NDT Advance Access originally published online on January 23, 2006
Nephrology Dialysis Transplantation 2006 21(6):1570-1574; doi:10.1093/ndt/gfk096
© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Original Articles: Clinical Nephrology
Association of MEGSIN 2093C–2180T haplotype at the 3' untranslated region with disease severity and progression of IgA nephropathy
Yunfeng Xia1,
Youji Li1,
Yong Du2,
Niansheng Yang1,
Caixia Li3,
Joseph C. K. Leung4,
Man F. Lam4,
Weijun Huang5,
Suqin Chen5,
Patrick H. Maxwell6,
Kar N. Lai4 and
Yiming Wang5
1 Department of Nephrology, First Affiliated Hospital, Zhongshan Medical College, Sun Yat-Sen University, Guangzhou, 2 Department of Nephrology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 3 Department of Medical Statistics, Zhongshan Medical College, Sun Yat-Sen University, Guangzhou, PR China, 4 Department of Medicine, Queen Marry Hospital, The University of Hong Kong, Hong Kong, 5 Department of Medical Genetics, Zhongshan Medical College, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, PR China and 6 Renal Section, Hammersmith Hospital, Imperial College, Du Cane Road,
London W12 0NN, UK
Correspondence and offprint requests to: Prof. Yiming Wang, Department of Medical Genetics, Zhongshan Medical College, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou 510089, PR China. Email: ywzhong{at}hotmail.com
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Abstract
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Background. MEGSIN is a gene predominantly expressed in the
renal mesangium, and is upregulated in IgA nephropathy (IgAN).
Our previous study has shown that the 2093C and 2180T alleles
at the 3' untranslated region (3'UTR) of the gene are associated
with susceptibility to IgAN, but the relationships of these
genetic variants with the clinical manifestations and renal
histological lesions of IgAN have not been examined previously.
Methods. 302 IgAN patients followed up for 52.8±22.5 months were investigated. Haplotypes at the 3'UTR were constructed using the 2093C/T and 2180C/T alleles. The genotype–phenotype relationship was studied by correlations of haplotypes and the clinical data and renal histopathological changes.
Results. The 2093C–2180T haplotype was present more often in patients with disease that progressed more rapidly (
2(C-T/others) = 8.429, P = 0.004), and was also correlated with hypertension (2(C-T/others) = 6.459, P = 0.012), severe proteinuria (
2 g/d) (2(C-T/others) = 6.332, P = 0.013), and Lee's class IV and V histological changes (2(C-T/others) = 9.640, P = 0.008).
Conclusion. In this Chinese population, the 2093C–2180T haplotype at the 3'UTR of MEGSIN gene is associated with more severe forms of IgAN, and more rapid disease progression. This provides further evidence for the involvement of genetic variations of MEGSIN in the pathogenesis of IgAN.
Keywords: Chinese; genetic variations; genotype–phenotype relationship; IgAN; MEGSIN
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Introduction
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IgA nephropathy (IgAN) is the most common primary glomerular
disease and a major cause of end-stage renal disease [
1–3].
There is now little doubt that genetic factors are involved
in the pathogenesis and clinical manifestation of IgAN. Many
genes have been reported to be associated with development and/or
progression of IgAN.
MEGSIN, also known as SERPINB7, serine
(or cysteine) proteinase inhibitor, clade B (ovalbumin), member
7 (
http://bioinfo.weizmann.ac.il, GenBank ID: AF027866
[GenBank]
), is
a gene predominantly expressed in the renal mesangium, whose
expression is upregulated in IgAN and diabetic nephropathy.
Both of these diseases are characterized by proliferation of
mesangial cells and accumulation of extracellular mesangial
matrix [
4,
5]. Overexpression of
MEGSIN in transgenic mice leads
to progressive mesangial matrix expansion and an increase in
the number of mesangial cells [
6]. Our previous study revealed
that the genetic variations of 2093C and 2180T at the 3' untranslated
region (3'UTR) of the
MEGSIN gene were associated with susceptibility
to IgAN in the Chinese population, both in a traditional association
study, and using a family-based approach which demonstrated
an increased transmission of 2093C and 2180T and their co-transmission
from parents to affected individuals [
7]. The relationships
of these genetic variants with the clinical manifestations and
renal histological lesions of IgAN have not been examined previously.
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Subjects and methods
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Subjects
This study includes 302 IgAN patients. They form the subset
of our previously described IgAN collection for whom we have
sufficient clinical and follow-up information to determine if
the disease is progressive. Recruitment to the collection was
described previously; patients were younger than 60 years, and
did not have liver disease or Henoch Schonlein purpura. Diagnosis
of IgAN was confirmed by a renal biopsy according to the World
Health Organization criteria [25]. The 2093C/T and 2180C/T genotypes
of the
MEGSIN gene had previously been determined for all patients
[
7]. The mean follow-up duration was 52.8±22.5 months,
and was defined as the time from the renal biopsy to the last
clinic visit. The university ethical committees had approved
the project.
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Methods
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Clinical and histological parameters
The patients were divided into a progressive group and relatively
stable group. The progressive group was defined on the basis
of an increase in the creatinine by 50% over any interval of
2 years or less between the time of biopsy and the latest follow-up.
The creatinine levels of the follow-up period are shown in
Table 1.
Only one patient commenced renal replacement therapy, and no
patients died. Clinical data was collected by retrospective
examination of the case notes. This included age, sex, duration
of follow-up, 24 h urinary protein (UP), serum creatinine, serum
IgA, serum cholesterol, serum triglyceride and blood pressure
at the time of biopsy. Renal histological lesions were evaluated
independently by two pathologists using Lee's grading criteria
[
8]. Where assessment differed, the biopsy was reexamined by
both pathologists together to achieve an agreed grade.
Statistical analyses
Haplotypes at the 3'UTR were constructed using the Phase 2.1
programme [
9] with the 2093C/T and 2180C/T allele information
reported previously [
7]. Categorical variables were compared
between groups by chi-square analyses. Metric variables were
compared between groups by analyses of variance (ANOVA). Hardy–Weinberg
equilibrium was tested by a chi-square test with 1 degree of
freedom.
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Results
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First, we compared clinical parameters in the 50 patients where
the disease progressed during the follow- up periods with the
252 patients whose disease was relatively stable. Patients in
the progressive group showed higher levels of systolic blood
pressure (124.7±21.1
vs 118.5±18.0,
P = 0.034;
Table 2) and 24 h UP (1.55±2.13
vs 1.04±1.35,
P = 0.032;
Table 2). The histopathological lesions in the progressive
group were found to be more severe than those in the relatively
stable group (
2 = 6.733,
P = 0.035;
Table 3). 62% of the patients
in the progressive group showed Lee's class IV + V and 4% class
I, whereas in the relatively stable group, 42.9% of the patients
were of Lee's class IV + V and 10.7% were class I (
Table 3).
No statistically significant differences were observed in the
other clinical data between the two groups.
We next investigated the relationship between genotype and disease
progression. Haplotype frequencies are shown in
Table 4. The
2093C–2180T haplotype had a higher frequency in the progressive
group (
2
(C-T/others) = 8.429,
P = 0.004;
Table 5) with 68%
in this group
vs 52.2% in the relatively stable group. To investigate
the relationship with hypertension and proteinuria, the patients
were divided into a hypertensive and non-hypertensive group
and 24 h UP <2 or
2 g/d groups. Hypertension was defined
as blood pressure greater than or equal to 140 mmHg systolic
or/and 90 mmHg diastolic on three occasions at diagnosis or
during the follow-up period, or the use of anti-hypertensive
medication to achieve normal blood pressure. The 2093C–2180T
haplotype was found to be present more often in the hypertensive
(
2 = 8.265,
P = 0.041;
2
(C-T/others) = 6.459,
P(C-T/others) = 0.012;
Table 6), and proteinuria
2 g/24 h groups (
2 = 8.883,
P = 0.031;
2
(C-T/others) = 6.332,
P(C-T/others) = 0.013;
Table 7).
The distribution of the haplotypes with different Lee's classes
of renal histological changes was also compared. A higher Lee's
class was observed with the 2093C–2180T haplotype (
2 =
14.527,
P = 0.024;
2
(C-T/others) = 9.640,
P(C-T/others) = 0.008;
Table 8).
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Discussion
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Given the high prevalence of IgAN worldwide, and the variable
clinical course of the condition, there has been great interest
in identifying factors which predict poor outcome. Many clinical
and histological factors have been shown to be associated with
progression of the disease. While it is generally accepted that
genetic factors will be important in determining the likelihood
of disease progression, little is known about this as yet [
10,
11].
MEGSIN is a member of the serpin superfamily, expressed predominantly in mesangial cells. The amino acid sequences in the reactive loop site show characteristic features of functional serpins. Binding and functional assays have identified plasmin as one of its biological substrates [4]. Serpins play a central role in the regulation of a wide variety of physiological and pathological processes including coagulation, fibrinolysis, matrix metabolism, blood pressure, malignancy and inflammation [12–15]. MEGSIN was first identified as a mesangial-expressed gene, associated with mesangial proliferation and extracellular matrix expansion accompanied by immune complex deposition [4]. In MEGSIN transgenic mice, overexpression leads to mesangial proliferation, decreased matrix degradation and immune complexes deposition, which eventually develop into a glomerulonephritis with similarities to human IgAN [6,16]. Taken together, these observations support a role for MEGSIN in IgA nephropathy, although the precise mechanisms by which it enhances mesangial proliferation and promotes extracellular matrix expansion are still not clear.
Our previous study revealed that the 2093C and 2180T alleles at the 3' untranslated region of the MEGSIN gene confer susceptibility to IgAN in the Chinese population. Furthermore, in a family-based analysis, the 2093C and 2180T alleles were each transmitted from parents to patients, and were co-transmitted, significantly more often than would be predicted. We hypothesized that in addition to predisposing to IgAN, genetic variants in MEGSIN could influence progression of the disease. The main finding of the current study is that the 2093C–2180T haplotype at the MEGSIN 3'UTR is associated with a more rapid progression of IgAN in the Chinese population.
A number of clinical and histological parameters are known to be useful in identifying patients likely to develop progressive IgAN. D’Amico [17] summarized histopathological changes from many studies and found that when a grading system of overall severity was used, more severe morphologic renal involvement was associated with an unfavourable prognosis in univariate analyses. Bartosik et al. [18] reported histologic Lee's class V as an independent risk factor for adverse outcome in IgAN. In studies of clinical prognostic factors in IgAN, arterial hypertension and heavy proteinuria at the time of presentation are known to be strong indicators of unfavourable prognosis according to univariate survivorship analyses [18–22]. As expected, in our study, we observed that patients with progressive disease presented with more severe renal histologic lesions, higher levels of blood pressure and 24 h UP than the relatively stable patients.
Our study suggests that genetic variations in MEGSIN are associated with more severe histologic lesions, higher levels of UP excretion and hypertension. The sample size did not allow us to perform multivariate analysis to determine which of the effects may be independent. At the current time, there is still much to learn about the biological function(s) of MEGSIN, and further studies will clearly be required to understand the role of MEGSIN in the development and progression of IgAN.
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Acknowledgments
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This project was supported by the National Natural Science Foundation
of China (30170434, 30570869), Guangdong Provincial Natural
Science Foundation (013140), and the China Medical Board of
New York (98–677, 05–827).
Conflict of interest statement. None declared.
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Received for publication: 19. 9.05
Accepted in revised form: 4. 1.06
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Abstract
Introduction