family with multiple SLE patients and genetic origin of SLE patients with HLA-DRB1 * 15, to discover the influence of linkage disequilibrium of HLA gene on SLE. METHODS: HLA-A, B, DR alleles were tested in 53 patients with SLE and 40 cases with their parents, 35 patients with SLE and HLA-DRB * 15 positive and 27 cases with their parents, a large family with SLE (18 members of three generations) and also 78 normal controls and 43 cases with their parents by microlymphocytotoxicity test and polymerase chain reaction - sequence specific primers (PCR-SSP). HLA-A, B, DR haplotype and genotype of SLE patients and controls were statistically calculated. The SLE patients with HLA-DRB1 * 15 and controls were analyzed for either the gene originated from the paternal or the maternal side. RESULTS: The variety of the haplotype in patient group (64/80) was less than that in control group (74/86). Only 9 haplotypes were found common between the patient group and control group. The frequency of the haplotype HLA-A9B40DRB1 * 15 was significantly higher in patient group than that in control group (P < 0.05), RR was 10.726 0. Five members of the large family had haplotype A9B40DRB1 * 15, 2 of them were patients with SLE, 1 of them was positive for ANA and had Raynaud's phenomenon and 2 of them were normal. The rest of the family members were normal. The frequency of genotypes DRB1 * 09/DRB1 * 15 and DRB1 * 03/DRB1 * 15 in SLE group was significantly higher than that of control group (P < 0.05), RR was 7.772 7 and 14.272 7, respectively. The number of SLE children with gene HLA-DRB1 * 15 derived from their fathers was significantly higher than that of the children with the gene derived from the mothers. CONCLUSION: These findings suggested that haplotype HLA-A9B40DRB1 * 15 and genotypes HLA-DRB1 * 09/DRB1 * 15, HLA-DRB1 * 03/DRB1 * 15 were correlated with SLE. The predisposition of multiple loci seems to have an additive effect. The children with their gene HLA-DRB1 * 15 derived from their fathers might more easily suffer from SLE than those with the gene derived from their mothers, the underlying mechanism needs further studies.