Park Byung Lae, Kim Lyoung Hyo, Shin Hyoung Doo, Park Yong Wook, Uhm Wan Sik, Bae Sang-Cheol
Department of Genetic Epidemiology, SNP Genetics, Inc., 11th Floor, MaeHun B/D, 13 Chongro 4 Ga, Chongro-Gu, Seoul, 110-834, South Korea.
Department of Internal Medicine, Division of Rheumatology, The Hospital for Rheumatic Diseases, Hanyang University, 17 Haengdang-Dong, Seongdong-Gu, Seoul, 133-792, South Korea.
J Hum Genet. 2004;49(11):642-646. doi: 10.1007/s10038-004-0192-x. Epub 2004 Sep 16.
The etiology of systemic lupus erythematosus (SLE) is very complex, and genetic factors appear to play a significant role in susceptibility to SLE, in determining the disease expression, and in the autoantibody profiles of individuals with SLE. DNA methyltransferase-1 (DNMT1) is a major enzyme that determines genomic methylation patterns and both maintains methyltransferase and exhibits de novo DNA methylation activity in vivo. In order to clarify the association of DNMT1 polymorphisms with SLE, we scrutinized the genetic polymorphisms in exons and their boundaries of DNMT1, including the -1,500 bp promoter region, by direct sequencing in 24 Korean individuals. Twenty-nine sequence variants were identified: two in 5'UTR, six in exons, and 21 in introns. Eight of these polymorphisms were selected for a larger-scale genotyping (n=680) by considering their allele frequencies, haplotype-tagging status, and linkage disequilibrium coefficiencies (LDs) among polymorphisms. The associations between DNMT1 polymorphisms and the clinical profiles of SLE were analyzed. No significant associations with the risk of SLE were detected. However, further analyses of association with autoantibody production among SLE patients revealed that one nonsynonymous SNP, +14463G>C (V120L) in exon 4, was weakly associated with an increased risk of anti-La antibody production (P=0.04), although the significance could not be retained after correction of multiple tests. The DNMT1 variations and haplotypes clarified in this study would provide valuable information for future genetic studies of other autoimmune diseases.
系统性红斑狼疮（SLE）的病因非常复杂，遗传因素似乎在SLE易感性、疾病表现的决定以及SLE患者的自身抗体谱方面发挥着重要作用。DNA甲基转移酶-1（DNMT1）是一种主要的酶，它决定基因组甲基化模式，在体内既能维持甲基转移酶活性，又能表现出从头DNA甲基化活性。为了阐明DNMT1多态性与SLE的关联，我们通过对24名韩国个体进行直接测序，仔细研究了DNMT1外显子及其边界（包括-1500 bp启动子区域）的基因多态性。共鉴定出29个序列变异：5'UTR中有2个，外显子中有6个，内含子中有21个。通过考虑这些多态性的等位基因频率、单倍型标签状态以及多态性之间的连锁不平衡系数（LDs），选择了其中8个多态性进行更大规模（n = 680）的基因分型。分析了DNMT1多态性与SLE临床特征之间的关联。未检测到与SLE风险的显著关联。然而，对SLE患者自身抗体产生关联的进一步分析显示，外显子4中的一个非同义SNP，+14463G>C（V120L）与抗La抗体产生风险增加存在弱关联（P = 0.04），尽管在多重检验校正后该显著性未能保留。本研究中阐明的DNMT1变异和单倍型将为未来其他自身免疫性疾病的遗传学研究提供有价值的信息。
