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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2014  |  Volume : 25  |  Issue : 5  |  Page : 992-997
Univariate and multiple linear regression analyses for 23 single nucleotide polymorphisms in 14 genes predisposing to chronic glomerular diseases and IgA nephropathy in Han Chinese


1 Central Laboratory of 181st Hospital, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin, Guangxi, R. P. China
2 Central Laboratory of 181st Hospital, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin, Guangxi; Clinical Medical Research Center, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong, R. P. China

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Date of Web Publication2-Sep-2014
 

   Abstract 

Immunoglobulin A nephropathy (IgAN) is a complex trait regulated by the inter­action among multiple physiologic regulatory systems and probably involving numerous genes, which leads to inconsistent findings in genetic studies. One possibility of failure to replicate some single-locus results is that the underlying genetics of IgAN nephropathy is based on multiple genes with minor effects. To learn the association between 23 single nucleotide polymorphisms (SNPs) in 14 genes predisposing to chronic glomerular diseases and IgAN in Han males, the 23 SNPs genotypes of 21 Han males were detected and analyzed with a BaiO gene chip, and their asso­ciations were analyzed with univariate analysis and multiple linear regression analysis. Analysis showed that CTLA4 rs231726 and CR2 rs1048971 revealed a significant association with IgAN. These findings support the multi-gene nature of the etiology of IgAN and propose a potential gene-gene interactive model for future studies.

How to cite this article:
Wang H, Sui W, Xue W, Wu J, Chen J, Dai Y. Univariate and multiple linear regression analyses for 23 single nucleotide polymorphisms in 14 genes predisposing to chronic glomerular diseases and IgA nephropathy in Han Chinese. Saudi J Kidney Dis Transpl 2014;25:992-7

How to cite this URL:
Wang H, Sui W, Xue W, Wu J, Chen J, Dai Y. Univariate and multiple linear regression analyses for 23 single nucleotide polymorphisms in 14 genes predisposing to chronic glomerular diseases and IgA nephropathy in Han Chinese. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2019 Nov 15];25:992-7. Available from: http://www.sjkdt.org/text.asp?2014/25/5/992/139882

   Introduction Top


Immunoglobulin A nephropathy (IgAN) is a primary glomerulonephritis of common inci­dence worldwide, the etiology and pathogenesis of which remain unresolved. [1] In Europe, the reported incidence is 20% and in Asia it is up to 50% of all biopsy-proven cases of glomerulo-nephritis. [2] The proliferative and crescentic forms of IgAN are found in up to 30% of cases, and are associated with nephritic-range proteinuria, accelerated hypertension and accelerated decline toward end-stage renal disease (ESRD). [3] The cure of IgAN is variable, and 15-40% of pa­tients progress to ESRD over 10-12 years. [4] The pathogenesis of IgAN is complex and incom­pletely understood. Humoral immunity is be­lieved to play an important role, characterized by the predominate mesangial IgA 1 deposition and associated secondary inflammatory response. [5] Although numerous genetic variations have shown the association with IgAN, these associations are often not reproducible. [6],[7] These inconsistent findings might be explained in part by the genetic and environmental heterogeneity among different ethnic groups. Another possible explanation for the discordant data regarding the association of these alleles with glomerulo-nephritis is that there are no major loci that make a major contribution to the variation in IgAN among different populations, but rather many genes exist that contribute very small effects to IgAN.

In the present study, a large-scale evaluation of 14 candidate gene polymorphisms was under­taken using the Sequenom ® MassARRAY ® sys­tem in Chinese southern Han males. We tested for single-locus association using one-way ana­lysis of variance (ANOVA) and multilocus association using multiple linear regression ana­lyses. Both single-locus and multilocus ana­lyses were applied to test our hypothesis that these candidate genes under study may contri­bute to the development of IgAN independently.


   Subjects and Methods Top


Subjects

Twenty-one unrelated patients of Han Chinese ethnicity with IgAN were chosen as the case group (10 male and 11 female, aged between 15 and 55 years, mean 41.6 years). They were tested for frequency of single nucleotide poly-merphisms (SNPs) along with 37 unrelated healthy individuals of Han Chinese ethnicity recruited from a company-based health scree­ning program in the Medical Examination Center of the 181 st Hospital of Chinese People's Liberation Army. The control group was aged between 34 and 54 years, with a mean of 44.32 years. To avoid disease-associated change in SNP properties, all subjects were recruited regardless of their health status. All participants signed an informed consent form according to the recommendations of the Chinese Academy of Medical Sciences ethical review committees, which approved the study.

Diagnosis

A kidney biopsy is necessary to confirm the diagnosis of IgAN. The biopsy specimen shows proliferation of the mesangium with IgA depo­sits on immunofluorescence and electron microscopy. The diagnosis of all 21 patients with IgAN in the case group was confirmed by biopsy.

Identification of SNPs

Genotyping of 23 SNPs in 14 genes was carried out by the BiaO gene array for genes predisposing to chronic glomerular diseases. The procedures of DNA extraction, polymerase chain reaction (PCR) amplification, hybridi­zation, gene array detection and analysis were strictly according to the manuals of the BaiO genotype detecting gene array kit. The accuracy and reproducibility of the gene array were vali­dated: The rate of accuracy of gene array was 97.8% (47/48) compared with DNA sequen­cing and the reproducibility of the gene array technology was good too.


   Statistical Analyses Top


All association analyses were carried out by calculating the odds ratio for each SNP marker, and significance was determined at the 5% level using either the χ2 test or the Fisher's exact test, as implemented in TYPER 4.0. Hardy-Weinberg equilibrium was evaluated by Fisher's exact text in 21 unrelated individuals. One-way ana­lysis of variance and multiple linear regression analyses, with age as co-variates, were used to test for associations of genotype of the 22 SNPs (one of 23 SNPs is mutation in our population) with IgAN within the Gui population. A P-value <0.05 was considered to indicate statistical significance.


   Results Top


Population characteristics and genetic structure data

The demographic and clinical characteristics of all of the individuals are shown in [Table 1]. [Table 2] lists the 22 SNPs examined of 14 candidate genes and the observed frequency of minor allele at each site among the control subjects. All the sites were in Hardy-Weinberg equilibrium in the control subjects. We retyped these polymorphisms in 14 randomly selected individuals and found 100% concordance with our original genotyping score, indicating that genotyping error could be excluded.
Table 1: Demographic and clinical data in the patient groups.

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Table 2: Genotype distributions in the two groups of subjects.

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Univariate and multivariate analysis regarding IgA nephropathy

[Table 2] shows the genotype distribution in the two groups of subjects. The genotyping com-pletion rate was ≥89.9% in all the SNPs except SNP rs 1143679. Two SNPs sites had significant differences in genotype frequency between IgAN and the matched controls for all of the 22 SNPs (P = 0.032 and 0.048, respectively). There were no significant differences in allele fre­quency between IgAN and the matched controls for any of the 22 SNPs. [Table 3] shows the allele analysis in the two groups of subjects. In this study, we did not analyze the interaction bet­ween the different genetic variants studied and IgAN.
Table 3: Allele analysis in the two groups of subjects.

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   Discussion Top


IgAN is the most common nephropathy in the world among adult patients undergoing renal biopsy (RB). However, there is a striking geo­graphic variation. [8] IgAN is an immune com­plex-mediated glomerulonephritis defined immunohistologically by the presence of glomerular IgA deposits accompanied by a variety of le­sions identified histopathologically. [9]

In the present study, we examined the rela­tionship of 22 polymorphisms in 14 candidate genes with IgAN using single-locus and multilocus analyses. Our study revealed that the two genes (CTLA4 and CR2) were associated with a significant risk of developing IgAN in the Chinese Han. To avoid false-positive findings, we included only Southern Han Chinese subjects.

Recently, Douglas et al reported that three SNPs (rs1048971, rs17615 and rs4308977) were significantly associated with decreased risk of developing systemic lupus erythematosus (SLE).

These findings implicate CR2 in the pathogenesis of SLE. [10] Their association with IgAN has not been previously reported. We tested all the three SNPs in the current study. However, we found an association with susceptibility either to rs4308977 or rs17615; only rs1048971 showed an association with increased risk of IgAN.

STAT4 is a transcription factor that transduces interleukin-12, interleukin-23 and type-1 inter-feron cytokine signals in T cells and monocytes, leading to differentiation of T-helper type-1 and T-helper type-17, monocyte activation and interferon-gamma production. [11] Some evidences suggest that the variant form of STAT4 (rs7574865) may have a putative key role in the development of a variety of autoimmune di-seases. [12] Using Fisher's exact test, Kobayashi et al observed a significant association of the STAT4 polymorphism with susceptibility to both rheumatoid arthritis and SLE. This finding indicates that STAT4 is a common genetic risk factor for autoimmune diseases, with similar strength across major racial groups, [13] which

was consistent with previous reports in pSS subjects of Caucasian ethnicity. [14] In our study, we also selected rs7574865 to examine the association between STAT4 and IgAN. How­ever, there were no significant differences in either allele frequency or genotype frequency between IgAN and the matched controls.

Logistic regression analysis showed that rs3733197 and rs17266594 from BANK1 had an independent contribution to the association with SLE (P = 0.037 and 6.63 × 10(-8), respec-tively). [15] The same set of SNPs defining the SLE-associated haplotype were then tested in several independent IgAN case series and heal­thy controls. On haplotype analysis, we could not found that any of the haplotypes were significantly associated with IgAN.


   Perspectives Top


The present study provides further evidence that several polymorphisms within candidate genes act in the etiology of IgAN. Our study also demonstrates the use of gene array me­thods in the study for a complex disease/trait. Further studies on larger independent samples are warranted.

Source(s) of support:

Funding for this work was received from the Guangxi Science and Technology Program (No.10124001B-18).

Conflict of interest:

The authors declare no conflict of interest.

 
   References Top

1.Obara W, Iida A, Suzuki Y, et al. Association of single-nucleotide polymorphisms in the poly­meric immunoglobulin receptor gene with immunoglobulin A nephropathy (IgAN) in Japanese patients. J Hum Genet 2003;48:293-9.  Back to cited text no. 1
    
2.Haubitz M, Wittke S, Weissinger EM, et al. Urine protein patterns can serve as diagnostic tools in patients with IgA nephropathy. Kidney Int 2005;67:2313-20.  Back to cited text no. 2
    
3.Kawasaki Y. The pathogenesis and treatment of IgA nephropathy. Fukushima J Med Sci 2008; 54:43-60.  Back to cited text no. 3
[PUBMED]    
4.Glassock RJ. IgA nephropathy: Challenges and opportunities. Cleve Clin J Med 2008;75:569-76.  Back to cited text no. 4
[PUBMED]    
5.Ghani AA, Al Waheeb S, Al Homoud E, Al Helal B, Hussain N. Clinical and histopathological spectrum of IgA nephropathy in Kuwait. Ann Saudi Med 2011;31:152-7.  Back to cited text no. 5
    
6.Herzenberg AM, Fogo AB, Reich HN, et al. Validation of the Oxford classification of IgA nephropathy. Kidney Int 2011;80:310-7.  Back to cited text no. 6
    
7.Khor CC, Hibberd ML. Host-pathogen inter­actions revealed by human genome-wide surveys. Trends Genet 2012;28:233-43.  Back to cited text no. 7
    
8.Maixnerová D, Merta M, Reiterová J, et al. The Influence of Three Endothelin-1 Polymorphisms on the Progression of IgA Nephropathy. Folia Biol (Praha) 2007;53:27-32.  Back to cited text no. 8
    
9.Khawajah AQ, Al-Maghrabi J, Kanaan HD, Al-Ghamdi S. IgA nephropathy: A clinico-pathologic study from two centers in Saudi Arabia. Saudi J Kidney Dis Transpl 2010;21: 269-75.  Back to cited text no. 9
[PUBMED]  Medknow Journal  
10.Douglas KB, Windel DC, Zhao J, et al. Com­plement receptor 2 polymorphisms associated with systemic lupus erythematosus modulate alternative splicing. Genes Immun 2009;10:457-69.  Back to cited text no. 10
    
11.O'Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 2012;36:542-50.  Back to cited text no. 11
    
12.Zervou MI, Vazgiourakisa VM, Yilmaz N, et al. TRAF1/C5, eNOS, C1q, but not STAT4 and PTPN22 gene polymorphisms are associated with genetic susceptibility to systemic lupus erythematosus in Turkey. Hum Immunol 2011; 72:1210-3.  Back to cited text no. 12
    
13.Kobayashi S, Ikari K, Kaneko H, et al. Asso­ciation of STAT4 with susceptibility to rheuma­toid arthritis and systemic lupus erythematosus in the Japanese population. Arthritis Rheum 2008;58:1940-6.  Back to cited text no. 13
    
14.Korman BD, Alba MI, Le JM, et al. Variant form of STAT4 is associated with primary Sjögren's syndrome. Genes Immun 2008;9:267-70.  Back to cited text no. 14
    
15.Orozco G, Abelson AK, González-Gay MA, et al. Study of functional variants of the BANK1 gene in rheumatoid arthritis. Arthritis Rheum 2009;60:372-9.  Back to cited text no. 15
    

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Correspondence Address:
Yong Dai
Clinical Medical Research Center of the Second Clinical Medical College, Jinan University, Shenzhen Peoples Hospital, Shenzhen 518020
R. P. China
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DOI: 10.4103/1319-2442.139882

PMID: 25193896

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    Abstract
   Introduction
   Subjects and Methods
   Statistical Analyses
   Results
   Discussion
   Perspectives
    References
    Article Tables
 

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