Morris D L, Graham R R, Erwig L-P, Gaffney P M, Moser K L, Behrens T W, Vyse T J, Graham D S Cunninghame
Section of Molecular Genetics and Rheumatology, Imperial College Faculty of Medicine, Hammersmith Hospital, London W12 ONN, UK.
Genes Immun. 2009 Jul;10(5):404-13. doi: 10.1038/gene.2009.17. Epub 2009 Apr 30.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Genome-wide linkage studies implicated a region containing the adhesion molecule P-Selectin. This family-based study revealed two regions of association within P-Selectin. The strongest signal, from a 21.4-kb risk haplotype, stretched from the promoter into the first two consensus repeat (CR) regions (P=8 x 10(-4)), with a second association from a 14.6-kb protective haplotype covering CR 2-9 (P=0.0198). The risk haplotype is tagged by the rare C allele of rs3753306, which disrupts the binding site of the trans-activating transcription factor HNF-1. One other variant (rs3917687) on the risk haplotype was significant after permutation (P(10000)<1 x 10(-5)), replicated in independent pseudo case-control analysis and was significant by meta-analysis (P=4.37 x 10(-6)). A third associated variant on the risk haplotype (rs3917657) replicated in 306 US SLE families and was significant in a joint UK-SLE data set after permutation. The protective haplotype is tagged by rs6133 (a non-synonymous variant in CR8 (P=9.00 x 10(-4)), which also shows association in the pseudo case-control analysis (P=1.09 x 10(-3)) and may contribute to another signal in P-Selectin. We propose that polymorphism in the upstream region may reduce expression of P-Selectin, the mechanism by which this promotes autoimmunity is unknown, although it may reduce the production of regulatory T cells.
系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病。全基因组连锁研究表明，一个包含黏附分子P-选择素的区域与之相关。这项基于家系的研究揭示了P-选择素基因内的两个关联区域。最强的信号来自一个21.4 kb的风险单倍型，从启动子延伸至前两个共有重复序列（CR）区域（P = 8×10⁻⁴），另一个关联信号来自一个14.6 kb的保护性单倍型，覆盖CR 2 - 9区域（P = 0.0198）。风险单倍型由rs3753306的罕见C等位基因标记，该等位基因破坏了反式激活转录因子HNF-1的结合位点。风险单倍型上的另一个变异体（rs3917687）在置换后具有显著性（P(10000) < 1×10⁻⁵），在独立的伪病例对照分析中得到重复验证，且通过荟萃分析具有显著性（P = 4.37×10⁻⁶）。风险单倍型上的第三个关联变异体（rs3917657）在306个美国SLE家系中得到重复验证，在置换后的英国 - SLE联合数据集中具有显著性。保护性单倍型由rs6133标记（CR8中的一个非同义变异体，P = 9.00×10⁻⁴），其在伪病例对照分析中也显示出关联性（P = 1.09×10⁻³），可能构成P-选择素中的另一个信号。我们提出，上游区域的多态性可能会降低P-选择素的表达，尽管这可能会减少调节性T细胞的产生，但其促进自身免疫的机制尚不清楚。
