Association of Megsin 2093C/T, 2180C/T and C25663G gene polymorphism with the risk of IgA nephropathy

Abstract

The association between megsin 2093C/T, 2180C/T and C25663G gene polymorphisms and IgA nephropathy (IgAN) risk remains unclear. We aimed to evaluate the association between megsin 2093C/T, 2180C/T and C25663G gene polymorphisms and IgAN risk by performing a meta-analysis. Eligible studies were searched according to predefined criteria by using electronic databases. Six articles were identified for the analysis of the association between megsin 2093C/T, 2180C/T and C25663G gene polymorphisms and IgAN risk. 2093C/T C allele was associated with IgAN risk in overall populations and Asians (overall populations: p = 0.014, Asians: p = 0.037). 2093C/T CC/TT genotype was not associated with IgAN risk in overall populations, Caucasians and Asians. 2180C/T C allele was correlated with IgAN risk in Caucasians (p = 0.024). 2180C/T CC/TT genotype was not associated with IgAN risk in overall populations, Caucasians and Asians. C25663G gene polymorphism was not associated with IgAN onset in Asians. In conclusion, megsin 2093C/T C allele may be genetic marker for IgAN susceptibility in overall populations and Asians. 2180C/T C allele may be risk factor for IgAN onset in Caucasians. However, more studies should be performed in the future.

• 2093C/T
• 2180C/T
• C25663G
• gene polymorphisms
• IgA nephropathy
• meta-analysis

Introduction

IgA nephropathy (IgAN), one of the most common forms of glomerulonephritis (GN), is characterized by an IgA deposits in the glomerular mesangial area.1 IgAN is responsible for approximately 20% of the patients reaching end-stage renal diseases (ESRD).2 Furthermore, IgAN has a variable clinical course,3 poor prognostic factors include hypertension, severe proteinuria, and histological appearance of the renal biopsy specimen.4 To date, the mechanism of IgAN is still unclear. Genetic factors might be associated with the risk of IgAN and might predict its onset.5,6 Finding genes that influence the onset or progression of IgAN is of particular importance.

Megsin appears to be a reasonable candidate for the onset of IgAN. Megsin belongs to the serpin family and is expressed in renal mesangial cells.7 Megsin was found to be upregulated in the glomeruli of patients with IgAN and diabetic nephropathy.7 Megsin plays a role in the regulation of coagulation, fibrinolysis, matrix turnover, and inflammation.8 In this sense, it is reasonable to postulate that megsin is involved in the pathogenesis of IgAN. It was reported that 2093C/T, 2180C/T and C25663G gene polymorphisms were associated with the risk of IgAN. However, the results were inconsistent among reported studies.3,7,9–12 An improved understanding of this issue may have important clinical implications provided the possibility that the megsin gene polymorphism may be genetic markers for the onset of IgAN.

Meta-analysis of the association between megsin gene polymorphisms and IgAN risk was rare. Thus, we conducted this meta-analysis to investigate the correlation between megsin 2093C/T, 2180C/T and C25663G gene polymorphisms and IgAN susceptibility with the aim of providing a much more reliable finding on the significance of the association.

Materials and methods

Search strategy

Published papers regarding the association between megsin gene polymorphisms and the risk of IgAN were searched through September 2013 by using Pubmed, Embase, Cochrane and China WanFang databases. No restriction was imposed on search language. The used search terms were as follows: (1) IgAN, immunoglobulin A nephropathy; (2) megsin, 2093C/T, 2180C/T, C25663G, gene polymorphism. We also reviewed the reference lists of extracted articles and reviews. If the same participants were enrolled in more than one study we chose the study with the most complete analysis.

Inclusion and exclusion criteria

Inclusion criteria

(1) A case–control study; (2) the outcome of interest was IgAN; (3) at least two comparison groups (IgAN group vs. control group).

Exclusion criteria

(1) Case reports, reviews and editorials; (2) association of other genes with IgAN risk; (3) multiple publications of the same data; and (4) investigation of the role of megsin to diseases.

Data extraction and synthesis

We extracted study characteristics from each study. Data were recorded as follows: first author’s last name, year of publication, ethnicity of study population, number of cases and controls for megsin genotype. Frequencies of C allele were calculated for case and control groups from the corresponding genotype distribution. Two authors independently performed the data extraction with any disagreements resolved by discussion.

Statistical analysis

Odds ratio (OR) was used to measure the association between megsin gene polymorphisms and IgAN risk across studies. Heterogeneity of ORs among studies was tested by using the Q statistic (significance level at p < 0.05). The I² statistic, a quantitative measure of inconsistency across studies, was also calculated. The combined ORs were calculated using either a fixed-effects model or, in the presence of heterogeneity, a random-effects model. Furthermore, 95% confidence intervals (CIs) were also calculated. The OR was calculated by using three methods: method 1, allele comparison (C allele vs. T/G allele); method 2, comparing CC homozygous with the other two combinations (CC vs. CT/CG + TT/GG); and method 3, comparing TT/GG genotype with the other two combinations (TT/GG vs. CT/CG + CC). A chi-square test using a web-based program was used to determine whether genotype distribution of the control population reported conformed to Hardy–Weinberg equilibrium (HWE) (HWE; p < 0.05 was considered significant). Potential publication bias was assessed by Begg’s test and Egger’s test at the p < 0.05 level of significance when the number of the included studies was more than 3. All analyses were performed using STATA version 12.0 (Stata Corp, College Station, TX). p < 0.05 was considered statistically significant, except where otherwise specified.

Results

Study characteristics

We initially extracted 112 publications from PubMed, Embase, Cochrane, and China WanFang databases. Of these, 106 publications were excluded according to the inclusion and exclusion criteria. Six papers3,7,9–12 were included in our analysis for the association between megsin gene polymorphisms and IgAN risk (Figure 1). All papers were published in English.

Figure 1. Flow chart of study selection.

Study characteristics for 2093C/T polymorphism with IgAN risk

Four studies3,7,9,10 were identified for the analysis of the association between 2093C/T polymorphism and IgAN risk (Table 1). Two studies3,7 were performed in Caucasians, and two9,10 in Asians. A total of 990 cases and 678 controls were included. The average frequency of the C allele was 50.2% in Caucasians patients and 47.2% in controls. For Asians, the average frequency of C allele was 69.3% in the case group and 64.9% for controls. The ratio of cases/controls for average frequency of C allele in Caucasians was a little lower compared with that in Asians (Caucasians: cases/controls = 1.06; Asians: cases/controls = 1.07).

Table 1. Characteristics of studies evaluating the effects of megsin gene polymorphisms on IgAN risk.

		IgAN				Controls				C allele (%)		HWE
Author, year	Ethnicity	CC	CT	TT	Total	CC	CT	TT	Total	Case	Control	p
2093C/T
Szelestei et al.	Caucasian	31	59	20	110	26	46	29	101	55	48.5	0.675
Li et al.	Asian	—	—	—	423	—	—	—	201	70.7	62.9	—
Maixnerov et al.	Caucasian	46	95	56	197	10	35	16	61	47.5	45.1	0.464
Lim et al.	Asian	121	106	33	260	137	143	35	315	66.9	66.2	0.968
2180C/T
Maixnerov et al.	Caucasian	52	92	53	197	17	33	11	61	49.7	54.9	0.770
Lim et al.	Asian	30	107	123	260	33	147	135	315	32.1	33.8	0.751
C25663G(C/G)
Xia et al.	Asian	277	169 25		471	108	72	17	197	76.8	73.1	0.611
Li et al.	Asian	28	12	4	44	46	36	18	100	77.3	64	0.091

HWE, Hardy–Weinberg equilibrium; IgAN, IgA nephropathy.

Study characteristics for 2180C/T polymorphism with IgAN risk

Two studies3,10 were enrolled for the analysis of the association between 2180C/T polymorphism and IgAN risk (Table 1). One study3 was performed in Caucasians, and one10 in Asians. A total of 457 cases and 376 controls were included. The average frequency of the C allele was 49.7% in Caucasians patients and 54.9% in controls. For Asians, the average frequency of C allele was 32.1% in the case group and 33.8% for controls. The ratio of cases/controls for average frequency of C allele in Caucasians was lower compared with that in Asians (Caucasians: cases/controls = 0.91; Asians: cases/controls = 0.95).

Study characteristics for C25663G polymorphism with IgAN risk

Two studies11,12 in Asians were identified for the analysis of the association between C25663G polymorphism and IgAN risk (Table 1). A total of 515 cases and 297 controls were included. The average frequency of the C allele was 76.8% in patients and 70% in controls.

Association of the 2093C/T polymorphism with IgAN risk

C allele was associated with the susceptibility of IgAN in overall populations and Asians (Figure 2; Table 2). No marked association between C allele and IgAN risk was observed in Caucasians (Table 2). Meanwhile, the CC/TT genotype was not associated with IgAN risk in overall populations, Caucasians and Asians (Table 2).

Figure 2. Association between 2093C/T C allele and IgAN risk.

Table 2. Meta-analysis of the association of megsin gene polymorphisms with IgAN risk.

Study	Ethnicity	Studies	Q test	Model selected	OR (95% CI)	p-Value
			p-Value
2093C/T
C versus T	Overall	4	0.324	Fixed	1.205(1.038–1.398)	0.014
	Caucasian	2	0.565	Fixed	1.201(0.908–1.587)	0.199
	Asian	2	0.076	Fixed	1.206(1.011–1.438)	0.037
CC versus (CT + TT)	Overall	3	0.888	Fixed	1.030(0.740–1.433)	0.861
	Caucasian	2	0.511	Fixed	0.969(0.632–1.486)	0.886
	Asian	1	0.790	Fixed	1.128(0.670–1.898)	0.652
TT versus (CT + CC)	Overall	3	0.990	Fixed	1.032(0.877–1.216)	0.703
	Caucasian	2	0.731	Fixed	1.009(0.591–1.721)	0.975
	Asian	1	0.945	Fixed	1.035(0.871–1.229)	0.697
2180C/T
C versus T	Overall	2	0.024	Random	1.199(0.686–2.095)	0.525
	Caucasian	1	—	Fixed	1.642(1.067–2.527)	0.024
	Asian	1	—	Fixed	0.926(0.723–1.186)	0.543
CC versus (CT + TT)	Overall	2	0.715	Fixed	0.950(0.752–1.200)	0.867
	Caucasian	1	—	Fixed	0.947(0.510–1.758)	0.863
	Asian	1	—	Fixed	1.101(0.654–1.854)	0.716
TT versus (CT + CC)	Overall	2	0.442	Fixed	1.157(0.883–1.5177)	0.290
	Caucasian	1	—	Fixed	1.492(0.733–3.035)	0.269
	Asian	1	—	Fixed	1.104(0.822–1.482)	0.511
C25663G
C versus G	Asian	2	0.521	Fixed	1.076(0.914–1.267)	0.377
CC versus (CG + GG)	Asian	2	0.444	Fixed	1.123(0.873–1.444)	0.367
GG versus (CG + CC)	Asian	2	0.767	Fixed	0.582(0.334–1.014)	0.056

OR, odds ratio; CI, confidence interval.

Association of the 2180C/T polymorphism with IgAN risk

C allele was associated with the onset of IgAN in Caucasians (Figure 3; Table 2). Meanwhile, C allele was not correlated with the risk of IgAN in overall populations and Asians. No significant association of CC/TT genotype with IgAN risk was observed in overall populations, Caucasians, and Asians (Table 2).

Figure 3. Association between 2180C/T C allele and IgAN risk.

Association of the C25663G polymorphism with IgAN risk

No significant association between C25663G polymorphism and IgAN risk was observed in Asians (Figure 4; Table 2).

Figure 4. Association between C25663G C allele and IgAN risk.

Evaluation of publication bias

Visual inspection of funnel plot showed no obvious asymmetry (Figure 5). No significant publication bias for overall populations was observed (2093C/T C vs. T: Begg p = 0.98, Egger p = 0.95).

Figure 5. Publication bias for the analysis of association of megsin 2093C/T gene polymorphism with IgAN risk for overall populations.

Discussion

Increasing attention has been paid to the investigation of the etiology of IgAN. The confirmation of possible genetic origin of IgAN would give an insight to early diagnosis of IgAN. Several studies have found that gene polymorphism was associated with the susceptibility of IgAN and could be used as a marker to predict the onset of IgAN.13–15 To our knowledge, this is the first meta-analysis of the association between megsin gene polymorphisms and IgAN risk. In our study, we investigated whether megsin 2093C/T, 2180C/T and C25663G gene polymorphisms were associated with IgAN risk and attempted to make a more robust conclusion.

In the analysis of 2093C/T polymorphism with IgAN risk, our results showed that C allele was associated with IgAN susceptibility in overall populations. No evidence of publication bias was observed, which indicated that the result for overall populations was robust. The ethnic differences might affect the association between 2093C/T polymorphism and IgAN susceptibility. In our meta-analysis, we observed that the average frequency of C allele in controls was 47.2%, 64.9% in Caucasians and Asians, respectively. The ratio of cases/controls for average frequency of C allele was 1.06, 1.07 in Caucasians and Asians, respectively. Subgroup analysis demonstrated that C allele was associated with IgAN susceptibility in Asians, not in Caucasians. Notably, there were only two, two studies investigating the association between C allele and IgAN risk in Caucasians and Asians, respectively, which limited its statistical power. More studies should be conducted in the future.

For the analysis of 2180C/T and C25663G polymorphisms with IgAN susceptibility, we observed that C allele was associated with the risk of IgAN in Caucasian, C25663G polymorphism was not associated with IgAN onset in Asians. Due to the limited number of participants in the investigations, more studies should be performed to elucidate its role in different ethnicities.

Several factors may explain our findings. First, megsin, mesangial cell-specific gene with homology to serpin, belongs to the serpin superfamily.16 The expression of megsin is upregulated in diseases with mesangial proliferation and extracellular matrix expansion in human and in animal models.17 Second, overexpression of megsin might impair the degradation of mesangial matrix, lead to disposal of immune complexes and mesangial dysfunction.3 Megsin therefore represents a good candidate for playing a role in the pathogenesis of IgAN. Finally, the gene polymorphisms might be associated with the protein concentrations.18

In the past, several studies showed that megsin was associated with various renal diseases. Inagi et al.19 found that megsin contributed to the onset of diabetic nephropathy. Onogi et al.20 reported that megsin had a biologically relevant influence on the development of glomerular damage. Miyata et al.17 reported that overexpression of the megsin induced progressive mesangial cell proliferation and expansion. Nangaku et al.21 reported that megsin was upregulated in mesangioproliferative nephritis.

Although our study had obvious strengths that no obvious heterogeneities and publication bias were observed, several limitations should be noted in our study. First, the reporting and language bias, variable study design and different interventions might affect the results. Two, the small sample size limited the statistical power which might make the results less robust. Finally, the differences of stages of IgAN, and even interactions among different sites of megsin gene or other genes might affect the results. More in-depth analysis should be performed in the future.

In conclusion, the results of our investigation indicate that megsin 2093C/T C allele may be genetic marker for IgAN risk in overall populations and Asians. 2180C/T C allele may be risk factor for IgAN risk in Caucasian. However, more well-designed, case–control studies are needed to clarify the role of megsin gene polymorphisms in IgAN risk of different ethnicities.

Declaration of interest

There is no conflict of interest for all authors.

This study was supported by Grants from the National Basic Research Program of China 973 Program (nos. 2012CB517602 and 2013CB530604), the National Natural Science Foundation of China (nos. 81170635 and 81270785) and the Research and innovation Project for College Graduates of Jiangsu Province, China (grant number CXLX13_556).