Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease affecting the central nervous system in young adults. Heparan sulfate proteoglycans (HSPGs) are ubiquitous to the cell surface and the extracellular matrix. HSPG biosynthesis is a complex process involving enzymatic attachment of heparan sulfate (HS) chains to a core protein. HS side chains mediate specific ligand and growth factor interactions directing cellular processes including cell adhesion, migration and differentiation. Two main families of HSPGs exist, the syndecans (SDC1-4) and glypicans (GPC1-6). The SDCs are transmembrane proteins, while the GPC family are GPI linked to the cell surface. SDC1 has well-documented interactions with numerous signalling pathways. Genome-wide association studies (GWAS) have identified regions of the genome associated with MS including a region on chromosome 13 containing GPC5 and GPC6. International studies have revealed significant associations between this region and disease development. The exostosin-1 (EXT1) and sulfatase-1 (SULF1) are key enzymes contributing to the generation of HS chains. EXT1, with documented tumour suppressor properties, is involved in the initiation and polymerisation of the growing HS chain. SULF1 removes 6-O-sulfate groups from HS chains, affecting protein-ligand interactions and subsequent downstream signalling with HS modification potentially having significant effects on MS progression. In this study, we identified significant associations between single nucleotide polymorphisms in SDC1, GPC5 and GPC6 and MS in an Australian Caucasian case-control population. Further significant associations in these genes were identified when the population was stratified by sex and disease subtype. No association was found for EXT1 or SULF1.

中文翻译：

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硫酸乙酰肝素蛋白聚糖核心蛋白和关键修饰酶在澳大利亚白种人多发性硬化症人群中的遗传多态性调查。

多发性硬化症（MS）是一种慢性炎症性脱髓鞘疾病，影响年轻人的中枢神经系统。硫酸乙酰肝素蛋白聚糖（HSPG）在细胞表面和细胞外基质中普遍存在。HSPG生物合成是一个复杂的过程，涉及硫酸乙酰肝素（HS）链与核心蛋白的酶促连接。HS侧链介导特定的配体和生长因子相互作用，指导细胞过程，包括细胞粘附，迁移和分化。HSPG存在两个主要家族，即同聚糖（SDC1-4）和Glypicans（GPC1-6）。SDC是跨膜蛋白，而GPC家族是与细胞表面相连的GPI。SDC1与许多信号传导途径有充分记录的相互作用。全基因组关联研究（GWAS）已确定与MS相关的基因组区域，包括13号染色体上包含GPC5和GPC6的区域。国际研究表明该地区与疾病发展之间存在显着关联。exostosin-1（EXT1）和硫酸酯酶-1（SULF1）是促成HS链生成的关键酶。具有已证明的抑癌特性的EXT1参与了正在增长的HS链的引发和聚合。SULF1从HS链上去除了6-O-硫酸盐基团，影响了蛋白质-配体的相互作用以及随后的带有HS修饰的下游信号传导，可能对MS的进展产生重大影响。在这项研究中，我们确定了SDC1中单核苷酸多态性之间的显着关联，澳大利亚高加索病例对照人群中的GPC5，GPC6和MS。当按性别和疾病亚型对人群进行分层时，在这些基因中发现了进一步的重要关联。找不到与EXT1或SULF1的关联。