Genome-wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation.
Genome-wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation.
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DOI：
10.1002/ajh.23118
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发表时间：
2012-04
影响因子：
12.8
通讯作者：
Mistry, Pramod K.
中科院分区：
文献类型：
--
作者：
Zhang, Clarence K.;Stein, Philip B.;Liu, Jun;Wang, Zuoheng;Yang, Ruhua;Cho, Judy H.;Gregersen, Peter K.;Aerts, Johannes M. F. G.;Zhao, Hongyu;Pastores, Gregory M.;Mistry, Pramod K.
GBA 1基因突变导致酸性β-葡萄糖苷酶缺陷和与葡萄糖神经酰胺负载巨噬细胞积聚相关的戈谢病（GD）的复杂表型。即使在携带相同GBA 1突变的患者中，表型也高度可变。我们假设修饰基因是GD表型多样性的基础，并在患有1型GD（GD 1）的德系犹太人患者（N370 S突变纯合子）中进行了GWAS研究。使用复合疾病严重程度评分系统将患者分配至轻度、中度或重度疾病类别。在139名符合条件的患者中，对> 500，000个SNP进行全基因组基因分型，以使用OQLS算法搜索关联。CLN 8基因座内连锁不平衡的几个SNP与GD 1严重程度相关：SNP rs 11986414与GD 1严重程度相关，p值为1.26 × 10−6。与轻度疾病相比，rs 11986414处的风险等位基因A赋予中度/重度疾病3.72的优势比。CLN 8的功能缺失突变会导致神经元蜡样脂褐质沉积症，但我们的研究结果表明，其表达增加可能会预防严重的GD 1。在培养的皮肤成纤维细胞中，与CLN 8风险等位基因过度表达的严重受累患者相比，轻度GD患者CLN 8的相对表达更高。在GD的体外细胞模型中，CLN 8表达增加，在生物活性底物葡糖基鞘氨醇存在下进一步增强。总之，CLN 8是GD 1的候选修饰基因，其可以作为保护性鞘脂传感器和/或在鞘糖脂运输中起作用。未来的研究应探讨CLN 8在GD病理生理学中的作用。
Mutations in GBA1 gene result in defective acid β-glucosidase and the complex phenotype of Gaucher disease (GD) related to the accumulation of glucosylceramide-laden macrophages. The phenotype is highly variable even among patients harboring identical GBA1 mutations. We hypothesized that modifier gene(s) underlie phenotypic diversity in GD and performed a GWAS study in Ashkenazi Jewish patients with type 1 GD (GD1), homozygous for N370S mutation. Patients were assigned to mild, moderate or severe disease category using composite disease severity scoring systems. Whole-genome genotyping for >500,000 SNPs was performed to search for associations using OQLS algorithm in 139 eligible patients. Several SNPs in linkage disequilibrium within the CLN8 gene locus were associated with the GD1 severity: SNP rs11986414 was associated with GD1 severity at p value 1.26 × 10−6. Compared to mild disease, risk allele A at rs11986414 conferred an odds ratio of 3.72 for moderate/severe disease. Loss of function mutations in CLN8 causes neuronal ceroid-lipofuscinosis but our results indicate that its increased expression may protect against severe GD1. In cultured skin fibroblasts, the relative expression of CLN8 was higher in mild GD compared to severely affected patients in whom CLN8 risk alleles were over-represented. In an in vitro cell model of GD, CLN8 expression was increased which was further enhanced in the presence of bioactive substrate, glucosylsphingosine. Taken together, CLN8 is a candidate modifier gene for GD1 that may function as a protective sphingolipid sensor and/or in glycosphingolipid trafficking. Future studies should explore the role of CLN8 in pathophysiology of GD.
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影响因子：
2.1
作者：
Choi, Yoonha;Wijsman, Ellen M.;Weir, Bruce S.
通讯作者：
Weir, Bruce S.
影响因子：
3.8
作者：
Altarescu, G;Zimran, A;Elstein, D
通讯作者：
Elstein, D
影响因子：
4.2
作者：
Amato, D;Stachiw, T;Rivard, GE
通讯作者：
Rivard, GE
影响因子：
2.3
作者：
Biegstraaten, M.;van Schaik, I. N.;Hollak, C. E. M.
通讯作者：
Hollak, C. E. M.
影响因子：
5.8
作者：
Johnson, Andrew D.;Handsaker, Robert E.;de Bakker, Paul I. W.
通讯作者：
de Bakker, Paul I. W.