Wu Sou-Pan, Leng Lin, Feng Zeny, Liu Nianjun, Zhao Hongyu, McDonald Courtney, Lee Annette, Arnett Frank C, Gregersen Peter K, Mayes Maureen D, Bucala Richard
Yale University School of Medicine, New Haven, Connecticut 06520-8031, USA.
Arthritis Rheum. 2006 Nov;54(11):3661-9. doi: 10.1002/art.22179.
To investigate the potential association between functional polymorphisms in the gene for the innate mediator, macrophage migration inhibitory factor (MIF), and the clinical expression of systemic sclerosis (SSc).
Genomic DNA samples and clinical data were collected from the Scleroderma Family Registry and DNA Repository at the University of Texas Health Science Center at Houston. A total of 740 subjects were studied; 203 of them had diffuse cutaneous SSc (dcSSc), 283 had limited cutaneous SSc (lcSSc), and the remaining 254 healthy subjects served as controls. Association analyses were performed on the whole data set and on patient and sex subsets. Significant relationships were determined between clinical variables and MIF polymorphisms for each disease subtype in the studied groups.
The frequency of the -173C MIF allele, which was previously reported to be associated with high production of MIF, was lower in the lcSSc group (12.6%) than in the dcSSc (19.2%) or control (18.5%) groups (P = 0.010 and P = 0.011, respectively). Haplotype analysis for 2 closely linked polymorphisms in the MIF promoter showed that in white subjects with lcSSc or dcSSc, the lcSSc population had a significantly lower representation of the high-expression MIF haplotype defined by -173C and -794 with 7 CATT repeats (C7) (P = 0.015, odds ratio 1.94 [95% confidence interval 1.14-3.32]). Fibroblasts encoding the C7 MIF haplotype were observed to produce more MIF upon in vitro stimulation than those with a non-C7 haplotype.
Functional promoter polymorphisms in the MIF gene affect the clinical presentation of SSc. The proinflammatory haplotype defined by C7 is underrepresented in patients with lcSSc.
研究先天性介质巨噬细胞移动抑制因子（MIF）基因的功能多态性与系统性硬化症（SSc）临床表型之间的潜在关联。
从休斯顿德克萨斯大学健康科学中心的硬皮病家族登记处和DNA储存库收集基因组DNA样本和临床数据。共研究了740名受试者；其中203人患有弥漫性皮肤型SSc（dcSSc），283人患有局限性皮肤型SSc（lcSSc），其余254名健康受试者作为对照。对整个数据集以及患者和性别亚组进行关联分析。确定研究组中每种疾病亚型的临床变量与MIF多态性之间的显著关系。
先前报道与MIF高产生相关的-173C MIF等位基因频率在lcSSc组（12.6%）中低于dcSSc组（19.2%）或对照组（18.5%）（P分别为0.010和0.011）。对MIF启动子中2个紧密连锁的多态性进行单倍型分析表明，在患有lcSSc或dcSSc的白人受试者中，lcSSc人群中由-173C和-794以及7个CATT重复序列（C7）定义的高表达MIF单倍型的比例显著较低（P = 0.015，优势比1.94 [95%置信区间1.14 - 3.32]）。观察到编码C7 MIF单倍型的成纤维细胞在体外刺激后比具有非C7单倍型的成纤维细胞产生更多的MIF。
MIF基因的功能性启动子多态性影响SSc的临床表现。由C7定义的促炎单倍型在lcSSc患者中比例较低。
