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)

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