患有25（OH）D和维生素D结合蛋白缺乏症的印度ASD先证者表现出更高的严重程度-动脉网

Indian ASD probands with 25(OH)D and vitamin D binding protein deficiency exhibited higher severity

Nature 等信源发布 2024-08-20 18:38

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AbstractThe severity of autism spectrum disorder (ASD) shows wide variations, though the reason remains unclear. Vitamin D (VitD) deficiency is considered a risk factor for ASD and its supplementation was reported to reduce symptom severity. Since VitD, either synthesized in the skin or absorbed from the food, is transported to the liver by the vitamin D binding protein (DBP), we have analyzed DBP genetic polymorphisms [rs7041 (A/C), rs4588 (G/T), and rs3755967 (C/T)] affecting DBP function [Case = 411; Control = 397], levels of plasma 25(OH)D and DBP [Case = 25; Control = 26], and DBP mRNA expression [Case = 74; Control = 44] in a group of Indo-Caucasoid ASD probands and neurotypical subjects.

自闭症谱系障碍（ASD）的严重程度差异很大，但原因尚不清楚。维生素D（VitD）缺乏被认为是ASD的危险因素，据报道补充维生素D可以减轻症状的严重程度。由于维生素D在皮肤中合成或从食物中吸收，通过维生素D结合蛋白（DBP）转运到肝脏，我们分析了DBP遗传多态性[rs7041（A/C），rs4588（G/T）和rs3755967（C/T）]影响DBP功能[案例411；对照组397，血浆25（OH）D和DBP水平[病例25；对照组26和DBP mRNA表达[病例74；在一组印度高加索ASD先证者和神经型受试者中进行对照。

ASD probands with rs7041’CC’, rs4588 ‘TT’, and rs3755967 ‘TT’ genotypes exhibited higher scores for a few traits. Scores for Imitation and Listening response were also higher in the presence of the “A-T” haplotype (rs7041–rs4588). Plasma 25(OH)D and DBP levels as well as DBP mRNA expressions were significantly lower in the ASD probands as compared to the neurotypical subjects.

具有rs7041'CC'，rs4588'TT'和rs3755967'TT'基因型的ASD先证者在一些性状上表现出较高的得分。在存在“A-T”单倍型（rs7041-rs4588）的情况下，模仿和倾听反应的得分也更高。与神经型受试者相比，ASD先证者的血浆25（OH）D和DBP水平以及DBP mRNA表达显着降低。

We infer that DBP deficiency, in the presence of risk genetic variants, could be one of the reasons for the reported 25(OH)D deficiency of the ASD probands..

我们推断，在存在风险遗传变异的情况下，DBP缺乏可能是ASD先证者报告的25（OH）D缺乏的原因之一。。

IntroductionAutism spectrum disorder (ASD) is the most prevalent and complex neurodevelopmental disorder all over the world1. As per the Diagnostic and Statistical Manual of Mental Disorders -5 (DSM-5)2, the cardinal features of ASD are characterized by deficits in social communication, language, and speech along with repetitive patterns of behaviors.

引言自闭症谱系障碍（ASD）是世界上最普遍和最复杂的神经发育障碍1。根据《精神障碍诊断与统计手册-5》（DSM-5）2，自闭症的主要特征是社交，语言和言语缺陷以及重复的行为模式。

Genetic, nutritional, and environmental factors are believed to confer a risk for ASD3. Vitamin D (VitD) and other nutrient deficiencies, stress, low birth weight, air pollution, etc. were also studied to understand their possible role in this disorder4.VitD, a neurosteroid, is known to have an important role in fetal brain development5 and a deficiency was reported in individuals with ASD6.

遗传，营养和环境因素被认为会导致ASD3的风险。。

VitD, synthesized in the human skin from the 7-dehydrocholesterol, is released into the bloodstream and binds with the VitD binding protein (DBP). The conjugate is then transported to the liver where the first hydroxylation takes place to form 25 hydroxy VitD [25(OH)D], the most stable circulating form of VitD7.

由7-脱氢胆固醇在人体皮肤中合成的维生素D被释放到血液中并与维生素D结合蛋白（DBP）结合。然后将缀合物转运至肝脏，在那里进行第一次羟基化以形成25-羟基-VitD[25（OH）D]，这是最稳定的VitD7循环形式。

The 2nd hydroxylation takes place in the kidney generating the biologically active form of VitD, the 1,25 dihydroxy VitD [1,25(OH)2D], which is then distributed to different organs and tissues including the brain8. Free 1,25(OH)2D has a higher affinity for the VitD receptors while having a 10–100-fold lower affinity for DBP as compared to the 25(OH)D9.About 85–90% of circulating VitD, i.e.

第二次羟基化发生在肾脏中，产生生物活性形式的维生素D，即1,25-二羟基维生素D[1,25（OH）2D]，然后将其分布到包括大脑在内的不同器官和组织8。游离1,25（OH）2D对VitD受体的亲和力较高，而对DBP的亲和力比25（OH）D9低10-100倍。约85-90%的循环VitD，即。

25(OH)D, is transported through DBP10 also known as the Group-specific Component (GC). DBP is encoded by the GC gene residing on chromosome 4q11–q1311 and carries several polymorphic sites12,13. The two most important functional single nucleotide polymorphisms of the GC gene, rs7041 (A > C causing substitution of aspartate to glutamate) and r.

25（OH）D通过DBP10转运，也称为基团特异性成分（GC）。DBP由位于染色体4q11–q1311上的GC基因编码，并带有几个多态位点12,13。GC基因的两个最重要的功能性单核苷酸多态性rs7041（导致天冬氨酸取代谷氨酸的A>）和r。

Table 1 Quantitative trait analysis performed to identify the impact of DBP genetic variants on the CARS2-ST scores.Full size tableStratified analysis based on the gender of the probands revealed a positive influence of rs7041 ‘CC’ (0.05) and rs4588 ‘TT’ (0.003) on the score for CARS2-ST Imitation of the male ASD probands (Table 1). No significant influence was noticed on the scores of the female probands (data not presented for brevity).Slightly higher scores for CARS2-ST Imitation [mean score = 2.31; GC1s vs GC2 q(P) = 4.27 (0.008); F(P) = 4.88 (0.009)] and CARS2-ST Listening response [mean score = 2.41 GC1s vs GC2 q(P) = 3.50 (0.03); F(P) = 3.09 (0.05)] were detected in the ASD probands having the GC2 isoform.

表1为确定DBP遗传变异对CARS2-ST评分的影响而进行的数量性状分析。基于先证者性别的全尺寸表分层分析显示，rs7041“CC”（0.05）和rs4588“TT”（0.003）对男性ASD先证者的CARS2-ST模仿得分有积极影响（表1）。没有发现对女性先证者的分数有显着影响（数据未简要介绍）。CARS2-ST模仿得分略高[平均得分=2.31；；F（P）=4.88（0.009）]和CARS2-ST听力反应[平均得分2.41 GC1s vs GC2 q（P）=3.50（0.03）；在具有GC2亚型的ASD先证者中检测到F（P）=3.09（0.05）]。

The data remained significant even after Post- hoc comparison was performed using the Bonferroni correction (Fig. 1; P = 0.016).Figure 1Comparative analysis on the trait scores of ASD probands stratified based on the GC isoforms. The box plot shows the values of each domain; lines within the boxes represent the median values.

即使使用Bonferroni校正进行事后比较，数据仍然显着（图1；P=0.016）。图1基于GC亚型分层的ASD先证者特征得分的比较分析。箱形图显示了每个域的值；框内的线表示中值。

Post hoc comparison after one-way ANOVA was performed by Tukey’s multiple comparison test followed by Bonferroni’s correction for multiple testing (significance set at P = 0.05/3 = 0.016).Full size imageAnalysis of plasma 25(OH)D and DBP levelsThe total plasma 25(OH)D level was significantly lower in the ASD probands (N = 25) than in the neurotypical subjects (N = 26) (10.52 ± 1.32 and 18.48 ± 1.13 respectively; P < 0.001) (Fig. 2a).Figure 2Case–control comparative analysis on (a) plasma 25(OH)D levels; (b) plasma DBP level.Full size imageThe plasma DBP levels were also significantly lower in the ASD probands (N = 25) [24.60 ± 0.83 µg/ml; P = 0.015] in comparison to the age-matched controls (N = 26) [50.64 ± 10.57 µg/ml] (Fig. 2b).ASD prob.

通过Tukey的多重比较检验进行单因素方差分析后的事后比较，然后进行Bonferroni的多重检验校正（显着性设置为P=0.05/3=0.016）。血浆25（OH）D和DBP水平的全尺寸图像分析ASD先证者（N=25）的总血浆25（OH）D水平显着低于神经型受试者（N=26）（分别为10.52±1.32和18.48±1.13；P<0.001）（图2a）。图2（a）血浆25（OH）D水平的病例对照比较分析；（b）血浆DBP水平。全尺寸图像ASD先证者的血浆DBP水平也显着降低（N=25）[24.60±0.83µg/ml；。ASD问题。

Data availability

数据可用性

Data generated for the study are presented in tabular format as Supplementary Tables and Additional files. Further details on data will be available from the corresponding author upon reasonable request.

为研究生成的数据以表格形式作为补充表格和附加文件提供。根据合理的要求，通讯作者将提供有关数据的更多详细信息。

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Download referencesAcknowledgementsThe authors are thankful to the participants for volunteering in the study. The authors are also thankful to the Ganapati Sugar Industries for partial financial support for the research work.Author informationAuthors and AffiliationsManovikas Biomedical Research and Diagnostic Centre, Manovikas Kendra, 482 Madudah, Plot I-24, Sector J, EM Bypass, Kolkata, West Bengal, 700107, IndiaSayanti Shom, Sharmistha Saha, Mahasweta Chatterjee, Swagata Sinha & Kanchan MukhopadhyayAuthorsSayanti ShomView author publicationsYou can also search for this author in.

。作者还感谢Ganapati糖业对研究工作的部分财政支持。作者信息作者和附属机构Manovikas Kendra生物医学研究和诊断中心，482 Madudah，Plot I-24，Sector J，EM Bypass，加尔各答，西孟加拉邦，700107，IndiaSayanti Shom，Sharmistha Saha，Mahasweta Chatterjee，Swagata Sinha＆Kanchan MukhopadhyayAuthorsSayanti ShomView作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarSharmistha SahaView author publicationsYou can also search for this author in

PubMed Google ScholarSharmistha SahaView作者出版物您也可以在

PubMed Google ScholarMahasweta ChatterjeeView author publicationsYou can also search for this author in

PubMed Google ScholarMahasweta ChatterjeeView作者出版物您也可以在

PubMed Google ScholarSwagata SinhaView author publicationsYou can also search for this author in

PubMed Google ScholarSwagata SinhaView作者出版物您也可以在

PubMed Google ScholarKanchan MukhopadhyayView author publicationsYou can also search for this author in

PubMed Google ScholarContributionsGenotyping, data collection, and analysis, as well as manuscript draft preparation, were performed by SShom. SSaha and MC assisted in data analysis. SSinha recruited the subjects and performed psychological evaluations. KM conceptualized the study and supervised the design, execution, interpretation, and manuscript editing.

。SSaha和MC协助数据分析。SSinha招募了受试者并进行了心理评估。KM将研究概念化，并监督设计，执行，解释和手稿编辑。

All the authors approved the final manuscript.Corresponding authorCorrespondence to.

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Reprints and permissionsAbout this articleCite this articleShom, S., Saha, S., Chatterjee, M. et al. Indian ASD probands with 25(OH)D and vitamin D binding protein deficiency exhibited higher severity.

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Keywords25(OH)DDBPrs7041rs4588rs3755967ASD

关键词25（OH）DDBPrs7041rs4588rs3755967ASD

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