Introduction
Primary IgA nephropathy (IgAN) is the most common
glomerular disease in children and adolescents who undergo renal
biopsy because of isolated microscopic hematuria or hematuria
associated with non-nephrotic proteinuria (1). Even though the exact pathogenesis is
not yet known, IgAN is characterized by glomerular mesangial
proliferation in response to the deposition of IgA. While the
disease is characterized by a single histopathological finding,
patients with IgAN show variable clinical and histopathological
features. Polymorphisms of candidate genes influence this
individual variability. To date, there has been evidence suggesting
that abnormal immune responses play an important role in the
pathogenesis of IgAN (2,3).
Interleukin 7 (IL7) is a well-known essential factor
for the development and maintenance of the immune system. IL7 works
through its receptor, IL7R (also known as CD127). IL7R, a member of
the hematopoietin receptor family, is a type 1 membrane
glycoprotein capable of binding α-helical cytokines (4). Signaling via IL7R induces somatic
recombination of the T-cell receptor and immunoglobulin genes,
promoting both the proliferation and differentiation of developing
B and T lymphocytes. The IL7R is heterodimeric and consists of the
IL7R α chain (IL7Rα, encoded by IL7R) and the common
cytokine-receptor γ chain (γc, encoded by IL2RG; also known
as CD132). IL7Rα transduces transmembrane signals through the
recruitment of intracellular messengers to its cytoplasmic tale.
IL7Rα is expressed on immature B and T cells, and genetic ablation
or the presence of neutralizing antibodies has been found to block
lymphocyte development (5). In
addition, mutation of IL7Rα has been implicated in the development
of a subtype of severe combined immunodeficiency. Functionally,
IL7Rα is important in the body's innate and adaptive inflammatory
and immunological response. This signaling is critical for T-cell
differentiation of CD4−CD8− thymocytes and
has a role in the survival of CD4+CD8+ cells
after positive selection. Moreover, IL7 signaling modulates
peripheral memory or naïve T-cell homeostasis (6) and production of several
proinflammatory (IFNr, IL2) and anti-inflammatory cytokines (IL4)
(7). Even though the downstream
signaling pathway of IL7R remains poorly understood, previous
studies have shown that it leads to activation of the
phosphatidylinositol-3-kinase pathway, the Ras/Raf signaling
cascade and Janus kinase/STAT pathways, which have all been
suggested to be important for the pathogenesis of various diseases,
including IgAN (8,9). In addition, the IL7/IL7R pathway has
been studied as part of the pathogenesis of various autoimmune
diseases, such as multiple sclerosis (MS), rheumatoid arthritis
(RA), systemic lupus erythematosus (SLE), sarcoidosis and psoriasis
(10,11).
Accordingly, the IL7/IL7R pathway is a very
attractive target for inflammatory disorders, and its genetic
variations have been proposed to be involved in the pathogenesis of
various autoimmune diseases (10,12).
However, no prior study has investigated the association between
SNPs of IL7R and renal diseases, especially in children.
Thus, the present study was conducted to investigate the
association between polymorphisms of the IL7R gene and
childhood IgAN.
Materials and methods
Patients and controls
We evaluated 198 Korean pediatric patients with
biopsy confirmed IgAN [12.64±5.17 years (mean age ± SD); 118 boys,
13.36±4.97 years; 80 girls, 11.58±5.31 years] and 288 healthy
controls (37.53±13.26 years; 156 males, 39.46±14.60 years; 132
females, 35.25±11.11 years). Patients were identified through a
school screening urinalysis; most had no symptoms of
glomerulonephritis (GN) other than abnormalities on the urinalysis.
Therefore, they were identified at a relatively early stage of the
disease.
Healthy controls were recruited based on the results
of routine screening. This screening included the completion of a
questionnaire that addressed symptoms and medical history, and
several laboratory test findings, including the results of a
urinalysis (protein, glucose and occult blood). Control candidates
with an abnormal result on any item were excluded.
There was a difference in mean age between our cases
and controls (12.64±5.17 vs. 37.53±13.26 years, respectively).
However, we were unable to enroll age-matched controls. IgAN is
known to develop in the third decade; therefore, healthy controls
>20 years of age were required to avoid the recruitment of
individuals with undetected or sub-clinical IgAN. Accordingly, the
presence of a substantial age gap between cases and controls
appears unavoidable in studies on pediatric IgAN. Other researchers
have also utilized adult controls in studies on SNPs in childhood
IgAN (13,14).
Patient subgroups
To determine the nature of the association between
SNPs of IL7R and the development of severe proteinuria, the
patients were divided into subgroups according to the presence of
nephrotic range proteinuria during the course of IgAN (>40 and
≤40 mg/m2/h).
Furthermore, we created subgroups of the IgAN
patients according to the presence of podocyte foot process
effacement on renal biopsy. In addition, IgAN patients were divided
into pathologically mild (Grade I–II) and advanced (Grade III–IV)
disease groups to evaluate the association of IL7R SNPs with
disease progression as determined by the modified H.S. Lee
histological grading system (15).
Demographic characteristics of the IgAN patients are shown in
Table I. This study was approved
by the Ethics Review Committee of the Medical Research Institute,
Kyung Hee University Medical Center, Seoul, Korea. Written informed
consent was obtained from all subjects and parents or legal
guardians.
 | Table IDemographics of the IgAN patients
(n=198). |
Table I
Demographics of the IgAN patients
(n=198).
| Subgroups | n (%) | Male: Female | Age (years) mean ±
SD | Pathological grade
(n)a
|
|---|
| I | II | III | IV | V | P-value |
|---|
| Nephrotic range
proteinuriab | | | | | | | | | |
| (+) | 32 (16.2) | 22:10 | 11.17±4.56 | 14 | 10 | 7 | 1 | 0 | 0.002 |
| (−) | 166 (83.8) | 95:71 | 12.93±5.25 | 113 | 43 | 8 | 2 | 0 | |
| Podocyte foot process
effacement | | | | | | | | | |
| (+) | 82 (41.4) | 52:30 | 13.45±5.66 | 34 | 31 | 14 | 3 | 0 | <0.001 |
| (−) | 116 (58.6) | 66:50 | 12.07±4.74 | 93 | 22 | 1 | 0 | 0 | |
| Pathological
progressionc | | | | | | | | | |
| (+) | 18 (9.1) | 15:3 | 16.17±7.78 | 0 | 0 | 15 | 3 | 0 | <0.001 |
| (−) | 180 (90.9) | 103:77 | 12.29±4.72 | 127 | 53 | 0 | 0 | 0 | |
SNP selection and genotyping
The missense SNPs of the IL7R gene were
selected based on the findings of extensive database searches
(http://www.ebi.ac.uk/ensemble/,
http://ncbi.nlm.nih.gov/SNP, BUILD131),
based on a heterozygosity >0.1 and a minor allele frequency of
>0.05 in the Asian population. The SNPs were also validated by
HapMap database.
Genomic DNA was extracted from the whole blood of
each subject using the DNA Isolation kit for blood (Roche,
Indianapolis, IN, USA). Genomic DNA was amplified using specific
primers: rs1494558 (sense, 5′-TGTCTGCCACAGAGTCTGCTAT-3′; antisense,
5′-GTGAAGGACAAGGAGTTTCAGG-3′; 395 bp) and rs1494555 (sense,
5′-TCAAAGTGACTTGCAGAGGAGA-3′; antisense,
5′-GGAAATGCACTACTAGGCCAAC-3′; 326 bp). Polymerase chain reaction
(PCR) products were sequenced using the ABI PRISM 3730XL analyzer
(PE Applied Biosystems, Foster City, CA, USA). Sequence data were
analyzed using the SeqManII software (DNAStar Inc., Madison, WI,
USA).
Statistical analysis
For the statistical analysis of pathological grading
in patient subgroups, the SPSS Statistics 17.0 software package
(SPSS Inc., Chicago, IL, USA) was used, and a P-value of <0.05
was considered statistically significant.
For the case-control association study,
Hardy-Weinberg equilibrium (HWE) for all SNPs was assessed using
SNPstats (Biostatistics and Bioinformatics Unit, Barcelona, Spain)
in both cases and controls (16);
the SNPs not in HWE (P<0.05) were excluded from the analysis.
For the logistic regression analysis and trend test, SNPstats and
SNPAnalyzer (Istech Inc., Goyang, Korea) were used. To show
alternative effects of the variants, logistic regression analysis
was performed in the three analysis models (codominant, dominant
and recessive). Allele frequencies of each SNP were compared by
Pearson's Chi-square test. To reduce experimental error, we
calculated sample power for the SNPs and the number of cases was
adjusted to achieve 80% power (α=0.05, genotype relative risk =
2-fold) using a genetic power calculator (http://pngu.mgh.harvard.edu/~purcell/gpc).
A linkage disequilibrium (LD) block of polymorphisms
and haplotype analysis were tested using Haploview version 4.2
(Broad Institute, Cambridge, MA, USA), HapAnalyzer version 1.0
(http://hap.ngri.go.kr/) and HelixTree (Golden
Helix Inc., Bozeman, MT, USA). Lewontin's |D'| and r2
were examined between all pairs of bi-allelic loci. The haplotypes
and their frequencies were inferred using the
expectation-maximization algorithm (17).
Results
In the analysis of demographics of IgAN patients, we
found that pathological grade was significantly associated with
proteinuria and podocyte foot process effacement (P=0.002 and
<0.001, respectively) (Table
I).
The genotypic distributions of all SNPs in this
study were consistent with HWE (P>0.05). The genotyping data of
the 198 cases and 288 controls showed a significant association
between the presence of IgAN and both of the candidate missense
SNPs by logistic regression analysis [rs1494558 (codominant model,
OR=1.63, 95% CI 1.24–2.14, P=0.0003; dominant model, OR=2.01, 95%
CI 1.36–2.97, P=0.0003; recessive model, OR=1.70, 95% CI 1.03–2.82,
P=0.0390) and rs1494555 (codominant model, OR=1.48, 95% CI
1.13–1.94, P=0.0038; dominant model, OR=1.70, 95% CI 1.13–2.56,
P=0.0099; recessive model, OR=1.63, 95% CI 1.03–2.60, P=0.0380)]
(Table II). Upon comparison of the
allelic frequencies, the G allele of rs1494558 (OR=1.59, 95% CI
1.22–2.06, P=0.0010) and T allele of rs1494555 (OR=1.43, 95% CI
1.11–1.85, P=0.0060) were found to be risk alleles for IgAN. In the
measurement of pair-wise LD, one LD block was identified by the
Gabriel method (18), and the
block consisted of both rs1494558 and rs1494555 (data not shown).
The haplotype analysis showed a statistical significance with the
haplotype AC (codominant model, OR=0.69, 95% CI 0.53–0.90,
P=0.0066; recessive model, OR=0.59, 95% CI 0.40–0.89, P=0.0124) and
the haplotype GT (codominant model, OR=1.62, 95% CI 1.24–2.12,
P=0.0005; dominant model, OR=1.97, 95% CI 1.34–2.90, P=0.0006;
recessive model, OR=1.72, 95% CI 1.04–2.85, P=0.0362) (Table III).
| Table IILogistic regression analysis of
IL7R polymorphisms in IgAN patients and healthy controls
adjusted for gender and age. |
Table II
Logistic regression analysis of
IL7R polymorphisms in IgAN patients and healthy controls
adjusted for gender and age.
| SNPs | IgAN, n (%) | Controls, n (%) | Model | OR (95% CI) | P-value |
|---|
| rs1494558
Ile66Thr | | | | | |
| Genotype | | | | | |
| A/A | 56 (28.3) | 126 (43.8) | Codominant | 1.63
(1.24–2.14) | 0.0003 |
| A/G | 105 (53.0) | 127 (44.1) | Dominant | 2.01
(1.36–2.97) | 0.0003 |
| G/G | 37 (18.7) | 35 (12.1) | Recessive | 1.70
(1.03–2.82) | 0.0390 |
| Allele | | | | | |
| A | 217 (54.8) | 379 (65.8) | | 1.59
(1.22–2.06) | 0.0010 |
| G | 179 (45.2) | 197 (34.2) | | | |
| rs1494555
Val138Ile | | | | | |
| Genotype | | | | | |
| C/C | 47 (23.7) | 99 (34.4) | Codominant | 1.48
(1.13–1.94) | 0.0038 |
| T/C | 106 (53.6) | 144 (50.0) | Dominant | 1.70
(1.13–2.56) | 0.0099 |
| T/T | 45 (22.7) | 45 (15.6) | Recessive | 1.63
(1.03–2.60) | 0.0380 |
| Allele | | | | | |
| C | 200 (50.5) | 342 (59.4) | | 1.43
(1.11–1.85) | 0.0060 |
| T | 196 (49.5) | 234 (40.6) | | | |
| Table IIIHaplotype analysis with polymorphisms
of the IL7R gene. |
Table III
Haplotype analysis with polymorphisms
of the IL7R gene.
| Haplotype | IgAN
| Controls
| Model | OR (95% CI) | P-value |
|---|
| n | Frequency | n | Frequency |
|---|
| AC | | | | | | | |
| H/H | 47 | | 99 | | Codominant | 0.69
(0.53–0.90) | 0.0066 |
| H/− | 106 | 0.51 | 143 | 0.59 | Dominant | 0.65
(0.41–1.02) | 0.0618 |
| −/− | 45 | | 46 | | Recessive | 0.59
(0.40–0.89) | 0.0124 |
| GT | | | | | | | |
| H/H | 37 | | 34 | | Codominant | 1.62
(1.24–2.12) | 0.0005 |
| H/− | 105 | 0.45 | 128 | 0.34 | Dominant | 1.97
(1.34–2.90) | 0.0006 |
| −/− | 56 | | 126 | | Recessive | 1.72
(1.04–2.85) | 0.0362 |
| AT | | | | | | | |
| H/H | 0 | | 2 | | Codominant | 0.64
(0.36–1.15) | 0.1331 |
| H/− | 17 | 0.04 | 34 | 0.07 | Dominant | 0.66
(0.36–1.21) | 0.1761 |
| −/− | 181 | | 252 | | Recessive | 0.00 (0.00-NA) | 0.9977 |
In order to verify our data, we calculated the
sample power for each SNP using a genetic power calculator; the
sample power was 0.9641 for rs1494558 (number of cases for 80%
power = 109) and 0.9662 for rs1494555 (number of cases for 80%
power = 108) with α=0.05 and genotype relative risk = 2-fold.
Accordingly, our case-control study was sufficiently powered to
detect a positive association.
When the genotypic association between the SNPs and
subgroups of IgAN patients was assessed, nephrotic range
proteinuria (>40 mg/m2/h) that developed during the
course of the disease was found to be associated with rs1494558
(codominant model, OR=1.92, 95% CI 1.06–3.46, P=0.0270; recessive
model, OR=2.81, 95% CI 1.18–6.67, P=0.0230) (Table IV). The allelic frequency analysis
showed that the G allele of rs1494558 (OR=1.83, 95% CI 1.07–3.15,
P=0.0270) and T allele of rs1494555 (OR=1.74, 95% CI 1.01–3.00,
P=0.0460) were associated with the risk of developing nephrotic
range proteinuria in IgAN patients. No significant difference was
shown in clinical subgroup analysis in podocyte foot process
effacement or pathological progression (data not shown).
| Table IVLogistic regression analysis of
IL7R polymorphisms in IgAN patients comparing groups with
nephrotic and nonnephrotic range proteinuria (>40 and ≤40
mg/m2/h) adjusted for gender and age. |
Table IV
Logistic regression analysis of
IL7R polymorphisms in IgAN patients comparing groups with
nephrotic and nonnephrotic range proteinuria (>40 and ≤40
mg/m2/h) adjusted for gender and age.
| SNPs | Nephrotic
proteinuriaa
n (%) | Non-nephrotic
proteinuria
n (%) | Model | OR (95% CI) | P-value |
|---|
| rs1494558
missense | | | | | |
| Ile66Thr | | | | | |
| Genotype | | | | | |
| A/A | 6 (18.8) | 50 (30.1) | Codominant | 1.92
(1.06–3.46) | 0.0270 |
| A/G | 15 (46.9) | 90 (54.2) | Dominant | 1.81
(0.69–4.74) | 0.2100 |
| G/G | 11 (34.4) | 26 (15.7) | Recessive | 2.81
(1.18–6.67) | 0.0230 |
| Allele | | | | | |
| A | 27 (42.2) | 190 (57.2) | | 1.83
(1.07–3.15) | 0.0270 |
| G | 37 (57.8) | 142 (42.8) | | | |
| rs1494555
missense | | | | | |
| Val138Ile | | | | | |
| Genotype | | | | | |
| C/C | 5 (15.6) | 42 (25.3) | Codominant | 1.81
(1.00–3.28) | 0.0460 |
| T/C | 15 (46.9) | 91 (54.8) | Dominant | 1.73
(0.61–4.88) | 0.0410 |
| T/T | 12 (37.5) | 33 (19.9) | Recessive | 0.70
(0.32–1.51) | 0.3600 |
| Allele | | | | | |
| C | 25 (39.1) | 175 (52.7) | | 1.74
(1.01–3.00) | 0.0460 |
| T | 39 (60.9) | 157 (47.3) | | | |
Discussion
The relationship between the IL7/IL7R pathway and
markers of inflammation has been observed in RA patients; influence
on the clinical disease activity and the production of IL6, CRP,
IL1b, IFN-γ and TNF-α was noted (7,11).
In addition, IL7 may induce matrix metalloproteinase (MMP)-13 and
matrix degradation (12,19). A study of patients with SLE
reported abnormal bone marrow-derived mesenchymal stem cells
showing IL7 down-regulation (10).
In addition, an inhibitory effect of IL7R has been reported in
allergic inflammation processes (20).
Recently, an association of IL7R
polymorphisms with certain target diseases was reported in several
studies. MS is the most studied disease, with well-replicated
results (21–23). In these studies, the SNPs and their
haplotypes of IL7R were suggested to be susceptibility
and/or progression markers for MS, and the authors even speculated
that overexpression of IL7R possibly results in increased
numbers of autoantigen-specific T cells (21,22).
Other studies have shown that SNPs of IL7 and/or IL7R
are associated with susceptibility to RA, sarcoidosis and type 1
diabetes (24,25). These reports suggest that the
IL7R locus may be involved in the pathogenesis of several
diseases with an immunologic basis.
In the present study, we found a strong association
between IL7R SNPs and IgAN susceptibility. Haplotype (AC and
TG) showed a strong association with IgAN susceptibility, as well.
The calculated sample power was sufficient to detect this
association. Furthermore, there was a weaker but significant
association with the development of nephrotic range proteinuria in
IgAN patients. When the allelic frequencies were compared to other
populations, both SNPs had a similar distribution in the Japanese
population from the HapMap database (http://www.hapmap.org). However, the A allele of
rs1494558 and C allele of rs1494555 showed slightly higher
frequencies than those of the other three populations used for
comparison. Both alleles were investigated as protective alleles in
the present analysis.
Two SNPs found to be significantly associated with
IgAN pathogenesis, rs1494558 and rs1494555, are missense SNPs in
the coding region that result in changes of amino acid sequences.
Thus, there is a potential of affecting protein function or
expression; consequently, the SNPs may be involved in the
pathogenesis of IgAN.
However, we could not demonstrate the association
between pathological progression of IgAN and IL7R SNPs,
despite their possible effects on the fibrotic process as reflected
by a previously proposed function on MMP-13 and fibroblasts. In
addition, even though an association with proteinuria was observed,
no significant relationship with podocyte foot process effacement
was found. These discrepancies could be a result of limitations of
our study. Patients were enrolled by school screening urinalysis
and, as reflected by the relatively mild pathological findings of
our patients, they were in an early stage of disease. As the
nephrotic proteinuria included late onset proteinuria that
developed during the follow-up period, it may not correspond to the
early stage biopsy findings.
In summary, there is evidence suggesting that
IL7R may be involved in the pathogenesis of IgAN, but
IL7R-related polymorphisms have not previously been studied
in patients with IgAN. In the present study, two missense SNPs of
IL7R, rs1494558 and rs1494555, were found to be
significantly associated with both susceptibility to IgAN and
nephrotic range proteinuria in IgAN patients.
Abbreviations:
|
GN
|
glomerulonephritis;
|
|
IgAN
|
IgA nephropathy;
|
|
IL7R
|
interleukin 7 receptor gene;
|
|
LD
|
linkage disequilibrium;
|
|
SNP
|
single nucleotide polymorphism
|
Acknowledgements
The authors would like to gratefully
acknowledge Dr Hyung-Jin Yoon for her advice.
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