Association of T869, C509T, G915C gene polymorphism of transforming growth factor-β1 with IgA nephropathy risk

Abstract

This meta-analysis was conducted to assess the association of transforming growth factor-β1 (TGF-β1) T869C, C509T, G915C gene polymorphism with the risk of IgA nephropathy (IgAN). The association literatures were identified from PubMed, Cochrane Library up to October 1, 2013, and eligible reports were recruited and synthesized. Five reports were recruited into this meta-analysis for the association of TGF-β1 T869C, C509T, G915C gene polymorphism with IgAN risk. In this meta-analysis, the association of TGF-β1 T869C, C509T, G915C gene polymorphism with IgAN risk was not found. In conclusion, TGF-β1 T869C, C509T, G915C gene polymorphism is not associated with the IgAN risk. However, more studies should be performed in the future to confirm this association.

• C509T
• G915C
• gene polymorphism
• IgA nephropathy
• meta-analysis
• transforming growth factor-β1
• T869C

Introduction

Immunoglobulin A nephropathy (IgAN), one of the most common varieties of primary glomerulonephritis, is characterized by predominant immunoglobulin A deposition in the mesangium, and it is initially regarded as a disease with a favorable prognosis, but data from long-term follow-up studies have revealed that IgAN may progress to end-stage renal failure in up to 30% of patients with a follow-up period of 20 years.1,2 There lacks a well-documented diagnostic approach for the IgAN risk; and the etiology of IgAN is not clear. Current evidence indicates that gene polymorphism of some genes are associated with the susceptibility of IgAN.3–5

The factor of gene polymorphism is one of the most important factors which take part in the etiology of some diseases. The evidence from meta-analysis might be powerful compared with the individual investigation. There were some interesting studies performed to assess the association of the polymorphism of some genes with the onset of some diseases. Zhou and Yin6 performed a meta-analysis to evaluate the association between endothelial nitric oxide synthase Glu298Asp gene polymorphism and end-stage renal disease (ESRD) susceptibility, and reported that T allele might become a significant genetic molecular marker for the onset of ESRD in overall populations, and in Asians. Bantis et al.7 evaluated the influence of C-344T polymorphism of aldosterone synthase gene, associated with serum aldosterone levels and the development of arterial hypertension, on IgAN, and indicated that aldosterone synthase gene C-344T polymorphism was a risk factor for accelerated progression in Caucasian patients with IgAN.

Transforming growth factor-β1 (TGF-β1), one of the most important cytokines, plays an important role in regulating cellular processes including growth, differentiation, extracellular matrix formation, and immune suppression.8,9 The TGF-β1 expression and activation are associated with the development of IgAN. The gene polymorphism can affect the activation of target gene, and the gene sites of T869C, C509T, and G915C were the important mutation points of TGF-β1. Some epidemiologic studies10–14 investigating the association of TGF-β1 T869C, C509T, G915C gene polymorphism with the risk of IgAN were conducted in the past decades. This meta-analysis was conducted to investigate whether the TGF-β1 T869C, C509T, G915C gene polymorphism was associated with the risk of IgAN, by widely collecting the reported studies.

Materials and methods

Search strategy for the association of TGF-β1 T869C, C509T, G915C gene polymorphism with the risk of IgAN

The relevant studies were searched from the electronic databases of PubMed, and Cochrane Library up to October 1, 2013. The retrieval strategy of “(IgA nephropathy OR IgA renal disease) AND (TGF-β1 OR transforming growth factor-β1) AND (polymorphism OR variant)” was entered into these databases. The additional reports were identified through references cited in recruited articles.

Inclusion and exclusion criteria

Inclusion criteria

(1) The outcome had to be IgAN; (2) there had to be at least two comparison groups (case group vs. control group); (3) investigation should provide the data of TGF-β1 T869C, C509T, G915C genotype distribution.

Exclusion criteria

(1) Review articles and editorials; (2) case reports; (3) preliminary result not on TGF-β1 T869C, C509T, G915C gene polymorphism or outcome; (4) investigating the role TGF-β1 gene expression to disease; (5) if multiple publications for the same data from the same study group occurred, we only recruited the later paper into our final analysis.

Data extraction and synthesis

The following information from each eligible study was extracted independently by two investigators: first author’s surname, year of publication, ethnicity, genotyping methods, control source of the control group and the number of cases and controls for TGF-β1 T869C, C509T, G915C genotypes. The results were compared and disagreement was resolved by discussion.

Statistical analysis

Cochrane Review Manager Version 5 (Cochrane Library, UK) was used to calculate the available data from each study. The pooled statistic was counted using the fixed effects model, but a random effects model was conducted when the p value of heterogeneity test was less than 0.1.15 Results were expressed with odds ratios (OR) for dichotomous data, and 95% confidence intervals (CI) were also calculated.16 p < 0.05 was required for the pooled OR to be statistically significant.17 I² was used to test the heterogeneity among the included studies. Sensitivity analysis was also performed according to source of the controls (healthy vs. hospital) and sample size of case (<100 vs. ≥100).

Results

Study characteristics

Five studies10–14 reporting the relationship between TGF-β1 T869C, C509T, and G915C gene polymorphism and IgAN susceptibility were included into this meta-analysis. Four investigations10,11,13,14 were conducted for the association of TGF-β1 T869C gene polymorphism with IgAN risk, five10–14 for TGF-β1 C509T gene polymorphism, and two11,14 for G915C gene polymorphism (Table 1). Those five investigations contained 820 IgAN patients and 1125 controls. The average distribution frequency of T allele of TGF-β1 T869C in IgAN group was 45.46% and the average frequency in control group was 46.01%. The average distribution frequency of T allele of TGF-β1 C509T in IgAN group was 40.48% and the average frequency in control group was 43.97%. Furthermore, the average distribution frequency of C allele of TGF-β1 G915C in IgAN group was 8.95% and the average frequency in control group was 7.11%. The average distribution frequency of case group for T allele, T allele, C allele in TGF-β1 T869C, C509T, G915C was similar to that in control group (T869C: case/control = 0.99; C509T: case/control = 1.01; G915C: case/control = 1.20).

Table 1. General characteristics of the studies included in the meta-analysis.

Author, year/Gene site	Ethnicity	Genotyping methods	Control source	Case			Controls
T869C				TT	CT	CC	TT	CT	CC
Sato 2004	Asian	PCR-RFLP	Healthy	76	167	86	65	152	80
Brezzi 2009	Caucasian	PCR-RFLP	Healthy	29	48	28	59	93	48
Vuong 2009	Caucasian	PCR-RFLP	Healthy	35	109	66	54	225	188
Lim 2005	Asian	PCR-RFLP	Healthy	4	79	25	0	52	2
C509T				TT	CT	CC	TT	CT	CC
Sato 2004	Asian	PCR-RFLP	Healthy	66	174	89	64	157	76
Brezzi 2009	Caucasian	PCR-RFLP	Healthy	23	55	27	54	95	51
Vuong 2009	Caucasian	PCR-RFLP	Healthy	17	104	88	38	185	245
Carturan 2004	Caucasian	PCR-RFLP	Healthy	11	48	36	21	45	39
Lim 2005	Asian	PCR-RFLP	Healthy	33	29	20	13	31	11
G915C				TT	CT	CC	TT	CT	CC
Brezzi 2009	Caucasian	PCR-RFLP	Healthy	0	18	87	1	25	174
Vuong 2009	Caucasian	PCR-RFLP	Healthy	5	29	175	0	71	404

Note: PCR-RFLP: polymerase chain reaction-restriction fragment length polymorphism.

Association of TGF-β1 T869C gene polymorphism with IgAN susceptibility

In this meta-analysis, we found that TGF-β1 T869C gene polymorphism was not associated with IgAN risk (T allele: OR = 1.03, 95% CI: 0.82–1.29, p = 0.79; TT: OR = 1.17, 95% CI: 0.91–1.50, p = 0.23; CC: OR = 1.09, 95% CI: 0.66–1.81, p = 0.75; Figure 1 and Table 2).

Figure 1. Association of TGF-β1 T869 gene polymorphism with IgAN susceptibility.

Table 2. Meta-analysis of the association of TGF-β1 T869C, C509T, G915C gene polymorphism with IgAN risk.

Gene sites	Studies	Q test	Model	OR	p
and comparison	number	p value	selected	(95%CI)
T869C
T versus C	4	0.07	Random	1.03 (0.82–1.29)	0.79
TT versus CT + CC	4	0.36	Fixed	1.17 (0.91–1.50)	0.23
CC versus TT +.CT	4	0.008	Random	1.09 (0.66–1.81)	0.75
C509T
T versus C	5	0.20	Fixed	1.03 (0.90–1.18)	0.68
TT versus CT + CC	5	0.12	Fixed	0.93 (0.73–1.19)	0.57
CC versus TT + CT	5	0.24	Fixed	0.90 (0.74–1.09)	0.28
G915C
C versus G	2	0.97	Fixed	1.28 (0.91–1.80)	0.16
CC versus GC + GG	2	0.09	Random	4.29 (0.11–166.63)	0.44
GG versus CC + GC	2	0.58	Fixed	0.84 (0.58–1.22)	0.36

Association of TGF-β1 C509T gene polymorphism with IgAN susceptibility

In this meta-analysis, TGF-β1 C509T gene polymorphism was not associated with IgAN risk (T allele: OR = 1.03, 95% CI: 0.90–1.18, p = 0.68; TT: OR = 0.93, 95% CI: 0.73–1.19, p = 0.57; CC: OR = 0.90, 95% CI: 0.74–1.09, p = 0.28; Figure 2 and Table 2).

Figure 2. Association of TGF-β1 C509T gene polymorphism with IgAN susceptibility.

Association of TGF-β1 G915C gene polymorphism with IgAN susceptibility

In this meta-analysis, TGF-β1 G915C gene polymorphism was not associated with IgAN risk (C allele: OR = 1.28, 95% CI: 0.91–1.80, p = 0.16; CC: OR = 4.29, 95% CI: 0.11–166.63, p = 0.44; GG: OR = 0.84, 95% CI: 0.58–1.22, p = 0.36; Figure 3 and Table 2).

Figure 3. Association of TGF-β1 G915C gene polymorphism with IgAN susceptibility.

Sensitivity analysis

Sensitivity analysis for the relationship between TGF-β1 T869C, C509T, G915C gene polymorphism and IgAN risk was also performed according to the source of the controls (healthy vs. hospital). The control source of all the included studies for TGF-β1 T869C, C509T, G915C was from healthy source, and the results were the same as non-sensitivity analysis.

Sensitivity analysis for the relationship between TGF-β1 T869C, C509T, G915C gene polymorphism and IgAN risk was also performed according to sample size of case (<100 vs. ≥100). We found that the results were also similar with the non-sensitivity analysis (data not shown).

Discussion

In this study, the average distribution frequency of TGF-β1 T869C T allele in IgAN group was 0.99-fold increase when compared with that in control group, and the average distribution frequency of TGF-β1 C509T T allele in IgAN group was 1.01-fold increase when compared with that in control group. Furthermore, TGF-β1 G915C C allele in case group was 1.20-fold increase when compared with that in control group. The average distribution frequency data indicated that there was no difference for T869C T allele, C509T T allele and G915C C allele between cases and controls. The meta-analysis data also confirmed this conclusion.

In this meta-analysis, we found that TGF-β1 T869C, C509T, G915C gene polymorphism was not associated with the IgAN risk. In the sensitivity analysis according to the source of the controls and the sample size of case, we found that the results were similar with those of non-sensitivity analysis. There was no publication bias among the studies. The results in our meta-analysis might be robust to some extent. However, the number of included studies is a little small, and more studies should be performed to evaluate the relationship in the future.

There were meta-analyses performed to investigate the association of TGF-β1 gene polymorphism with the risk of IgAN in past. Wang et al.18 performed a meta-analysis to assess the association of TGF-β1 gene -C509T polymorphism with susceptibility to IgAN, including eight reports; and suggested that the TGF-β1 gene -C509T polymorphism would not be a risk factor for IgAN in Asians but might play a role in Europeans. Vuong et al.14 performed a meta-analysis for TGF-β SNP rs1982073 for combined patients and controls from their study together with published data from two independent studies showed a significant association. This study was also conducted to assess the relationship between TGF-β1 gene polymorphism and the risk of IgAN. However, there was no an association of TGF-β1 T869C, C509T, G915C gene polymorphism with the risk of IgAN. More studies should be conducted to explore this relationship.

There were some meta-analyses to study the role of gene polymorphism in IgAN disease. Huang et al.19 conducted a meta-analysis, and provided evidence for genetic variation at the putative promoter region of Fc fragment of IgA conferring susceptibility to IgAN, suggesting –27C and its haplotype might be causative for the susceptibility among the Chinese Han population. Yong et al.20 performed a meta-analysis to evaluate the association of ACE I/D polymorphism with IgAN in different ethnic groups, and reported that ACE I/D polymorphism was associated with IgAN. Those results indicated that the gene polymorphism of some gene sites was associated with IgAN risk.

Our meta-analysis indicated that there was no association between TGF-β1 T869C, C509T, G915C gene polymorphism and the IgAN risk. The outcome might be robust to some extent. However, those findings should be regarded cautiously because many other ingredients, such as small sample size of the included report, limited statistical power, heterogeneity of enrolled cases, variable study designs and different interventions, were closely related to affect the results.

In conclusion, the results in our study support that TGF-β1 T869C, C509T, G915C gene polymorphism was not associated with the IgAN risk. However, more association investigations are required to further clarify the role of the TGF-β1 T869C, C509T, G915C gene polymorphism in predicting the risk of IgAN.

Declaration of interest

The authors declare no competing interests.

This study was supported by the sub-item of 985 Project Foundation of Sun Yat-Sen (The Hundred Talents Program Foundation; No. 88000-3311300).