IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy.
Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy.
Autism Res. 2020 May;13(5):680-690. doi: 10.1002/aur.2279. Epub 2020 Feb 21.
Vitamin D is endowed with a number of biological properties, including down-regulation of inflammation, and might contribute to the pathogenesis of autism spectrum disorders (ASD). Vitamin D binds to the vitamin D Receptor (VDR); the biological activity of the ensuing complex depends on VDR FokI, BsmI, ApaI, and TaqI gene polymorphisms. We evaluated such Single Nucletoide Polymorphismsm (SNPs) in a cohort of 100 Italian families with ASD children. FokI genotype distribution was skewed in ASD children compared with their healthy sibs (P = 0.03 2 df) and to a group of 170 Italian healthy women (HC) (P = 0.04 2 df). FokI genotype and allelic distribution skewing were also observed in mothers of ASD children compared to HC (P = 0.04 2 df). Both Transmission Disequilibrium Test for single loci and haplotype analysis distribution revealed a major FokI (C) allele-mediated protective effect, which was more frequently transmitted (73%) than not transmitted to healthy sibs (P = 0.02). A protective FokI-, BsmI-, ApaI-, and TaqI (CCAG) haplotype was more frequently carried by healthy sibs than by ASD children (P = 1 × 10 ; OR: 0.1, 95% CI: 0.03-0.4) too. Finally, a strong gene-dose association of FokI (T) allele with both higher Childhood Autism Rating Scale score (P = 0.01) and, particularly, with hyperactivity behavior (P = 0.006) emerged in ASD children. Because the protein produced by the FokI (T) allele is transcriptionally less active than that produced by the FokI (C) allele, the reduced biological activity of the vitamin D/VDR complex prevalent in ASD could favor ASD- and maternal immune activation- associated inflammation. Vitamin D supplementation might be useful in preventative and rehabilitation protocols for ASD. Autism Res 2020, 13: 680-690. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Vitamin D deficiency and Vitamin D receptor (VDR) polymorphisms are associated with structural and functional brain abnormalities and behavioral disorders. We analyzed the association of VDR gene polymorphisms in a cohort of 100 Italian families with ASD children. A strong correlation between one of the VDR polymorphisms and hyperactivity behavior was evidenced in ASD children. In healthy mothers, the same VDR polymorphism was also correlated with an increased risk of giving birth to children with ASD.
维生素 D 具有多种生物学特性，包括下调炎症，可能有助于自闭症谱系障碍 (ASD) 的发病机制。维生素 D 与维生素 D 受体 (VDR) 结合；随后的复合物的生物学活性取决于 VDR FokI、BsmI、ApaI 和 TaqI 基因多态性。我们在 100 个意大利 ASD 儿童家庭的队列中评估了这种单核苷酸多态性 (SNP)。与健康同胞（P = 0.03 2 df）和 170 名意大利健康女性（HC）（P = 0.04 2 df）相比，FokI 基因型分布在 ASD 儿童中存在偏倚。与 HC（P = 0.04 2 df）相比，ASD 儿童的母亲也观察到 FokI 基因型和等位基因分布偏倚。单基因座传递不平衡检验和单倍型分析分布均显示 FokI (C) 等位基因介导的主要保护作用，该等位基因更频繁地传递（73%）而不是不传递给健康同胞（P = 0.02）。FokI-、BsmI-、ApaI-和 TaqI (CCAG) 保护性单倍型在健康同胞中携带频率高于 ASD 儿童（P = 1×10；OR：0.1，95%CI：0.03-0.4）。最后，FokI（T）等位基因与儿童自闭症评定量表评分较高（P = 0.01），尤其是多动行为（P = 0.006）之间存在强烈的基因剂量关联。由于 FokI（T）等位基因产生的蛋白质转录活性低于 FokI（C）等位基因产生的蛋白质，ASD 中普遍存在的维生素 D/VDR 复合物的生物学活性降低可能有利于 ASD 和母体免疫激活相关炎症。维生素 D 补充可能对 ASD 的预防和康复方案有用。自闭症研究 2020, 13: 680-690。© 2020 自闭症研究国际协会，威利在线期刊，公司。
