Interleukin-18 genetic polymorphisms contribute differentially to the susceptibility to Crohn’s disease

Table 1 Main characteristics and methodological quality of all eligible studies of the relationship between interleukin-18 genetic polymorphisms and the risk of developing Crohn’s disease

Ref.	Year	Country	Ethnicity	Number		Gender (M/F)		Age (yr)		Genotyping method	SNP type	HWE test (Pvalue)	NOS score
				CD	Control	CD	Control	CD	Control
Ben Aleya et al[21]	2011	Tunisia	African	105	100	50/55	52/48	23-60	-	PCR-SSP	rs1946518 A>C	0.051	6
											rs187238 G>C	0.284
Dema et al[27]	2009	Spain	Caucasian	722	794	274/448	-	-	-	TaqMan	rs917997 C>T	0.609	5
Haas et al[29]	2005	Germany	Caucasian	470	347	139/331	122/225	-	-	TaqMan	rs187238 G>C	0.637	6
Glas et al[28]	2005	Germany	Caucasian	210	265	83/127	141/124	39.1 ± 13.6	43.2 ± 12.5	PCR-RFLP	rs1946518 A>C	0.592	8
											rs187238 G>C	0.123
											codon 35 A>C	0.774
Tamura et al[31]	2008	Japan	Asian	134	110	102/32	55/55	15-65	15-75	Direct sequencing	codon 35 A>C	0.606	8
Takagawa et al[30]	2005	Japan	Asian	210	212	150/60	97/115	32.4 ± 9.8	38.2 ± 13.7	PCR-SSP	rs1946518 A>C	0.298	8
											rs187238 G>C	0.197
Aizawa et al[26]	2005	Japan	Asian	79	102	61/18	50/52	36.8 ± 9.2	37.6 ± 6.9	Direct sequencing	rs1946519 G>T	0.947	8
											rs1946518 A>C	0.840
											rs187238 G>C	0.586
											rs360718 A> C	0.327

M/F: Male/female; CD: Crohn’s disease; SNP: Single nucleotide polymorphism; HWE: Hardy-Weinberg Equilibrium; NOS: Newcastle-Ottawa Scale; PCR-SSP: Polymerase chain reaction-sequence-specific primers; RFLP: Restriction fragment length polymorphism.

Table 2 Meta-analysis of subgroups for the relationships between IL-18 genetic polymorphisms and Crohn’s disease risk

	W allele vs M allele (Allele model)			WW + WM vs MM (Dominant model)			WW vs WM + MM (Recessive model)			WW vs MM (Homozygous model)			WW vs WM (Heterozygous model)
	OR	95%CI	Pvalue	OR	95%CI	Pvalue	OR	95%CI	Pvalue	OR	95%CI	Pvalue	OR	95%CI	Pvalue
SNP type
rs1946518 A>C	1.45	1.22-1.72	0.000	1.62	1.22-2.14	0.001	1.59	1.26-2.01	0.000	1.98	1.45-2.72	0.000	1.43	1.12-1.84	0.005
rs187238 G>C	1.69	1.39-2.06	0.000	2.04	1.48-2.81	0.000	1.81	1.42-2.31	0.000	2.53	1.82-3.52	0.000	1.66	1.29-2.13	0.000
rs360718 A>C	2.03	1.20-3.43	0.008	2.33	0.46-11.88	0.308	2.39	1.29-4.43	0.006	3.17	0.61-16.40	0.169	2.31	1.22-4.38	0.010
rs917997 C>T	0.91	0.77-1.06	0.229	0.80	0.55-1.18	0.267	0.91	0.74-1.11	0.349	0.78	0.52-1.16	0.220	0.93	0.76-1.15	0.525
codon 35 A>C	1.15	0.91-1.45	0.256	1.30	0.75-2.26	0.355	1.15	0.85-1.55	0.360	1.41	0.79-2.52	0.250	1.11	0.81-1.52	0.523
rs1946519 G>T	1.14	0.74-1.77	0.545	1.24	0.51-3.03	0.641	1.17	0.64-2.13	0.604	1.32	0.51-3.43	0.566	1.13	0.60-2.13	0.697
Ethnicity
Asians	1.54	1.28-1.85	0.000	1.81	1.29-2.53	0.001	1.65	1.28-2.12	0.000	2.25	1.56-3.24	0.000	1.54	1.18-2.00	0.001
Africans	1.99	1.42-2.79	0.000	2.69	1.55-4.67	0.000	2.11	1.38-3.22	0.001	3.55	1.67-7.53	0.001	1.66	1.07-2.59	0.025
Caucasians	1.23	0.97-1.54	0.083	1.27	0.92-1.77	0.148	1.29	0.97-1.73	0.079	1.44	0.94-2.22	0.096	1.25	0.97-1.61	0.086
Genotyping method
PCR-SSP	1.67	1.35-2.07	0.000	1.91	1.37-2.67	0.000	1.84	1.45-2.34	0.000	2.35	1.55-3.56	0.000	1.67	1.30-2.15	0.000
TaqMan	1.20	0.69-2.10	0.521	1.17	0.55-2.53	0.681	1.29	0.64-2.58	0.479	1.32	0.46-3.80	0.603	1.27	0.68-2.36	0.450
PCR-RFLP	1.25	1.07-1.46	0.005	1.36	1.00-1.85	0.053	1.31	1.06-1.63	0.013	1.55	1.11-2.16	0.011	1.25	0.99-1.56	0.059
Direct sequencing	1.56	1.16-2.11	0.003	2.46	1.37-4.43	0.003	1.61	1.08-2.42	0.021	3.21	1.72-5.99	0.000	1.46	0.98-2.18	0.061
Sample size
Small sample-size (n ≤ 200)	1.61	1.29-2.01	0.000	2.29	1.60-3.27	0.000	1.66	1.25-2.20	0.001	2.85	1.93-4.20	0.000	1.46	1.12-1.90	0.005
Large sample-size (n > 200)	1.33	1.08-1.63	0.007	1.33	1.02-1.74	0.038	1.44	1.11-1.86	0.007	1.54	1.07-2.21	0.019	1.38	1.08-1.76	0.009

W: Wild-type allele; M: Mutant allele; WW: Wild-type homozygote; WM: Heterozygote; MM: Mutant homozygote; OR: Odds ratio; SNP: Single nucleotide polymorphism.

Table 3 Univariate and multivariate meta-regression analyses of potential sources of heterogeneity

Heterogeneity factors	Coefficient	SE	Z	Pvalue	95%CI
					LL	UL
Publication year
Univariate	0.004	0.036	0.12	0.908	-0.066	0.075
Multivariate	-0.052	0.038	-1.39	0.166	-0.126	0.022
SNP type
Univariate	-0.188	0.084	-2.25	0.025	-0.353	-0.024
Multivariate	-0.077	0.091	-0.84	0.398	-0.256	0.102
Ethnicity
Univariate	0.241	0.095	2.55	0.011	0.056	0.427
Multivariate	0.476	0.250	1.90	0.057	-0.014	0.967
Genotyping method
Univariate	-0.082	0.066	-1.25	0.211	-0.211	0.047
Multivariate	0.075	0.082	0.92	0.360	-0.085	0.235
Sample size
Univariate	0.194	0.148	1.31	0.190	-0.096	0.485
Multivariate	-0.216	0.244	-0.89	0.376	-0.696	0.263

SE: Standard error; SNP: Single nucleotide polymorphism; UL: Upper limit; LL: Lower limit.