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BASIC RESEARCH
Year : 2007  |  Volume : 52  |  Issue : 1  |  Page : 21-26
The combination of Ile225Thr polymorphism of Fcg receptor IIB gene and hypersensitiveness as risk factor for human systemic lupus erythematosus in chinese populations


1 Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei 230032, China
2 Department of Rheumatology, Anhui Provincial Hospital, Hefei 230000, China
3 Department of Rheumatology, First Affiliated hospital, Anhui Medical University, Hefei 230032, China

Correspondence Address:
Dongqing Ye
Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 69 Meishan Road, Hefei, Anhui 230032
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.31919

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   Abstract 

Background: The aim of this study was to investigate the role of FcgRIIB gene in susceptibility to systemic lupus erythematosus (SLE) using family-based association study and to examine possible interaction between the Ile225Thr (rs1050501, exon 5) polymorphism of Fcg receptor IIB gene and hypersensitivity. Objectives: A total of 119 patients with SLE from 95 nuclear families, aged 14 to 78 years, according to the American College of Rheumatology (ACR) 1997 criteria were recruited. In addition, 316 family members of these patients were also genotyped. Seventy patients and their 70 normal siblings from 95 nuclear families were selected by the case-combined-control design. Materials and Methods: A family-based association study was used to explore the relationship between gene polymorphism and SLE. We studied a single-nucleotide polymorphisms (SNPs) encoding non-synonymous substitution in the FcgRIIB gene with respect to genetic susceptibility to SLE, the FcgRIIB gene were genotyped by restriction fragment length polymorphism (RFLP) method. The interaction of gene-environment was assessed by conditional logistic regression model.
Results:
Among 119 SLE patients, The frequencies of FcgRIIB Ile225Ile, Ile225Thr and Thr 225 Thr genotypes were 8.1%, 61.3% and 30.6%. Univariate (single-marker) family-based association tests (FBATs) demonstrated that variant allele at SNP rs1050501, in exon 5 of FcgRIIB gene was significantly associated with genetic susceptibility to SLE in additive model (exon 5, Z=3.707, P =0.00020). Transmission/disequilibrium test (TDT) and sibship disequilibuium test (SDT) analysis showed an excess of the allele of 225Thr ( Ile225Thr loci) from heterozygous parents to affected offspring (c 2=7.14, P =0.0105); Moreover, conditional logistic regression results showed that there was statistically significant multiplicative interaction of FcgRa!B gene and the Hypersensitiveness [c 2=5.013, P =0.024; OR=2.444, CI (1.126-5.309)]. Conclusions: Our findings provide strong evidence suggesting a Ile225Thr polymorphism might be the susceptibility factor of SLE; a possible gene-environment interaction between hypersensitiveness and Ile225Thr mutation in Chinese population.


Keywords: Chinese, family based association test (FBAT), FcgRIIB, gene-environment interaction, lupus erythematosus, polymorphism, single nucleotide, susceptibility, systemic


How to cite this article:
Pan F, Ye D, Zhang K, Li X, Xu J, Chen H, Su H. The combination of Ile225Thr polymorphism of Fcg receptor IIB gene and hypersensitiveness as risk factor for human systemic lupus erythematosus in chinese populations. Indian J Dermatol 2007;52:21-6

How to cite this URL:
Pan F, Ye D, Zhang K, Li X, Xu J, Chen H, Su H. The combination of Ile225Thr polymorphism of Fcg receptor IIB gene and hypersensitiveness as risk factor for human systemic lupus erythematosus in chinese populations. Indian J Dermatol [serial online] 2007 [cited 2019 Jun 19];52:21-6. Available from: http://www.e-ijd.org/text.asp?2007/52/1/21/31919



   Introduction Top


Systemic lupus erythematosus (SLE) is a multifactorial systemic autoimmune disease characterized by production of an array of autoantibodies and immune complexes that leads to inflammation and damage of multiple organs. The etiology of the disease is still not clear but genetic, immunological, hormonal and environmental factors are considered to be important triggers. Human low-affinity receptors Fc g Rs consist of three Fc g RII ( IIA, IIB,IIC) and two Fc g RIII ( IIIA,IIIB ), which vary in their cellular distribution and affinity for different IgG isotypes. Fc g Rs are expressed in immune effector cells and thought to play an important role in the pathogenesis of autoimmune diseases.[1] FcgRIIB mediates the retension and conversion of immune complexes to a high immunogenic form, which facilitates B cell recall responses.[2],[3],[4],[5] Thus FcgRIIB gene may play multiple roles in modulating immune function and maintaining homeostasis. Polymorphisms with established functional relevance are present at least in FcgRIIA , FcgRIIIA and FcgRIIIB , correlation of which with autoimmune or infectious diseases have been extensively studied. In animal experiment, mouse models have highlighted the role of FcgRIIB in the development of autoimmune diseases, FcgRIIB -deficient mice have increased antibody responses, cytokine production, macrophage activation and immune-mediated pathology including spontaneous SLE.[6],[7] Indeed, numerous studies on the association of Fc g Rs polymorphisms with SLE have been carried out in different populations, however, the results are inconsistent. Recent extensive Meta-analyses demonstrated that Fcg RIIA-131H[8] is associated with the development of SLE, as well as Fcg RIIIA-176F[9] is a risk factor for the development of nephritis. Fcg RIIIB*2 allele encoding HNA-1b antigen (also referred to as NA2 ) has been shown to be associated with SLE or lupus nephritis; however, the results are disputed among studies.[10] Such discrepancies may be caused by the difference in the genetic background of each population and the exposure of environmental risk factors. Many environmental factors are known to affect the immune system and may play a role as triggers of the autoimmune diseases, such as infection,[11] cigarette smoking[12] and ultraviolet ray exposure, etc. The question was recently raised as to whether Hypersensitiveness body might be a triggering factor of the autoimmune diseases. However, information concerning the association between FcgRIIB polymorphism and Hypersensitiveness body with SLE is very limited in the Chinese, moreover, many studies were used case-control methods. Above results need to be confirmed in genetic background of each population by various methods, in our study, we performed a family-based association study on the FcgRIIB single-marker polymorphism and hypersensitiveness body in the Chinese nuclear families with SLE.


   Materials and Methods Top


Study subjects

A family-based association study was carried out for 435 subjects (119 patients and 316 other families members) from 95 nuclear families (aged 37.42 14.55 years) with SLE classified according to the ACR (American College of Rheumatology) 1997 revised criteria were recruited from the Department of rheumatology, Anhui provincial hospital and the Department of Rheumatology, first affiliate hospital, Anhui Medical University. In a total of 435 subjects (121 parents, 314 siblings)from 95 qualified nuclear families (47 [49.5%] families had both parents, 8 [8.4%] families had a single parent and 40 [42.1%] had no available parents) were finally recruited. The family criteria used for subject selection were as follows: (1) at least two siblings and (2) at least one parent or one additional sibling. All subjects were given their written informed consent and blood drawing and the study protocol was approved by the Department of Epidemiology and Biostatistics, Anhui Medical University. The SNP of FcgRIIB SNP came from NCBI dbSNP (dbSNP home page), the SNP residing in the FcgRIIB gene , rs1050501 (T C transiton; Ile Thr) was located in exon 5 (Amino acid position 225), this SNP was nonsynonymous mutation and change the code of amino acid. Schematic representation of the SNP located on the FcgRIIB gene is shown in [Figure - 1]. Exposure information was derived from a detailed interviewer-administered questionnaire; an in-home interview was conducted to gather information on environmental risk factors. The definition of hypersensitiveness body included food, drugs, sunlight, cold water, dust, at least one occurs among above. All subjects were asked to voluntarily participate in our study.

Phlebotomy

Forearm venous blood samples were collected in 10 ml vacationer tubes containing EDTA and citrate from each subject by venipuncture. Iced tubes were centrifuged at 2000 revolutions for 10 min, then excluding the plasma from the cell pellet by pipetting. All samples were stored at -80C.

Genotyping of FcgRIIB polymorphism

Genomic DNA was extracted from peripheral circulating blood specimens taken at the time of interview using the QIAamp Blood Kit and stored at -20C until the genotype analysis was performed. FcgRIIB-Ile225Thr polymorphisms were genotyped by PCR-restriction fragment length polymorphism method. The Ile225Thr polymorphism. A 100-bp fragment was amplified using the specific sense and anti-sense primer pair: 5'- TGC CTG TCC TGA TGT CTG TC -3' and 3'- CAG CAA CAA TGG CCG CGA CAG CA-5'. After a 4 min incubation at 96C, 35 cycles of PCR were performed (96C 30 s 60C 30 s 72C 90 s), followed by a 7 min extension at 72C until genotype analysis was performed following a standard protocol. PCR was performed in 10 ml volumes. The PCR product was then incubated with Pshal endonuclease at 37C overnight, PCR fragments containing 225 Thr/Thr are digested into two fragments (100,22bp), whereas PCR fragments containing 225Ile/Th r are digested into three fragments (22,78,100 bp), The 22-bp fragments are not visible on the agarose gel. The 225Ile/ Ile genotypes are undigested. DNA samples of all families, as well as blind duplicate samples were included in each round of amplification to check for consistency and to ensure genotype quality control, in neither cohort were genotyping discrepancies detected between the repeated samples.

Statistical analysis

In order to avoid the bias of population admixture by arising from population-based association study, an extension of the transmission/disequilibrium test, unified family-based association test (FBAT),[13] were performed under dominant, recessive and additive genetic models. The number of informative families was dependent on the genetic models. The statistical power of FBAT depended on the number of informative families. The Single-marker FBAT analysis was used to estimate the single loci frequencies. Each test counted how often a specific locus was present in informative families with SLE. Positive Z statistic of single locus FBAT indicates a specific single locus was more frequently transmitted into patients with SLE in informative families than expected under the null hypothesis of no linkage and no association. To test transmission disequilibrium in families, we applied both the conventional TDT statistic (disequilibrium of transmission of alleles from heterozygous parents to affected child) and the SDT (considering patient and other normal siblings), Statistic is calculated as (b-c) 2 /(b+c), where b and c are, respectively, the number of transmissions and non-transmissions of the allele. Crude and adjusted ORs and 95% CIs for the association of FcgRIIB genotype and Hypersensitiveness with SLE were calculated using conditional logistic regression. This was accomplished using SPSS 10.1 software (SPSS Inc., 2000).


   Results Top


A total of 119 patients with SLE from 95 nuclear families that contained complete genotype were used in the data analysis. Also 316 family members of these patients were genotyped. [Table - 1] shows the family structures of recruited SLE.

Stratified by FcgRIIB-Ile225Thr genotypes, among 119 patients, the frequencies of FcgRIIB-Ile225Thr, Ile/Ile, Ile225Thr and Ter225Thr genotypes were 8.1%, 61.3% and 30.6%. The 225Ile and 225Thr allele frequencies were 38.8% and 61.2% [Table - 2]. The genotype distribution of Ile225Thr polymorphisms was not significantly deviated from Hardy-Weinberg's expectation (c 2=5.526, P =0.063).

In FcgRIIB-Ile225Thr single loci analysis, the relation between FcgRIIB polymorphisim and SLE by family-based association test (single-marker FBAT analysis) showed that the allele of FcgRIIB-225Thr was significantly associated with SLE (Z=3.707, P =0.00021) in additive model; dominant model (Z=2.904, P =0.003) and recessive model (Z=3.088, P =0.002). The results of single-marker FBAT analyses are summarized in [Table - 3]. TDT and SDT analysis also revealed increased transmission for the major allele of the SNP (rs1050501) to SLE offspring (c 2= 7.14, P =0.0105) [Table - 4].

In addition, the univariate conditional logistic regression model show that some environmental factors were significant between the SLE case with their normal siblings, such as sex ( P =0.000, OR=0.063, CI=0.015-0.261), hypersensitiveness ( P =0.017, OR=2.556, CI=1.183-5.523) and FcgRIIB - Ile225Thr ( P =0.024, OR=2.444, CI=1.126-5.309) [Table - 5],[Table - 6],[Table - 7]; multi-conditional logistic regression model shows that a possible interaction of hypersensitiveness and FcgRIIB - Ile225Thr polymorphism ( P =0.044, OR=3.726, CI=1.033-13.441) [Table - 8].


   Discussions Top


In study, we first demonstrated that FcgRIIB-225Thr allele were often transmitted to SLE offspring using family-based association study in Chinese population. Therefore, we consider that FcgRIIB gene may play an important role in the susceptibility to SLE. Because FcgRIIB is the only gene among the FcgR family that contains an immunoreceptor tyrosine-based inhibitory motif ( ITIM ) and has the ability to transmit inhibitory signals in B cells and myelomonocytic cells.[14] As described earlier, FcgRIIB -deficient mice have been shown to become susceptible to lupus-like disease[15] and lupus prone mice have been shown to have polymorphisms in the FcgRIIB gene,[16],[17] moreover, FcgRIIB has a higher affinity to IgG3 than other IgG subclasses[18] and IgG3 antinucleosome antibodies have been reported to be most strongly associated with disease activity of SLE.[18] However, significant linkage disequilibria were observed between the alleles of FcgR gene family, the status of linkage disequilibrium has been shown to be different in various populations. Therefore, our results may either be caused by the linkage disequilibrium with another primarily associated gene.

Our findings of gene-environment interaction suggest a possible interaction between the FcgRIIB - Ile225Thr polymorphism and the hypersensitiveness using conditional logistic model adjusted age, sex and occupation. The individual carrying both the 225Thr allel and hypersensitiveness has more highly risk than others.

There are several limitations in this study. The number patients are limited and the biologic significance of the tested FcgRIIB SNPs has not assessed. Independent confirmation in various SLE is required in future study. The advantage of our study is the family-based association study and conditional logistic model.

In conclusion, the present study has demonstrated that FcgRIIB-Ile225Thr polymorphism were significantly with genetic susceptibility to SLE in Chinese population by family-based association test. A possible interaction between the FcgRIIB- Ile225Thr polymorphism and the hypersensitiveness Moreover, the SNP was first reported on association with SLE in the Chinese population and other racial population. Further genetic studies need to be replicated in populations of ancestries other than Chinese.

Electronic-database information:

  1. dbSNP Home Page, http://www.ncbi.nlm.nih.gov/SNP (for FcgRIIB polymorphisms [cluster IDs rs1050501])
  2. FBAT, http://www.biostat.harvard.edu/~fbat/fbat.htm (The haplotype FBAT method has been integrated into the FABT version 5.5)
  3. Gen Bank, http://www.ncbi.nlm.nih.gov/Genbank/(for chromosome 1 genomic contig [accession number NT_004487], human FcgRIIB cDNA [accession number NM_004001])
  4. Online Mendelian Inheritance in Man(OMIN), http://www.ncbi.nlm.nih.gov/Omim/ (for SLE, Fcg RIIB ) or http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db= OMim
  5. Primer3, http://www-genome.wi.mit.edu/cgi-bin/primer/primer3_www.cgi
  6. GSC BLAST Search, http://www.genome.wustl.edu/projects/chimp/blast/pan_client.pl (for chimpanzee genome sequence)



   Acknowledgments Top


This work was supported by grants from the National Natural Science Foundation of China (30371247, 30571608) and grant number 2002kj175ZD from the Department of Education Emphasis Foundation from AnHui Province. We thank all families with SLE for their enthusiastic participation in the genetic epidemiology.

 
   References Top

1.Salmon JE, Pricop L. Human receptors for immunoglobulin G: Key elements in the pathogenesis of rheumatic disease. Arthrits Rheum 2001;44:739-50.  Back to cited text no. 1      
2.Qin D, Wu J, Vora KA, Ravetch JV, Szakal AK, Manser T, et al . Fc gamma receptor IIB on follicular dendritic cells regulates the B cell recall response. J Immunol 2000;164:6268-75.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]  
3.Tew JG, Wu J, Fakher M, Szakal AK, Qin D. Follicular dendritic cells: Beyond the necessity of T-cell help. Trends Immunol 2001;22:361-7.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]  
4.Haberman AM, Shlomchik MJ. Reassessing the function of immune-complex retention by follicular dendritic cells. Nat Rev Immunol 2003;3:757-64.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
5.Kosco-Vilbois MH. Are follicular dendritic cells really good for nothing? Nat Rev Immunol 2003;3:764-9.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]  
6.Takai TM, Ono M, Hikida H, Ohmori JV, Ravetch JV. Augmented humoral and anaphylactic responses in Fc gamma RII-dificient mice. Nature 1996;379:346-9.  Back to cited text no. 6      
7.Clynes R, Maizes JS, Guinamard R, Ono M, Takai T, Ravetch JV. Modulation of immune complex-induced inflammation in vivo by the coordinate expression of activation and inhibitory Fc receptors. J Exp Med 1999;89:179-85.  Back to cited text no. 7      
8.Karassa FB, Trikalinos TA, Ioannidis JP; FcgammaRIIa-SLE Meta-Analysis Investigators. The FcgRIIa-SLE Meta-Analysis Investigators: Role of the Fcg receptor IIa polymorphism in susceptibility to systemic lupus nephritis. Arthritis Rheum 2002;46:1563-71.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]  
9.Karassa FB, Trikalinos TA, Ioannidis PA; FcgRIIIA-SLE Meta-Analysis Investigators. The FcgRIIIA-F158 allele is a risk factor for the development of lupus nephritis: A meta-analysis. Kidney Int 2003;63:1475-82.  Back to cited text no. 9      
10.Edberg JC, Langefeld CD, Wu J, Moser KL, Kaufman KM, Kelly J, et al . Genetic linkage and association of Fcg receptor IIIA (CD16) on chromosome 1q23 with human systemic erythematosus. Arthritis Rheum 2002;46:2132-40.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]  
11.Molina V, Shoenfeld Y. Infection, vaccines and other environmental triggers of autoimmunity. Autoimmunity 2005;38:235-45.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]  
12.Boeckler P, Milea M, Meyer A, Uring-Lambert B, Heid E, Hauptmann G, et al . The combination of complement deficiency and cigarette smoking as risk factor for cutaneaous lupus erythematosus in men: A focus on combined C2/C4 deficiency. Br J Dermatol 2005;152:265-70.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]  
13.Rabinowitz D, Laird N. A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 2000;50:211-23.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]  
14.Ravetch JV, Bolland S. IgG Fc receptors. Annu Rev Immunol 2001;19:275-90.   Back to cited text no. 14  [PUBMED]  [FULLTEXT]  
15.Bolland S, Ravetch JV. Spontaneous autoimmune disease in FcRIIB-deficient mice results from strain-specific epistasis. Immunity 2000;13:277-85.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]  
16.Dijstelbloem HM, van de Winkel JG, Kallenberg CG. Inflammation in autoimmunity: Receptors for IgG revisited. Trends Immunol 2001;22:510-6.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]  
17.van der Pol WL, van de Winkel JG. IgG receptor polymorphisms: Risk factor for disease. Immunogenetics 1998;48:222-32.  Back to cited text no. 17      
18.Amoura Z, Koutozov S, Chabre H, Cacoub P, Amoura I, Musset L, et al . Presence of antinucleosome autoantibodies in a restricted set of connective tissue diseases: Antinucleosome antibodies of the IgG3 subclass are markers of renal pathogenicity in systemic lupus erythematosus. Arthritis Rheum 2000;43:76-84.  Back to cited text no. 18      


    Figures

  [Figure - 1]
 
 
    Tables

  [Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6], [Table - 7], [Table - 8]

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