Association between MTHFR gene C677T polymorphism and risk of autism spectrum disorder in children: a Meta-analysis

doi:10.3877/cma.j.issn.1673-5250.2021.02.011

Objective

To study to evaluate the association of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and the risk of autism spectrum disorder (ASD) in children.

Methods

PubMed, EMbase, Cochrane Library, VIP, China National Knowledge Infrastructure (CNKI) and Wanfang databases were electronically searched to collect case-control (CCS) studies about the association between the MTHFR gene C677T polymorphism and the risk of ASD in children from inception to June 2019. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. The Meta-analysis was performed using Stata 14.0 software.

Results

According to the literature retrieval strategies of this study, 14 pieces of CCS literature (4 141 cases) were included in final Meta-analysis, including 2 024 cases diagnosed with ASD in study group and 2 117 cases with out any genetic or neurological disorders in control group.The results of Meta-analysis showed as the following. ① The MTHFR gene C677T polymorphism allele model (T vs C) was associated with risk of ASD in children (OR=1.99, 95%CI: 1.41-2.79, P<0.001). Further analysis was carried out according to the population of study subjects. The results showed that the MTHFR gene C677T polymorphism allele model (T vs C) was associated with risk of ASD in children in Caucasian (OR=1.66, 95%CI: 1.19-2.30, P<0.001), was not associated with risk of ASD in children in Asian (OR=2.31, 95%CI: 0.93-5.75, P<0.001). ②In the homozygous model (TT vs CC) and heterozygous model (CT vs CC), MTHFR gene C677T polymorphism was associated with risk of ASD in children (OR=1.65, 95%CI: 1.12-2.42, P=0.011; OR=1.60, 95%CI: 1.26-2.02, P<0.001 ).

Conclusions

MTHFR gene C677T polymorphism is associated with risk of ASD in children in Caucasian. However, in Asian, MTHFR gene C677T polymorphism is not associated with risk of ASD in children.

Key words: Methylenetetrahydrofolate reductase (NADPH2), Autistic disorder, Ethnic groups, Alleles, Meta analysis, Case-control studies, Child

图1 文献筛选流程及结果

表1 14篇有关MTHFR基因C677T多态性与ASD发病风险的CCS文献的基本特征

文献(第1作者，文献发表年)	患儿例数		地区	患儿年龄(岁，±s)		男、女性患儿性别比
文献(第1作者，文献发表年)	研究组	对照组	地区	研究组	对照组	研究组	对照组
El-Baz, 2017^[11]	31	39	高加索地区	4.57±2.00	—	—	—
Guo^[12], 2012	186	186	亚洲地区	—	—	—	—
Ismail^[13], 2019	78	80	其他地区	4.6	—	65∶13	—
Liu^[14], 2011	205	384	高加索地区	—		—	1∶1
Mohammad^[15], 2009	138	138	亚洲地区	4.4±1.7	4.4±1.6	20∶3	20∶3
James^[18], 2006	356	205	高加索地区	7.3±3.2	10.8±4.1	—	—
Pasca^[19], 2009	39	80	高加索地区	6.90±0.82	8.3±0.8	31∶8	29∶26
Santos^[20], 2010	151	100	高加索地区	—	—	116∶35	57∶43
Schmidt^[21], 2011	294	180	高加索地区	—	—	—	—
Shawky^[22], 2014	20	20	高加索地区	4.57±1.36	4.9±1.6	13∶7	13∶7
Meguid^[23], 2015	24	30	高加索地区	—	—	—	—
Park^[24], 2014	251	425	亚洲地区	—	—	107∶11	253∶170
Zhang^[25], 2018	201	200	亚洲地区	—	—	—	—
Divyakolu^[26], 2013	50	50	其他地区	—	—	—	—

表1 14篇有关MTHFR基因C677T多态性与ASD发病风险的CCS文献的基本特征

文献(第1作者，文献发表年)	患儿例数		地区	患儿年龄(岁，±s)		男、女性患儿性别比
文献(第1作者，文献发表年)	研究组	对照组	地区	研究组	对照组	研究组	对照组
El-Baz, 2017^[11]	31	39	高加索地区	4.57±2.00	—	—	—
Guo^[12], 2012	186	186	亚洲地区	—	—	—	—
Ismail^[13], 2019	78	80	其他地区	4.6	—	65∶13	—
Liu^[14], 2011	205	384	高加索地区	—		—	1∶1
Mohammad^[15], 2009	138	138	亚洲地区	4.4±1.7	4.4±1.6	20∶3	20∶3
James^[18], 2006	356	205	高加索地区	7.3±3.2	10.8±4.1	—	—
Pasca^[19], 2009	39	80	高加索地区	6.90±0.82	8.3±0.8	31∶8	29∶26
Santos^[20], 2010	151	100	高加索地区	—	—	116∶35	57∶43
Schmidt^[21], 2011	294	180	高加索地区	—	—	—	—
Shawky^[22], 2014	20	20	高加索地区	4.57±1.36	4.9±1.6	13∶7	13∶7
Meguid^[23], 2015	24	30	高加索地区	—	—	—	—
Park^[24], 2014	251	425	亚洲地区	—	—	107∶11	253∶170
Zhang^[25], 2018	201	200	亚洲地区	—	—	—	—
Divyakolu^[26], 2013	50	50	其他地区	—	—	—	—

表2 14篇有关MTHFR基因C677T多态性与ASD发病风险的CCS文献纳入患儿的基因型分布

文献(第1作者，文献发表年)	研究组基因型			对照组基因型			Hardy-Weinberg平衡检验
文献(第1作者，文献发表年)	CC	CT	TT	CC	CT	TT	χ²值	P值
El-Baz^[11], 2017	12	15	4	35	4	0	0.114	0.736
Guo^[12], 2012	79	77	30	87	83	16	0.371	0.542
Ismail^[13], 2019	37	28	13	60	17	3	1.497	0.221
Liu^[14], 2011	68	98	39	177	166	41	0.050	0.823
Mohammad^[15], 2009	98	35	5	120	18	0	0.935	0.412
James^[18], 2006	134	176	46	93	90	22	0.001	0.974
Pasca^[19], 2009	21	14	4	46	28	6	0.356	0.551
Santos^[20], 2010	60	68	23	45	41	14	0.862	0.353
Schmidt^[21], 2011	128	133	33	74	77	29	1.375	0.241
Shawky^[22], 2014	7	10	3	14	6	0	0.623	0.429
Meguid^[23], 2015	11	11	2	20	8	2	0.833	0.361
Park^[24], 2014	76	136	37	139	204	80	0.113	0.737
Zhang^[25], 2018	32	101	68	42	86	71	2.721	0.099
Divyakolu^[26], 2013	27	22	1	42	8	0	0.378	0.538

表2 14篇有关MTHFR基因C677T多态性与ASD发病风险的CCS文献纳入患儿的基因型分布

文献(第1作者，文献发表年)	研究组基因型			对照组基因型			Hardy-Weinberg平衡检验
文献(第1作者，文献发表年)	CC	CT	TT	CC	CT	TT	χ²值	P值
El-Baz^[11], 2017	12	15	4	35	4	0	0.114	0.736
Guo^[12], 2012	79	77	30	87	83	16	0.371	0.542
Ismail^[13], 2019	37	28	13	60	17	3	1.497	0.221
Liu^[14], 2011	68	98	39	177	166	41	0.050	0.823
Mohammad^[15], 2009	98	35	5	120	18	0	0.935	0.412
James^[18], 2006	134	176	46	93	90	22	0.001	0.974
Pasca^[19], 2009	21	14	4	46	28	6	0.356	0.551
Santos^[20], 2010	60	68	23	45	41	14	0.862	0.353
Schmidt^[21], 2011	128	133	33	74	77	29	1.375	0.241
Shawky^[22], 2014	7	10	3	14	6	0	0.623	0.429
Meguid^[23], 2015	11	11	2	20	8	2	0.833	0.361
Park^[24], 2014	76	136	37	139	204	80	0.113	0.737
Zhang^[25], 2018	32	101	68	42	86	71	2.721	0.099
Divyakolu^[26], 2013	27	22	1	42	8	0	0.378	0.538

表3 纳入研究14篇有关MTHFR基因C677T多态性与ASD发病风险的CCS文献的偏倚风险评价(分)

文献(第一作者，文献发表年份)	对象选择	可比性	暴露水平	总分
El-Baz^[11]，2017	1	2	3	6
Guo^[12]，2012	3	1	2	6
Ismail^[13]，2019	2	1	2	5
Liu^[14]，2011	2	1	2	5
Mohammad^[15]，2009	3	2	3	8
James^[18]，2006	3	1	3	7
Pasca^[19]，2009	2	1	3	6
Santos^[20]，2010	3	1	3	7
Schmidt^[21]，2011	4	1	3	8
Shawky^[22]，2014	2	2	2	6
Meguid^[23]，2015	3	2	3	8
Park^[24]，2014	3	1	2	6
Zhang^[25]，2018	4	1	3	8
Divyakolu^[26]，2013	2	1	2	5

表3 纳入研究14篇有关MTHFR基因C677T多态性与ASD发病风险的CCS文献的偏倚风险评价(分)

文献(第一作者，文献发表年份)	对象选择	可比性	暴露水平	总分
El-Baz^[11]，2017	1	2	3	6
Guo^[12]，2012	3	1	2	6
Ismail^[13]，2019	2	1	2	5
Liu^[14]，2011	2	1	2	5
Mohammad^[15]，2009	3	2	3	8
James^[18]，2006	3	1	3	7
Pasca^[19]，2009	2	1	3	6
Santos^[20]，2010	3	1	3	7
Schmidt^[21]，2011	4	1	3	8
Shawky^[22]，2014	2	2	2	6
Meguid^[23]，2015	3	2	3	8
Park^[24]，2014	3	1	2	6
Zhang^[25]，2018	4	1	3	8
Divyakolu^[26]，2013	2	1	2	5

图2 MTHFR基因C677T多态性等位基因模型(T vs C)与ASD发病风险的Meta分析结果

图3 MTHFR基因C677T多态性纯合子模型(TT vs CC)与ASD发病风险的Meta分析结果

图4 MTHFR基因C677T多态性杂合子模型(CT vs CC)与ASD发病风险的Meta分析结果

图5 剔除单个研究后进行敏感性分析等位基因模型(T vs C)

[1]	Elsabbagh M, Divan G, Koh YJ, et al. Global prevalence of autism and other pervasive developmental disorders[J]. Autism Res, 2012, 5(3): 160-179. DOI: 10.1002/aur.239.
[2]	Lyall K, Croen L, Daniels J, et al. The changing epidemiology of autism spectrum disorders[J]. Annu Rev Public Health, 2017, 38: 81-102. DOI: 10.1146/annurev-publhealth-031816-044318.
[3]	Messinger DS, Young GS, Webb SJ, et al. Early sex differences are not autism-specific: a Baby Siblings Research Consortium (BSRC) study[J]. Mol Autism, 2015, 6: 32. DOI: 10.1186/s13229-015-0027-y.
[4]	Tick B, Bolton P, Happé F, et al. Heritability of autism spectrum disorders: a Meta-analysis of twin studies[J]. J Child Psychol Psychiatry, 2016, 57(5): 585-595. DOI: 10.1111/jcpp.12499.
[5]	Chen H, Yang X, Lu M. Methylenetetrahydrofolate reductase gene polymorphisms and recurrent pregnancy loss in China: a systematic review and Meta-analysis[J]. Arch Gynecol Obstet, 2016, 293(2): 283-290. DOI: 10.1007/s00404-015-3894-8.
[6]	Yuan Y, Shao W, Li Y. Associations between C677T and A1298C polymorphisms of MTHFR and susceptibility to rheumatoid arthritis: a systematic review and Meta-analysis[J]. Rheumatol Int, 2017, 37(4): 557-569. DOI: 10.1007/s00296-017-3650-4.
[7]	Yi K, Yang L, Lan Z, et al. The association between MTHFR polymorphisms and cervical cancer risk: a system review and Meta analysis[J]. Arch Gynecol Obstet, 2016, 294(3): 579-588. DOI: 10.1007/s00404-016-4037-6.
[8]	Wu YL, Hu CY, Lu SS, et al. Association between methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and essential hypertension: a systematic review and Meta-analysis[J]. Metabolism, 2014, 63(12)：1503-1511. DOI: 10.1016/j.metabol.2014.10.001.
[9]	Fu LY, Dai LM, Li XG, et al. Association of methylenetetrahydrofolate reductase gene C677T polymorphism with polycystic ovary syndrome risk: a systematic review and Meta-analysis update[J]. Eur J Obstet Gynecol Reprod Biol, 2014, 172：56-61. DOI: 10.1016/j.ejogrb.2013.10.001.
[10]	Wang W, Jiao XH, Wang XP, et al. MTR, MTRR, and MTHFR gene polymorphisms and susceptibility to nonsyndromic cleft lip with or without cleft palate[J]. Genet Test Mol Biomarkers, 2016, 20(6)：297-303. DOI: 10.1089/gtmb.2015.0186.
[11]	El-Baz F, El-Aal MA, Kamal TM, et al. Study of the C677T and 1298AC polymorphic genotypes of MTHFR gene in autism spectrum disorder[J]. Electron Physician, 2017, 9(9)：5287-5293. DOI: 10.19082/5287.
[12]	Guo T, Chen H, Liu B, et al. Methylenetetrahydrofolate reductase polymorphisms C677T and risk of autism in the Chinese Han population[J]. Genet Test Mol Biomarkers, 2012, 16(8)：968-973. DOI: 10.1089/gtmb.2012.0091.
[13]	Ismail S, Senna AA, Behiry EG, et al. Study of C677T variant of methylene tetrahydrofolate reductase gene in autistic spectrum disorder Egyptian children[J]. Am J Med Genet B Neuropsychiatr Genet, 2019, 180(5)：305-309. DOI: 10.1002/ajmg.b.32729.
[14]	Liu X, Solehdin F, Cohen IL, et al. Population- and family-based studies associate the MTHFR gene with idiopathic autism in simplex families[J]. J Autism Dev Disord, 2011, 41(7)：938-944. DOI: 10.1007/s10803-010-1120-x.
[15]	Mohammad NS, Jain JM, Chintakindi KP, et al. Aberrations in folate metabolic pathway and altered susceptibility to autism[J]. Psychiatr Genet, 2009, 19(4)：171-176. DOI: 10.1097/YPG.0b013e32832cebd2.
[16]	Sharma SR, Gonda X, Tarazi FI. Autism spectrum disorder: classification, diagnosis and therapy[J]. Pharmacol Ther, 2018, 190：91-104. DOI: 10.1016/j.pharmthera.2018.05.007.
[17]	Stang A. Critical evaluation of the Newcastle-Ottawa Scale for the assessment of the quality of nonrandomized studies in Meta-analyses[J]. Eur J Epidemiol, 2010, 25(9)：603-605. DOI: 10.1007/s10654-010-9491-z.
[18]	James SJ, Melnyk S, Jernigan S, et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism[J]. Am J Med Genet B Neuropsychiatr Genet, 2006, 141B(8)：947-956. DOI: 10.1002/ajmg.b.30366.
[19]	Paca SP, Dronca E, Kaucsár T, et al. One carbon metabolism disturbances and the C677T MTHFR gene polymorphism in children with autism spectrum disorders[J]. J Cell Mol Med, 2009, 13(10)：4229-4238. DOI: 10.1111/j.1582-4934.2008.00463.x.
[20]	dos Santos PA, Longo D, Brandalize AP, et al. MTHFR C677T is not a risk factor for autism spectrum disorders in South Brazil[J]. Psychiatr Genet, 2010, 20(4)：187-189. DOI: 10.1097/YPG.0b013e32833a2220.
[21]	Schmidt RJ, Hansen RL, Hartiala J, et al. Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism[J]. Epidemiology, 2011, 22(4)：476-485. DOI: 10.1097/EDE.0b013e31821d0e30.
[22]	Shawky RM, El-baz F, Kamal TM, et al. Study of genotype-phenotype correlation of methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms in a sample of Egyptian autistic children[J]．Egyptian J Medi Hum Gene, 2014，15(4)：335-41.DOI: 10.1016/j.ejmhg.2014.05.004.
[23]	Nagwa M, Khalil R, Gebril O, et al. Evaluation of MTHFR genetic polymorphism as a risk factor in Egyptian autistic children and mothers[J]. Afr J Psychiatry.2015，18(1)：179.DOI: 10.4172/psychiatry.1000179.
[24]	Park J, Ro M, Pyun JA, et al. MTHFR 1298A>C is a risk factor for autism spectrum disorder in the Korean population[J]. Psychiatry Res, 2014, 215(1)：258-259. DOI: 10.1016/j.psychres.2013.11.006.
[25]	Zhang Z, Yu L, Li S, et al. Association study of polymorphisms in genes relevant to vitamin B12 and folate metabolism with childhood autism spectrum disorder in a Han Chinese population[J]. Med Sci Monit, 2018, 24：370-376. DOI: 10.12659/msm.905567.
[26]	Divyakolu S, Tejaswini Y, Thomas WW, et al. Evaluation of C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene in various neurological disorders[J]．J Neurol Disrders, 2013，2(1)：1000142.DOI: 10.4172/2329-6895.1000142.
[27]	Boris M, Goldblatt A, Galanko J, et al. Association of MTHFR gene variants with autism [J]．J Am Physicians Surgeons, 2004，9(4): 106-108.
[28]	Sener EF, Oztop DB, Ozkul Y. MTHFR gene C677T polymorphism in autism spectrum disorders[J]. Genet Res Int, 2014, 2014：698574. DOI: 10.1155/2014/698574.
[29]	赵栋，夏薇，孙彩虹，等. 孤独症儿童亚甲基四氢叶酸还原酶基因C677T多态性分析[J]. 中国儿童保健杂志，2012, 20(7): 585-587, 590.
[30]	赵栋，孙彩虹，杨晓巍，等. MTHFR基因C677T和A1298C多态性与儿童孤独症的关系[J]. 中国学校卫生，2013, 34(1): 52-55, 58.
[31]	Altun H, Kurutass EB, Şahin N, et al. The levels of vitamin D, vitamin D receptor, homocysteine and complex B vitamin in children with autism spectrum disorders[J]. Clin Psychopharmacol Neurosci, 2018, 16(4)：383-390. DOI: 10.9758/cpn.2018.16.4.383.
[32]	Yektas C, Alpay M, Tufan AE. Comparison of serum B12, folate and homocysteine concentrations in children with autism spectrum disorder or attention deficit hyperactivity disorder and healthy controls[J]. Neuropsychiatr Dis Treat, 2019, 15：2213-2219. DOI: 10.2147/NDT.S212361.
[33]	李志君，孙擎，张晶，等．MTHFR C677T基因多态性与孤独症谱系障碍遗传易感性的Meta分析[J]．吉林医药学院学报.2017，38(6)：418-422.
[34]	Bölte S, Girdler S, Marschik PB. The contribution of environmental exposure to the etiology of autism spectrum disorder[J]. Cell Mol Life Sci, 2019, 76(7)：1275-1297. DOI: 10.1007/s00018-018-2988-4.

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