Lack of association between MTHFR A1298C variant and Alzheimer’s disease: evidence from a systematic review and cumulative meta-analysis

Figures & data

Figure 1. Flow diagram of the process used to select eligible studies.

Table 1. The baseline characteristics of all the included studies in this meta-analysis.

	Year	Area	Ethnicity	No. of cases	No. of controls	Cases			Controls			Source of control	HWE (Control)	Genotyping method	Diagnosis criteria
First author						AA	AC	CC	AA	AC	CC		P
Wakutani	2002	Japan	Asian	241	352	174	51	16	210	127	15	NA	0.538	LA-PCR	NA
Bosco	2004	Italy	Caucasian	152	136	69	67	16	59	61	16	PB	1	PCR-RFLP	CERAD
Ravaglia	2004	Italy	Caucasian	48	122	26	18	4	52	63	7	PB	0.037	PCR-RFLP	NINCDS-ADRDA
Linnebank	2004	German	Caucasian	162	169	75	68	19	71	71	27	PB	0.191	PCR-RFLP	DSM-IV
Anello	2004	Italy	Caucasian	180	180	83	78	19	82	79	19	PB	1	PCR-RFLP	CERAD
Silva	2006	Brazil	Mixed	43	50	21	21	1	27	22	1	PB	0.249	PCR-RFLP	NINCDS-ADRDA
Dorszewska	2007	Polan	Caucasian	38	50	13	18	7	21	23	6	PB	1	PCR-RFLP	NINCDS-ADRDA
Giedraitis	2009	Sweden	Caucasian	85	400	32	41	12	176	180	44	PB	0.911	NA	NINCDS-ADRDA&DSM-IV
Mansouri	2012	India	Asian	80	120	20	41	19	44	59	17	HB	0.847	NA	NINCDS-ADRDA&NINDS-AIREN
Mansouri	2013	Tunisia	Caucasian	38	100	15	23	0	93	7	0	PB	1	PCR-RFLP	NINCDS-ADRDA

Note: NA: not available, PB: population-based, HB: hospital-based.

Table 2. Quality assessment scheme for included studies (Newcastle–Ottawa Scale).

Literatures	Selection				Comparability	Exposure			Total
	I	II	III	IV	V	VI	VII	VIII
Mansouri (2013)	*	*	*	*	*		*	*	*******
Mansouri (2012)	*	*		*	*		*	*	*******
Giedraitis (2009)	*	*	*	*	*		*	*	*******
Dorszewska (2007)	*	*		*	*		*	*	******
Silva (2006)	*	*	*	*	*		*	*	*******
Bosco (2004)	*	*		*	*	*	*	*	*******
Ravaglia (2004)	*	*		*	*		*	*	******
Linnebank (2004)	*	*	*	*	**		*	*	********
Anello (2004)	*	*	*	*	*	*	*	*	********
Wakutani (2002)	*	*		*	*		*	*	******

Notes: I: Is the case definition adequate?, II: Representativeness of the cases, III: Selection of Controls, IV: Definition of Controls, V: Comparability of cases and controls on the basis of the design or analysis, VI: Ascertainment of exposure, VII: Same method of ascertainment for cases and controls, VIII: Non-Response rate.

Figure 2. Forest plots of MTHFR A1298C polymorphism and the risk of Alzheimer’s disease in five genetic models: A: the allelic model (C vs. A), B: the homozygous model (CC vs. AA), C: the heterozygous model (CA vs. AA), D: the dominant model (CC + CA vs. AA), E: the recessive model (CC vs. CA + AA), and F: the allelic model (C vs. A) in cumulative meta-analysis by publication year.

Figure 3. Funnel plot for the allelic model (C vs. A) to analyze publication bias between MTHFR A1298C polymorphism and AD risk.

Notes: Studies: included studies in this meta-analysis, 5 and 10%: contour lines aiding the interpretation of the funnel plot, Filled: filled estimated studies using the trim and fill method, F.E.: the combined effect with estimated studies not filled. and F.E.Filled: the combined effect with estimated studies filled.

Table 3. Meta-analysis of the association between MTHFR A1298C polymorphism and the risk of AD.

Genetic comparisons	I^2 (%)	Effect model	OR (95% CI)	POR	Egger’s test (t, P)
C vs. A	79.0	Random	1.17 (0.88–1.56)	0.27	2.46, 0.04
CC vs. AA	0	Fixed	1.15 (0.87–1.53)	0.33	0.67, 0.53
CA vs. AA	83.2	Random	1.19 (0.76–1.86)	0.44	1.91, 0.09
CC + CA vs. AA	82.6	Random	1.23 (0.81–1.87)	0.33	2.00, 0.08
CC vs. CA + AA	0	Fixed	1.16 (0.89–1.52)	0.26	0.65, 0.53