Sequence variation, linkage disequilibrium and association with Crohn's disease on chromosome 5q31
Sequence variation, linkage disequilibrium and association with Crohn's disease on chromosome 5q31
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DOI：
10.1038/sj.gene.6364307
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发表时间：
2006-07-01
影响因子：
5
通讯作者：
Mathew, C. G.
中科院分区：
文献类型：
--
作者：
Onnie, C.;Fisher, S. A.;Mathew, C. G.
染色体5q31包含一组与免疫反应有关的基因，包括与克罗恩病(CD)易感性相关的250kb风险单倍型。最近，编码阳离子转运蛋白OCTN1和OCTN2的SLC22A4和SLC22A5的两个功能变异(L503F和G-207C)被认为是CD的原因变异，但关于它们的贡献存在相互矛盾的遗传学证据。我们对24例CD患者的10个基因的编码区进行了重新测序，并得出了27个单核苷酸多态(SNPs)的连锁不平衡(LD)图谱。对观察到的10个代表LD组的SNP进行了Cd关联测试。SLC22A4的L503F是唯一一个与CD显著相关的非同义SNP(P=0.003)，但在缺乏其他250kb风险单倍型标记的情况下，与疾病无关。位于250kb风险单倍型外的两个SNP，IRF1中的rs11242115和RAD50中的rs17166050也与Cd相关(分别为P=0.019和P=0.0080)。Rad50基因包含一个控制Th2细胞因子基因表达的位点控制区。因此，该区域其他尚未发现的SNP可能会调节基因表达，从而导致CD的风险，可能还会导致其他炎症表型。基因与免疫(2006)7,359-365。DOI：10.1038/Sj.吉恩。6364307；2006年5月18日在线出版。
Chromosome 5q31 contains a cluster of genes involved in immune response, including a 250 kb risk haplotype associated with Crohn's disease (CD) susceptibility. Recently, two functional variants in SLC22A4 and SLC22A5 (L503F and G-207C), encoding the cation transporters OCTN1 and OCTN2, were proposed as causal variants for CD, but with conflicting genetic evidence regarding their contribution. We investigated this locus by resequencing the coding regions of 10 genes in 24 CD cases and deriving a linkage disequilibrium (LD) map of the 27 single nucleotide polymorphisms (SNPs) detected. Ten SNPs representative of the LD groups observed, were tested for CD association. L503F in SLC22A4 was the only nonsynonymous SNP significantly associated with CD (P = 0.003),but was not associated with disease in the absence of other markers of the 250 kb risk haplotype. Two other SNPs, rs11242115 in IRF1 and rs17166050 in RAD50, lying outside the 250 kb risk haplotype, also showed CD association (P = 0.019 and P = 0.0080,respectively). The RAD50 gene contains a locus control region regulating expression of the Th2 cytokine genes at this locus. Other as yet undiscovered SNPs in this region may therefore modulate gene expression and contribute to the risk of CD, and perhaps of other inflammatory phenotypes. Genes and Immunity (2006) 7, 359-365. doi: 10.1038/sj. gene. 6364307; published online 18 May 2006.