荟萃分析：亚甲基四氢叶酸还原酶基因C677T（MTHFR-C677T）多态性与糖尿病视网膜病变（DR）的关系

doi:10.24920/003535

摘要/Abstract

摘要：

目的探讨亚甲基四氢叶酸还原酶基因C677T（MTHFR-C677T）多态性与糖尿病视网膜病变（DR）的关系。
方法本研究共纳入23项研究共6971名受试者,其中DR患者2707例,对照4264名。应用随机效应模型估计MTHFR基因C677T多态性对DR风险的总体效应和分层效应,并对研究质量进行评价。
结果 MTHFR基因C677T多态性与DR密切相关。DR组与健康对照相比,MTHFR-C677T突变发生的比值比在等位基因对比模型（95%CI：1.29-2.18,P<0.001,I ²=78.4%）、显性模型（95%CI：1.62-3.29,P<0.001,I ²=74.7%）和纯合子模型（95%CI：1.70-3.83,P=0.008,I ²=54.4%）中分别为1.68、2.55和2.31。DR组与非复杂糖尿病组相比,MTHFR-C677T突变发生的比值比在等位基因对比模型中为1.50（95%CI：1.07-2.11,P=0.032,I ²=62.1%）,在纯合子模型中为2.39（95%CI：1.06-5.38,P=0.017,I ²=66.7%）,在显性模型中为1.59（95%CI：0.97-2.62,P=0.056,I ²=56.5%）。在杂合子模型中,DR组与健康对照组相比,MTHFR-C677T突变的发生的比值比为1.46（95%CI：1.64-3.69,P=0,I ²=77.3%）,而杂合子模型中,DR组与非复杂糖尿病组相比,MTHFR-C677T突变发生的差异无统计学意义（OR=1.38,95%CI：0.87-2.18,P=0.356,I ²=3.1%）。在隐性模型中,DR组与非复杂糖尿病组相比,MTHFR-C677T突变发生的比值比为1.92（95%CI：1.07-3.43,P=0.064,I ²=55%）。DR组与糖尿病对照组相比,发生MTHFR-C677T突变的差异在各模型中均无有统计学意义。
结论 MTHFR基因C677T多态性与DR存在相关性,尤其与非复杂糖尿病对照组相比。今后需要进一步的研究以明确这种关系。

关键词: 亚甲基四氢叶酸还原酶基因C677T, 多态性, 糖尿病视网膜病变, 荟萃分析

Abstract:

Objective To investigate the association between the methylenetetrahydrofolate reductase gene C677T (MTHFR C677T) polymorphism and diabetic retinopathy (DR).
Methods A total of 6971 subjects including 2707 DR patients and 4264 controls from 23 studies were enrolled in the study. A random-effects model was applied to estimate the overall effects and the stratified effects of the MTHFR C677T polymorphism on the risk of DR, and study quality was also assessed.
Results Strong associations were observed between the MTHFR C677T polymorphism and DR. The carries of MTHFR C677T were more likely to be found in the DR group in relative to the healthy control group with odds ratio 1.68, 2.55, and 2.31 respectively in allele contrast model (T vs. C, 95%CI: 1.29-2.18, P<0.001, I ²=78.4%), homozygous model (TT vs. CC, 95%CI: 1.70-3.83, P=0.008, I ²=54.4%) and dominant model (TT+CT vs. CC, 95%CI: 1.62-3.29, P<0.001, I ²=74.7%). This association can also be found in contrast to the Ncd (non-complicated diabetic mellitus) group (allele contrast, OR=1.50, 95%CI: 1.07-2.11, P=0.032, I ²=62.1%; homozygous, OR=2.39, 95%CI: 1.06-5.38, P=0.017, I ²=66.7%; dominant, OR=1.59, 95%CI: 0.97-2.62, P=0.056, I ²=56.5%). For the heterozygous model (CT vs. CC), the association was significant in contrast to the healthy control group (OR=1.46, 95%CI: 1.64-3.69, P=0, I ²=77.3%), while in contrast to the Ncd control group the association was not statistically meaningful (OR=1.38, 95%CI: 0.87-2.18, P=0.131, I ²=43.7%). For the recessive model, 1.92-fold increased risk was found only in contrast to the Ncd control group (95%CI: 1.07-3.43, P=0.064, I ²=55.0%). There was no significant association found in the models in contrast to the DM control group.
Conclusion In this meta-analysis, we found an association between the MTHFR C677T polymorphism and DR, especially in contrast to the Ncd control group. Further studies are required to establish more definite relationship.

Key words: methylenetrahydrofolate reductase gene C677T, polymorphism, diabetic retinopathy, meta-analysis

Shen Chang, Zhao Meng, Li Yunyun, Liu Ningpu. Methylenetrahydrofolate Reductase Gene C677T Polymorphism and Diabetic Retinopathy: a Meta-Analysis[J].Chinese Medical Sciences Journal, 2020, 35(1): 71-84.

图/表 9

References	Year of publication	Race	Case					Control
References	Year of publication	Race	Sample size (n)	Age (yrs)	DM duration (yrs)	Definition of case	DR diagnosis	Sample size (n)	Age (yrs)	DM^§ duration (yrs)	Defination of control	DM type	HWE^*	MAF^*	NOS	Quality assessment
Beata et al.^[12]	2017	European	64	62.8±9.7	16.97±9.2	DR with DF	ETDRS	50	65.7±9.7	17.1±9.48	DM	T2DM	0.64	0.73	5	4.5
Najiba et al.^[16]	2017	American	44	50.4±12.92 (all)	8.98±6.9	DR	NM	200	50.5±12.77	NA	healthy	T2DM	0.72	0.21	5	5
Xing et al.^[17]	2016	Chinese	76	NM	NM	DR with/without DN	OC	56	no	NA	healthy	T2DM	0.009	0.32	6	4.5
Wei et al.^[18]	2012	Chinese	61	59.3±12.7	6(median)	DR	OC	64	58.3±14.1	4(median)	Ncd	T2DM	0.254	0.258	6	4.5
Sun et al.^[19]	2014	Chinese	176	62.38±8.15	16.36±6.47	DR	DA	241	62.95±8.71	12.82±6.1	DM	T2DM	0.99	0.624	6	4.5
Guo et al.^[20]	2002	Chinese	52	54.63±12.04	4.5 (3.0-8.0)	DR	OC	28	56.57±10.75	NA	healthy	T2DM	0.39	0.375	5	4.5
Guo et al.^[20]	2002	Chinese	52	54.63±12.04	4.5 (3.0-8.0)	DR	OC	52	55.17±6.87	15(median)	Ncd	T2DM	0.43	0.45	5	4.5
Wang et al.^[21]	2001	Chinese	62	62.5±8.08	8.29±6.39	DR	OC	117	59.42±14.87	7.28±5.8	DM	T2DM	0.68	0.3	7	4
Wang et al.^[21]	2001	Chinese	62	62.5±8.08	8.29±6.39	DR	OC	85	41.83±17.1	NA	healthy	T2DM	0	0.73	7	3.5
Yang et al.^[22]	2001	Chinese	60	50.7±12.1	<5	DR	DA	102	48±8.2	>10	Ncd	T2DM	0.17	0.41	6	4
Yang et al.^[22]	2001	Chinese	60	50.7±12.1	<5	DR	DA	62	52.6±14.9	NA	healthy	T2DM	0.91	0.35	6	5
Sun et al.^[23]	2003	Chinese	110	55.6±6.7	<5	DR	OC	98	54.7±7.1	>10	DM	T2DM	0	0.33	7	4
Sun et al.^[23]	2003	Chinese	110	55.6±6.7	<5	DR	OC	57	42.3±6.1	NA	healthy	T2DM	0	0.31	7	4.5
Huang et al.^[24]	2005	Chinese	50	NM	NM	DR (72% with DN)	OC	47	no	NA	healthy	T2DM	0.96	0.25	5	4.5
Yi et al.^[25]	2005	Chinese	245	56.53±10.45	5.9±4.8	DR (27% with protein urine)	OC	65	no	NA	healthy	T2DM	0.01	0.31	4	3.5
Liu et al.^[26]	2006	Chinese	44	51.9±7.5	NM	DR	DA	84	54.0±13.2	NA	healthy	T2DM	0.01	0.25	6	4
Ren et al.^[27]	2011	Chinese	219	59.95±10.55	11(median)	DR	DA	294	58.52±12.26	7 (median)	DM	T2DM	0.23	0.41	6	4.5
Santos et al.^[28]	2003	American	99	58.7±12(all)	14.9 (median)	DR	OC	111	58.7±12 (all)	6.6 (median)	DM	T2DM	0.98	0.39	5	5
Errara et al.^[29]	2003	American	46	55.43±15.33	18±8.67	DR(NPDR81, PDR60)	OC	106	66.11±7.06	NA	healthy	T1DM	0.24	0.39	4	5.5
Errara et al.^[29]	2003	American	95	55.43±15.33	18±8.67	DR(NPDR81, PDR60)	OC	106	66.11±7.06	NA	healthy	T2DM	0.24	0.39	4	6.5
Maeda et al.^[30]	2008	Japanese	75	NM	NM	DR	OC	115	NM	NM	DM	T2DM	0.06	0.35	5	4
Yigit et al.^[31]	2013	West Asian	230	57.15±10.58	7.73±6.006	DPN(81DR+DN, 129DN)	ETDRS	282	55.55±8.14	NA	healthy	T1DM+T2DM	0.46	0.19	6	6
Yosioka et al.^[32]	2003	Japanese	98	60 (median)	11.7 (median)	DR(52NPDR, 46PDR)	NM	268	60	11.7	Ncd	T2DM	0.46	0.38	4	4
Maeda et al.^[33]	2003	Japanese	51	NM	NM	DR(33NPDR)	OC	105	NM	NM	Ncd	T2DM	0.06	0.37	4	4
Neugebauer et al.^[34]	1998	Japanese	67	57-61	14-16	DR with DN	NM	146	39-43	NA	healthy	T2DM	0.003	0.26	6	4
Lauszus et al.^[35]	2001	European	112	NM	NM	DR(T1DM pregnant)	OC	1084	NA	NA	healthy	T2DM	0.53	0.29	4	6
Ukinc et al.^[36]	2009	West Asian	25	52.7±9.9 (all)	7.6±6.2 (all)	DR	OC	27	52.7±9.9 (all)	7.6±6.2 (all)	DM	T1DM	0.09	0.24	4	2.5
Liu et al.^#	2017	Chinese	262	66.69±8.28	14.40±6.51	DR(18.1% with microalbuminuria)	ETDRS	212	65.37±7.46	14.32±6.11	DM	T2DM	0.34	0.57	8	8

Groups		Genetic models	No. of studies (All/Sensitivity)	OR(95%CI)	P	I²(%)	OR_se(95%CI)	P_se	I²_se(%)
Healthy control	Asian	Allele (T vs. C)	9/7	1.93 (1.43-2.61)	0.001	69.2	2.18 (1.79-2.65)	0.701	0
		Heterozygous (CT vs. CC)	9/7	3.22 (2.30-4.51)	0.163	31.9	2.80 (2.05-3.83)	0.630	0
		Homozygous (TT vs. CC)	9/7	3.09 (2.08-4.60)	0.170	31.1	3.55 (2.38-5.29)	0.405	2.7
		Dominant model (TT+CT vs. CC)	9/7	2.90 (2.27-3.70)	0.598	0	2.96 (2.22-3.94)	0.448	0
		Recessive model (TT vs. CT+CC)	9/7	1.68 (0.96-2.95)	0	74.1	2.08 (1.47-2.96)	0.782	0
	Non-Asian	Allele (T vs. C)	5/4	1.32 (0.83-2.09)	0	84.4	1.36 (0.72-2.58)	0	88.0
		Heterozygous (CT vs. CC)	5/4	1.53 (0.77-3.06)	0	85.4	1.58 (0.58-4.29)	0	89.0
		Homozygous (TT vs. CC)	5/4	1.60 (0.67-3.83)	0.015	67.8	1.80 (0.56-5.83)	0.014	71.9
		Dominant model (TT+CT vs. CC)	5/4	1.54 (0.78-3.04)	0	85.9	1.61 (0.61-4.29)	0	89.5
		Recessive model (TT vs. CT+CC)	5/4	1.13 (0.43-2.91)	0.003	74.9	1.16 (0.31-4.34)	0.002	79.7
DM control	Asian	Allele (T vs. C)	7/5	1.49 (0.98-2.26)	0	88.9	1.30 (0.89-1.90)	0	85.7
		Heterozygous (CT vs. CC)	7/5	1.38 (0.84-2.28)	0	75.9	1.25 (0.73-2.14)	0.001	77.5
		Homozygous (TT vs. CC)	7/5	2.39 (1.05-5.45)	0	88.5	1.70 (0.84-3.44)	0	83.4
		Dominant model (TT+CT vs. CC)	7/5	1.58 (0.90-2.78)	0	83.7	1.36 (0.77-2.39)	0	82.5
		Recessive model (TT vs. CT+CC)	7/5	1.85 (1.03-3.31)	0	85.6	1.44 (0.88-2.35)	0.001	77.8
	Non-Asian	Allele (T vs. C)	2/2	0.91 (0.66-1.26)	0.455	0	?	?	?
		Heterozygous (CT vs. CC)	2/2	1.12 (0.65-1.95)	0.523	0	?	?	?
		Homozygous (TT vs. CC)	2/2	0.76 (0.36-1.60)	0.602	0	?	?	?
		Dominant model (TT+CT vs. CC)	2/2	1.03 (0.61-1.75)	0.45	0	?	?	?
		Recessive model (TT vs. CT+CC)	2/2	0.74 (0.43-1.37)	0.913	0	?	?	?
DM control	T2DM	Allele (T vs. C)	8/7	1.37 (0.94-1.98)	0	88.1	1.18 (0.87-1.60)	0	80.9
		Heterozygous (CT vs. CC)	8/7	1.36 (0.88-2.11)	0.001	72.0	1.20 (0.79-1.82)	0.005	67.2
		Homozygous (TT vs. CC)	8/7	1.83 (0.91-3.69)	0	85.6	1.39 (0.77-2.52)	0	78.0
		Dominant model (TT+CT vs. CC)	8/7	1.49 (0.90-2.47)	0	81.6	1.25 (0.80-1.96)	0	75.3
		Recessive model (TT vs. CT+CC)	8/7	1.49 (0.91-2.44)	0	82.3	1.22 (0.82-1.83)	0.002	71.6
Healthy control	T2DM	Allele (T vs. C)	11/9	1.81 (1.31-2.49)	0	78.8	1.97 (1.43-2.71)	0	72.3
		Heterozygous (CT vs. CC)	11/9	2.82 (1.78-4.48)	0	78.5	2.67 (1.52-4.70)	0	77.3
		Homozygous (TT vs. CC)	11/9	2.70 (1.78-4.09)	0.065	42.8	2.97 (1.83-4.80)	0.096	40.7
		Dominant model (TT+CT vs. CC)	11/9	2.75 (1.77-4.27)	0	74.6	2.82 (1.63-4.89)	0	79.2
		Recessive model (TT vs. CT+CC)	11/9	1.48 (0.89-1.51)	0	70.3	1.78 (1.25-2.52)	0.323	13.3

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40.	Stewart LA, Clarke M, Rovers M , et al. Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data: the PRISMA-IPD Statement. JAMA 2015; 313(16):1657-65. doi: 10.1001/jama.2015.3656.
41.	Luo S, Wang F, Shi C , et al. A meta-analysis of association between methylenetetrahydrofolate reductase gene (MTHFR) 677C/T polymorphism and diabetic retinopathy. Int J Environ Res Public Health 2016; 13(8):806-21. doi: 10.3390/ijerph13080806.
42.	Chen D, Wang J, Dan Z , et al. The relationship between methylenetetrahydrofolate reductase C677T polymorphism and diabetic retinopathy: a meta-analysis in multiethnic groups. Ophthalmic Genet 2018; 39(2):200-7. doi: 10.1080/13816810.2017.1401087.

Criteria	Score
Representativeness of cases
DR diagnosed according to ETDRS	2
DR diagnosed according to other DR criteria	1.5
DR diagnosed according to doctors’ assessments	1
Not mentioned	0
Source of controls
Population or community based	3
Hospital-based DM-free controls	2
DR-free DM patients without other complications	1
DR-free DM patients with other complications	0.5
Not described	1
Sample size (n)
>200	2
100-200	1
<100	0
Quality control of genotyping methods
Repetition of partial/total tested samples with a different method	2
Repetition of partial/total tested samples with the same method	1
Not described	0
Hardy-Weinberg equilibrium
Hardy-Weinberg equilibrium in control subjects	1
Hardy-Weinberg disequilibrium in control subjects	0
Quality scores	10

Clinical characteristics	Ncd group (n=212)	DR group (n=262)	P value
Age of diabetic onset (yrs)	53.12±7.68	50.75±9.09	0.001
Sex (Male/Female, n)	85/127	121/141	0.184
Duration of diabetes (yrs)	14.67±4.73	13.96±7.25	0.203
BMI (kg/m²)	25.18±3.97	25.58±3.94	0.275
WHR	0.92±0.06	0.93±0.06	0.295
High albuminuria (-/+, n)	181/28	188/69	<0.001
Systolic blood pressure (mm Hg)	136.96±1.46	137.92±17.14	0.539
Diastolic blood pressure (mm Hg)	77.82±9.51	78.91±9.43	0.211
Insulin therapy (yes/no, n)	65/147	136/125	<0.001
HbA1c (%)	6.96±1.32	7.62±1.73	<0.001
FPG (mmol/L)	8.02±2.31	8.89±3.06	0.001
Creatinine (µmol/L)	67.81±17.93	73.56±47.56	0.096
Uric acid (µmol/L)	281.72±79.24	279.40±76.15	0.844
Cholesterol (mmol/L)	5.07±0.97	5.13±1.13	0.728
Triglycerides (mmol/L)	1.58±0.99	1.63±1.34	0.682
HDLC (mmol/L)	1.23±0.29	1.23±0.30	0.988
LDLC (mmol/L)	3.08±0.83	3.07±0.90	0.682

Groups	Genetic models	No. of studies (All/Sensitivity)	OR (95%CI)	P	I²(%)	OR_se(95%CI)	P_se	I²_se(%)
Overall	Allele (T vs. C)	28/21	1.52 (1.27-1.83)	0	80.2	1.46 (1.18-1.82)	0	81.8
	Heterozygous (CT vs. CC)	28/21	1.81 (1.40-2.35)	0	73.5	1.49 (1.12-1.97)	0	70.1
	Homozygous (TT vs. CC)	27/20	2.27 (1.62-3.18)	0	72.3	2.21 (1.41-3.48)	0	78.2
	Dominant model (TT+CT vs. CC)	28/21	1.86 (1.45-2.39)	0	75.0	1.65 (1.22-2.24)	0	77.2
	Recessive model (TT vs. CT+CC)	27/20	1.55 (1.16-2.07)	0	73.7	1.65 (1.17-2.32)	0	74.5
Healthy control	Allele (T vs. C)	14/11	1.68 (1.29-2.18)	0	78.4	1.84 (1.38-2.46)	0	73.9
	Heterozygous (CT vs. CC)	14/11	2.46 (1.64-3.69)	0	77.3	2.27 (1.42-3.63)	0	75.8
	Homozygous (TT vs. CC)	14/11	2.55 (1.70-3.83)	0.008	54.4	3.02 (1.90-4.80)	0.036	48.3
	Dominant model (TT+CT vs. CC)	14/11	2.31 (1.62-3.29)	0	74.7	2.43 (1.53-3.84)	0	78.0
	Recessive model (TT vs. CT+CC)	14/11	1.49 (0.94-2.37)	0	72.3	1.87 (1.23-2.83)	0.042	47.1
Ncd control	Allele (T vs. C)	5/3	1.50 (1.07-2.11)	0.032	62.1	1.76 (1.03-3.03)	0.041	68.7
	Heterozygous (CT vs. CC)	5/3	1.38 (0.87-2.18)	0.131	43.7	1.95 (1.16-3.28)	0.356	3.1
	Homozygous (TT vs. CC)	5/3	2.39 (1.06-5.38)	0.017	66.7	2.47 (1.05-5.84)	0.069	62.6
	Dominant model (TT+CT vs. CC)	5/3	1.59 (0.97-2.62)	0.056	56.5	2.33 (1.03-5.28)	0.071	62.2
	Recessive model (TT vs. CT+CC)	5/3	1.92 (1.07-3.43)	0.064	55.0	1.93 (0.79-4.69)	0.042	47.1
DM control	Allele (T vs. C)	9/7	1.32 (0.93-1.88)	0	86.6	1.17 (0.83-1.66)	0	84.1
	Heterozygous (CT vs. CC)	9/7	1.31 (0.87-1.97)	0.001	68.7	1.20 (0.79-1.82)	0.005	67.2
	Homozygous (TT vs. CC)	9/7	1.83 (0.91-3.69)	0	85.6	1.39 (0.77-2.52)	0	78.0
	Dominant model (TT+CT vs. CC)	9/7	1.42 (0.89-2.28)	0	79.4	1.25 (0.80-1.96)	0	75.3
	Recessive model (TT vs. CT+CC)	9/7	1.49 (0.91-2.44)	0	82.3	1.22 (0.82-1.83)	0.002	71.6

Genetic models	Begg’s adjusted rank correlation test (P value)	Egger’s regression asymmetry test (P value)
Allele	0.221	0.089
CT vs. CC	0.048	0.031
TT vs. CC	0.288	0.142
Dominant model	0.048	0.056
Recessive model	0.327	0.177

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