全身型幼年特发性关节炎患者的巨噬细胞活化综合征与MUNC13 - 4基因多态性相关。
Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms.
作者信息
Zhang Kejian, Biroschak Jennifer, Glass David N, Thompson Susan D, Finkel Terri, Passo Murray H, Binstadt Bryce A, Filipovich Alexandra, Grom Alexei A
机构信息
Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
出版信息
Arthritis Rheum. 2008 Sep;58(9):2892-6. doi: 10.1002/art.23734.
OBJECTIVE
Systemic juvenile idiopathic arthritis (JIA) is associated with macrophage activation syndrome. Macrophage activation syndrome bears a close resemblance to familial hemophagocytic lymphohistiocytosis (HLH). The development of familial HLH has been recently associated with mutations in MUNC13-4. The purpose of this study was to assess for possible sequence alterations in MUNC13-4 in patients with systemic JIA/macrophage activation syndrome.
METHODS
The MUNC13-4 sequence was analyzed in 18 unrelated patients with systemic JIA/macrophage activation syndrome, using 32 primer pair sets designed to amplify the 32 exons and at least 100 basepairs of the adjacent intronic regions. DNA samples obtained from 73 unrelated patients with systemic JIA and no history of macrophage activation syndrome and 229 unrelated healthy individuals were used as controls.
RESULTS
The biallelic sequence variants in MUNC13-4 reported in familial HLH were present in 2 of the 18 patients with JIA/macrophage activation syndrome. Further analysis of the MUNC13-4 sequences revealed an identical combination of 12 single-nucleotide polymorphisms (SNPs) in 9 of the remaining 16 patients with systemic JIA/macrophage activation syndrome (56%). Additional analysis suggested that these 12 SNPs (154[-19] g>a, 261[+26] c>g, 388[+81] g>a, 388[+122] c>t, 570[-60] t>g, 888 G>C, 1389[+36] g>a, 1992[+5] g>a, 2447[+144] c>t, 2599 A>G, 2830[+37] c>g, 3198 A>G) were inherited as an extended haplotype. In several patients, in addition to the described haplotype, there were other SNPs in the second allele of MUNC13-4. Moreover, 1 patient had a complex mutation with 2 changes, 2542 A>C and 2943 G>C, in a cis configuration. The haplotype was present in only 27 (12%) of 229 healthy control subjects (chi(2) = 23.5) and in 6 (8.2%) of 73 patients with systemic JIA and no history of macrophage activation syndrome.
CONCLUSION
The data suggest an association between MUNC13-4 polymorphisms and macrophage activation syndrome in patients with systemic JIA.
目的
全身型幼年特发性关节炎（JIA）与巨噬细胞活化综合征相关。巨噬细胞活化综合征与家族性噬血细胞性淋巴组织细胞增生症（HLH）极为相似。家族性HLH的发病最近与MUNC13 - 4基因突变有关。本研究的目的是评估全身型JIA/巨噬细胞活化综合征患者中MUNC13 - 4是否存在可能的序列改变。
方法
使用32对引物对，对18例无亲缘关系的全身型JIA/巨噬细胞活化综合征患者的MUNC13 - 4序列进行分析，这些引物对用于扩增32个外显子及相邻内含子区域至少100个碱基对。从73例无亲缘关系的无巨噬细胞活化综合征病史的全身型JIA患者及229例无亲缘关系的健康个体获取的DNA样本用作对照。
结果
18例JIA/巨噬细胞活化综合征患者中有2例存在家族性HLH中报道的MUNC13 - 4双等位基因序列变异。对MUNC13 - 4序列的进一步分析显示，其余16例全身型JIA/巨噬细胞活化综合征患者中有9例（56%）存在相同的12个单核苷酸多态性（SNP）组合。进一步分析表明，这12个SNP（154[-19] g>a、261[+26] c>g, 388[+81] g>a、388[+122] c>t、570[-60] t>g、888 G>C、1389[+36] g>a、1992[+5] g>a、2447[+144] c>t、2599 A>G、2830[+37] c>g、3198 A>G）作为一个扩展单倍型遗传。在一些患者中，除了所述单倍型外，MUNC13 - 4的第二个等位基因中还有其他SNP。此外，1例患者有一个复杂突变，顺式构型中有2个变化，即2542 A>C和2943 G>C。该单倍型仅在229例健康对照者中的27例（12%）（χ² = 23.5）以及73例无巨噬细胞活化综合征病史的全身型JIA患者中的6例（8.2%）中出现。
结论
数据表明MUNC13 - 4多态性与全身型JIA患者的巨噬细胞活化综合征之间存在关联。
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