Department of Neurology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain.
Laboratory of Neurobiology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain.
Brain Behav. 2019 Apr;9(4):e01272. doi: 10.1002/brb3.1272. Epub 2019 Mar 21.
Vitamin D (VD) deficiency has been associated with multiple sclerosis (MS) and other autoimmune diseases (AIDs). However, the effect of the genetics of VD on the risk of MS is subject to debate. This study focuses on genes linked to the VD signaling pathway in families with MS. The evaluation of gene variants in all the members of families could contribute to an additional knowledge on the information obtained from case-control studies that use nonrelated healthy people.
We studied 94 individuals from 15 families including at least two patients with MS. We performed whole-exome next generation sequencing on all individuals and analyzed variants of the DHCR7, CYP2R1, CYP3A4, CYP27A1, GC, CYP27B1, LRP2, CUBN, DAB2, FCGR, RXR, VDR, CYP24A1, and PDIA3 genes. We also studied PTH, FGF23, METTL1, METTL21B, and the role of the linkage disequilibrium block on the long arm of chromosome 12, through analysis of the CDK4, TSFM, AGAP2, and AVIL genes. We compared patients with MS, other AIDs and unaffected members from different family types.
The study described the variants in the VD signaling pathway that appear in families with at least two patients with MS. Some infrequent variants were detected in these families, but no significant difference was observed between patients with MS and/or other AIDs and unaffected family members in the frequency of these variants. Variants previously associated with MS in the literature were not observed in these families or were distributed similarly in patients and unaffected family members.
The study of genes involved in the VD signaling pathway in families that include more than one patient with MS did not identify any variants that could explain the presence of the disease, suggesting that VD metabolism could probably play a role in MS more as an environmental factor rather than as a genetic factor. Our study also supports the analysis of cases and unaffected individuals within families in order to determine the influence of genetic factors.
维生素 D（VD）缺乏与多发性硬化症（MS）和其他自身免疫性疾病（AIDs）有关。然而，VD 遗传对 MS 风险的影响仍存在争议。本研究关注与 MS 家族中 VD 信号通路相关的基因。评估家族中所有成员的基因变异可能有助于增加从使用非相关健康人群的病例对照研究中获得的信息。
我们研究了来自 15 个家族的 94 名个体，其中至少有 2 名 MS 患者。我们对所有个体进行了全外显子组下一代测序，并分析了 DHCR7、CYP2R1、CYP3A4、CYP27A1、GC、CYP27B1、LRP2、CUBN、DAB2、FCGR、RXR、VDR、CYP24A1 和 PDIA3 基因的变体。我们还通过分析 CDK4、TSFM、AGAP2 和 AVIL 基因，研究了 PTH、FGF23、METTL1、METTL21B 和 12 号染色体长臂上的连锁不平衡块的作用。我们比较了 MS 患者、其他 AIDs 患者和不同家族类型的未受影响的成员。
本研究描述了至少有 2 名 MS 患者的家族中 VD 信号通路的变异。在这些家族中检测到了一些罕见的变异，但在 MS 和/或其他 AIDs 患者与未受影响的家族成员之间，这些变异的频率没有观察到显著差异。在这些家族中未观察到文献中与 MS 相关的变异，或者在患者和未受影响的家族成员中分布相似。
对包括多名 MS 患者的家族中参与 VD 信号通路的基因进行研究，并未发现任何可以解释疾病存在的变异，这表明 VD 代谢可能更多地作为环境因素而不是遗传因素在 MS 中发挥作用。我们的研究还支持在家族中对病例和未受影响的个体进行分析，以确定遗传因素的影响。
