Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain.
Eur J Hum Genet. 2010 May;18(5):618-20. doi: 10.1038/ejhg.2009.213. Epub 2009 Nov 25.
A recent genome-wide association study (GWAS) performed by the The Wellcome Trust Case-Control Consortium based on 12 374 nonsynonymous single-nucleotide polymorphisms (SNPs) provided evidence for several genes involved in multiple sclerosis (MS) susceptibility. In this study, we aimed at verifying the association of 19 SNPs with MS, with P-values < or =0.005, in an independent cohort of 732 patients and 974 controls, all Caucasian from the South of Spain. We observed an association of the rs17368528 polymorphism with MS (P=0.04, odds ratio (OR)=0.801, 95% confidence interval (CI)=0.648-0.990). The association of this polymorphism with MS was further validated in an independent set of 1318 patients from the Canadian Collaborative Project (P=0.04, OR=0.838, 95% CI=0.716-0.964). This marker is located on chromosome 1p36.22, which is 1 Mb away from the MS-associated kinesin motor protein KIF1B, although linkage disequilibrium was not observed between these two markers. The rs17368528 SNP results in an amino-acid substitution (proline to leucine) in the fifth exon of the hexose-6-phosphate dehydrogenase (H6PD) gene, in which some variants have been reported to attenuate or abolish H6PD activity, in individuals with cortisone reductase deficiency. This study corroborates the association of one locus determined by GWAS and points to H6PD as a new candidate gene for MS.
最近，由威康信托基金会病例对照联合会进行的一项全基因组关联研究（GWAS）基于 12374 个非同义单核苷酸多态性（SNP），为多发性硬化症（MS）易感性相关的多个基因提供了证据。在这项研究中，我们旨在验证 19 个与 MS 相关的 SNP（P 值<或=0.005）在一个独立的 732 例患者和 974 例对照（均来自西班牙南部的白人）队列中的关联性。我们观察到 rs17368528 多态性与 MS 相关（P=0.04，比值比（OR）=0.801，95%置信区间（CI）=0.648-0.990）。该多态性与 MS 的关联在来自加拿大合作项目的另一组 1318 例患者中得到进一步验证（P=0.04，OR=0.838，95%CI=0.716-0.964）。该标记位于 1p36.22 染色体上，距离与 MS 相关的驱动蛋白马达蛋白 KIF1B 有 1 Mb 远，尽管这两个标记之间没有观察到连锁不平衡。rs17368528 SNP 导致第六外显子的己糖-6-磷酸脱氢酶（H6PD）基因中的一个氨基酸替换（脯氨酸到亮氨酸），一些变体被报道会减弱或消除皮质酮还原酶缺乏个体的 H6PD 活性。这项研究证实了 GWAS 确定的一个位点的相关性，并指出 H6PD 是 MS 的一个新候选基因。
