Cunninghame Graham D S, Akil M, Vyse T J
Imperial College, Rheumatology Section, Hammersmith Hospital, De Cane Road, London W12 0NN, UK.
Rheumatology (Oxford). 2007 Jun;46(6):927-30. doi: 10.1093/rheumatology/kel449. Epub 2007 Mar 23.
This is a family-based association study to investigate the genetic contribution of tyrosine kinase 2 (TYK2 ) to disease susceptibility in 380 UK systemic lupus erythematosus (SLE) families, consisting of parents and affected offspring.
Genotyping was performed using the Sequenom platform on DNA from affected individuals and their parents. Haplotypes were constructed using Haploview from the founders, and family-based association was conducted using GENEHUNTER-TDT and Family-Based Association Test.
There are two associated haplotypes across TYK2, both carrying alleles with distorted inheritance. One SNP shows individual association to SLE. This is the under-transmitted rare A allele of TYK2 SNP 6 (P = 0.004), which tags the under-transmitted haplotype 2 (P = 0.055). A second SNP shows a trend for association. This is the A allele of TYK2 SNP 13, which is unique to the over-transmitted haplotype 1 (P = 0.014). We defined a 2.8 kb core association region in TYK2, between these two variants, which narrows down the 5.7 kb gap in the study by Sigurdsson et al. (Sigurdsson S, Nordmark G, Goring HH et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet 2005;76:528-37).
We have shown association to SLE from individual SNPs and haplotypes in TYK2. The strongest individual association, which is carried on the associated haplotype, is from TYK2 SNP 6. The variant is located close to an intron/exon boundary, suggesting a role for mis-splicing events in molecular pathogenesis. The associated haplotype also carries a missense mutation at TYK2. Therefore it is likely that the allelic contribution of TYK2 to SLE is complex, our data confirm previous findings and provide additional resolution regarding the causal polymorphisms in this gene.
这是一项基于家系的关联研究，旨在调查酪氨酸激酶2（TYK2）对380个英国家系中疾病易感性的遗传贡献，这些家系由父母和患病后代组成。
使用Sequenom平台对患病个体及其父母的DNA进行基因分型。利用Haploview从奠基者构建单倍型，并使用GENEHUNTER-TDT和基于家系的关联检验进行家系关联分析。
TYK2存在两种相关单倍型，均携带遗传扭曲的等位基因。一个单核苷酸多态性（SNP）显示与系统性红斑狼疮（SLE）存在个体关联。这是TYK2 SNP 6的传递不足的罕见A等位基因（P = 0.004），它标记了传递不足的单倍型2（P = 0.055）。另一个SNP显示出关联趋势。这是TYK2 SNP 13的A等位基因，它是传递过多的单倍型1所特有的（P = 0.014）。我们在TYK2中定义了一个2.8 kb的核心关联区域，位于这两个变异之间，这缩小了Sigurdsson等人研究中的5.7 kb差距（Sigurdsson S，Nordmark G，Goring HH等。酪氨酸激酶2和干扰素调节因子5基因多态性与系统性红斑狼疮相关。《美国人类遗传学杂志》2005；76：528 - 37）。
我们已经证明TYK2中的个体SNP和单倍型与SLE存在关联。最强的个体关联存在于相关单倍型上，来自TYK2 SNP 6。该变异位于内含子/外显子边界附近，提示错配剪接事件在分子发病机制中的作用。相关单倍型在TYK2处还携带一个错义突变。因此，TYK2对SLE的等位基因贡献可能很复杂，我们的数据证实了先前的发现，并提供了关于该基因因果多态性的额外分辨率。
