Association of protein kinase C alpha (PRKCA) gene with multiple sclerosis in a UK population
Association of protein kinase C alpha (PRKCA) gene with multiple sclerosis in a UK population
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DOI：
10.1093/brain/awh193
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发表时间：
2004-08-01
期刊：
影响因子：
14.5
通讯作者：
Worthington, J
中科院分区：
文献类型：
--
作者：
Barton, A;Woolmore, JA;Worthington, J
双胞胎、家庭和收养研究表明，多发性硬化症的易感性很大程度上是由遗传因素介导的。与人类染色体 17q 的连锁，与多发性硬化症实验动物模型的基因座同源，已被广泛复制，并且可能含有多发性硬化症易感基因的区域最近已被细化为 17q22-24 的 2.5 Mb 区域。使用病例对照方法测试了候选多发性硬化症易感基因蛋白激酶 C α (PRKCA) 在此区间内的图谱，并与 35 个单核苷酸多态性 (SNP) 标记关联，跨越该基因，中位间距为 7.8 kb。在英国多发性硬化症无关病例 (n=184) 和健康对照 (n=340) 中比较单标记基因型和估计单倍型频率，以调查与疾病易感性的关联。映射到基因近端区域的两个 SNP 的单倍型显示了与易感性相关的证据（Bonferroni 校正的 P 值=1.1x10(-5)）。这些发现表明，有必要对 PRKCA 基因进行进一步研究，特别是在有证据表明与 17q22 存在关联的队列中。本研究中研究的大多数 SNP 都是内含子，现在需要进行筛选来识别与疾病相关的功能突变。我们的结果表明，在任何筛选策略中，启动子和近端基因区域不仅应包括在内，而且应优先考虑。
Twin, family and adoption studies suggest that susceptibility to multiple sclerosis is substantially mediated by genetic factors. Linkage to human chromosome 17q, homologous to a locus linked to experimental animal models of multiple sclerosis, has been widely replicated and the region likely to harbour a multiple sclerosis susceptibility gene has recently been refined to a 2.5 Mb region of 17q22-24. The candidate multiple sclerosis susceptibility gene, protein kinase C alpha (PRKCA), maps within this interval and association with 35 single-nucleotide polymorphism (SNP) markers, spanning the gene with a median spacing of 7.8 kb, was tested using a case-control approach. Single-marker genotype and estimated haplotype frequencies were compared in UK unrelated cases with multiple sclerosis (n=184) and healthy controls (n=340) in order to investigate association with susceptibility to disease. A haplotype of two SNPs mapping to the proximal region of the gene showed evidence for association with susceptibility (Bonferroni-corrected P value=1.1x10(-5)). These findings suggest that further investigation of the PRKCA gene is warranted, particularly in cohorts with evidence of linkage to 17q22. Most of the SNPs investigated in this study were intronic and screening to identify disease-associated functional mutations is now required. Our results suggest that the promoter and proximal gene region should be not only included but prioritized in any screening strategy.