Independent association of HLA-DR and FC{gamma} receptor polymorphisms in Korean patients with systemic lupus erythematosus

H. S. Lee, Y. H. Chung1, T. G. Kim2, T. H. Kim, J. B. Jun, S. Jung, S. C. Bae and D. H. Yoo

Division of Rheumatology, The Hospital for Rheumatic Diseases, Hanyang University, Seoul, 1Department of Microbiology, Hanyang University Medical College, Seoul and 2Department of Microbiology and Immunology, Catholic University College of Medicine, Seoul, Korea.

Correspondence to: D. H. Yoo, The Hospital for Rheumatic Diseases, Hanyang University, Seoul, 133–792, Korea. E-mail: dhyoo{at}hanyang.ac.kr


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. To determine the distribution of HLA-DR type and Fc{gamma}RIIa/IIIa polymorphisms, and to analyse the combined effects of these genes for susceptibility in Korean systemic lupus erythematosus (SLE) patients.

Methods. A total of 299 SLE patients meeting 1982 ACR criteria and 144 Korean disease-free controls were enrolled. Genotyping for the Fc{gamma}RIIa 131 R/H and Fc{gamma}RIIIa 176 F/V was performed by polymerase chain reaction (PCR) of genomic DNA using allele-specific primers. HLA-DRB1 typing was performed by the PCR-SSOP method.

Results. There was significant skewing in the distribution of the three Fc{gamma}RIIa genotypes between the SLE patients and the controls [P = 0.002 for R/R131 vs R/H131 and H/H131, relative risk (RR) 2.6 (95% CI 1.3–5.2)], but not in Fc{gamma}RIIIa genotypes. HLA-DRB1*15 allele was significantly more prevalent among SLE patients than the control population [P < 0.02, RR = 1.7 (1.1–2.6)]. HLA-DRB1 genotypes or allele frequencies of the SLE patients with nephritis did not differ significantly from those of the SLE patients without nephritis. We analysed the combined effects of the two candidate genes on SLE susceptibility. HLA-DRB1*15 allele was a significant predictor of SLE in individuals who were not homozygous for Fc{gamma}RIIa-R/R131 [RR = 2.1 (1.2–3.7), P < 0.008], and the Fc{gamma}RIIa-R/R131 genotype vice versa [RR = 5.3 (1.9–15.4), P < 0.001]. However, an additive or synergistic effect of both susceptible genes on relative risk for SLE was not evident.

Conclusions. Our results suggest that Fc{gamma}RIIa-R/R131 homozygote and HLA-DRB1*15 allele are independent risk factors in Korean SLE patients without additive or synergistic effects.

KEY WORDS: SLE, HLA-DR type, Fc{gamma}RIIa and IIIa polymorphism.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune dysregulation, leading to high levels of autoantibody production, immune complex deposition and tissue injury. Epidemiological studies such as twin studies and familial aggregation studies suggest a strong genetic component for susceptibility to SLE; siblings of SLE patients have a much greater relative risk for disease in comparison with the population as a whole ({lambda} >= 15) [13].

Several genetic strategies have been used to define susceptibility genes of genetically complex diseases like SLE. These involve the systemic genome-wide scan approach, animal models and the candidate gene approach. To date, there are six published genome-wide screens in SLE families and these screens have identified six regions meeting criteria for significant linkage (LOD score >3.3) [49]. Using several animal models of SLE and genetic dissection, similar candidate genes or gene families responsible for susceptibility to SLE in both mouse and humans were suggested [1014]. Candidate gene approaches in both population association and family linkage studies have been widely used and thus there are hundreds of published studies. Despite several potential difficulties such as population admixture and genetic drift, this association study has the significant advantage over the other strategies of having greater power to detect small effects [3, 15, 16]. Among these candidate genes, the HLA region, complement components and low-affinity receptors for IgG showed significant association with SLE susceptibility [3, 15].

HLA genes have received significant attention in human SLE, and there is evidence supporting a role for specific extended HLA haplotypes as genetic risk factors for disease expression in several populations [1721]. HLA-DR2 and -DR3 have shown consistent associations with SLE in European Caucasian populations [22]. In Korea, significant increased frequency of HLA-DRB1*1501 to DRB5*0101, and DR9 was reported in SLE patients [23, 24]. These HLA regions also showed stronger association with autoantibody production in SLE than with disease expression itself [22]. Although the precise genes attributed to these associations are not known, genome-wide scan studies have indicated that this MHC region is a very important gene location for susceptibility to SLE [4, 5, 9]. Recent studies have shown that Fc{gamma} receptors (Fc{gamma}R) could be one of the non-MHC susceptibility genes for SLE [4, 2528]. Fc{gamma}RIIa and IIIa are located within the same cluster in chromosome 1q21-23 and they have allelic variants which differ substantially in their functional capacities of immune complex clearance. Fc{gamma}RIIa alleles, R131 and H131, differ at amino acid position 131 in the extracellular domain and also differ in their ability to bind human IgG2: R131 is the low-binding allele, H131 is high binding and heterozygotes have intermediate function. Fc{gamma}RIIIa alleles, F176 and V176, which differ in one amino acid at position 176 in the extracellular domain and differ in their ability to bind human IgG1 and IgG3: F176 is the low-binding allele, V176 is high binding. Although there are a few reports about linkage disequilibrium (LD) between Fc{gamma}RIIa and IIIa in other ethnic groups, there have been no reports to date in Korean populations.

We have previously reported that Fc{gamma}RIIa-R131 homozygote and R131 allele were predisposing factors for SLE development [29]. Recently, the importance of epistasis and epistatic interaction between two susceptibility alleles in multigenic diseases such as SLE has been emphasized in genetic pathogenesis based on various genetic studies. Thus we studied whether the epistatic effect between HLA-DR and Fc{gamma}RIIa/IIIa among the many important candidate genes in SLE was observed in Korean patients with SLE.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A total of 299 Korean patients meeting the American College of Rheumatology (ACR) criteria for SLE [30] were recruited from eight rheumatology departments based in university hospitals throughout the country. A disease-free control group consisted of 144 medical students and laboratory workers from Hanyang University medical centre. All SLE patients and control subjects were ethnically matched Koreans. Written informed consent was obtained from each subject. Patients were classified as having nephritis if they fulfilled the ACR criteria for renal involvement. The other major organ involvement was defined according to the criteria of the ACR. Clinical and laboratory data including sex, age, age of the first symptom onset, age at the time of clinical diagnosis and ACR diagnosis were obtained retrospectively from the medical record. Testing for antinuclear antibodies (ANA) was carried out by indirect immunofluorescence using IT-1 cells; C3 and C4 by nephelometry (Beckman, USA); anti-double-stranded DNA antibody by radioimmunoassay or Crithidia lucillae assay; anti-Sm, -Ro, -La and -nRNP by double immunodiffusion; and anticardiolipin antibody (aCL) by ELISA. We used the lowest complement values and the highest value for the amount of daily proteinuria.

Fc{gamma}RIIa/IIIa genotyping and Fc{gamma}RIIIa genomic DNA sequencing
For genotyping of Fc{gamma}RIIa and Fc{gamma}RIIIa, DNA was isolated from peripheral blood (Puregene kit, Gentra systems, Minneapolis, MN) and polymerase chain reaction (PCR) was performed as previously described [29, 31, 32]. To confirm the Fc{gamma}RIIIa genomic sequence of 17 individuals whose PCR results were inadequate, PCR was done with primers to amplify a portion of exon 4 of Fc{gamma}RIIIa which corresponds to EC2 [29, 32]. PCR products were purified by Qiagen Column (Qiagen, Germany) and genomic DNA sequencing was performed on an ABI PRISM 310 (Perkin Elmer, USA).

HLA-DRB1 typing
HLA-DRB1 typing was performed by the PCR-SSOP method, which was essentially the same as that described at the 12th International Workshop, with minor modifications [33]. Specific HLA-DRB1 primers were used to amplify DRB1 products, which were then denatured and immobilized on a nylon membrane and probed with a series of digoxigenin-labelled oligonucleotides specific for the known hypervariable sequences. Stringent washing was performed in the presence of tetramethyl ammonium chloride (TMAC, Sigma chemical Co., St. Louis, USA). The hybridized probe was detected according to the manufacturer’s instructions with the anti-digoxigenin antibody conjugated with alkaline phosphatase, followed by addition of chemiluminescent substrate CSPD (Boehringer Mannheim, GmbH, Germany). Chemiluminescence was detected by exposing to radiographic film.

Statistical analysis
The distribution of the allele and genotype of Fc{gamma}RIIa, Fc{gamma}RIIIa and HLA-DRB1 between two groups (SLE patients vs controls, SLE with nephritis vs SLE without nephritis, SLE with nephritis vs controls) was compared with 3 x 2 or 2 x 2 contingency tables using the {chi}2-test.

We used the EH program for haplotype analysis [34, 35]. The frequency of each haplotype of Fc{gamma}RIIa 131–Fc{gamma}RIIIa 176 (RF, RV, HF and HV) can be calculated from this linkage utility program. The odds ratio (OR) for patients with the low-binding haplotype Fc{gamma}RIIa R131–Fc{gamma}RIIIa F176 (RF) and the high-binding haplotype Fc{gamma}RIIa H131–Fc{gamma}RIIIa V176 (HV) for disease susceptibility and prevention from disease development was calculated, respectively.

Linkage disequilibrium between Fc{gamma}RIIa and Fc{gamma}RIIIa was assessed using the D value for non-random assortment of alleles [36]. To observe the additive effect of Fc{gamma}RIIa/IIIa and HLA-DRB1 on the development of SLE or lupus nephritis, groups with both risk alleles were compared with reference groups without both risk alleles using {chi}2. We applied corrected P values to this multiple testing [37]. In brief, when an initial 2 x C contingency table is partitioned into non-independent 2 x 2 tables, the value of corrected a' is obtained as follows: a' = a/2(C - 1). The value of C in our multiple testing is 4.

A probability of 0.05 (2-tailed) was used to reject the null hypothesis that there was no difference in the distribution of allele and genotype between the groups. Odds ratios with 95% confidence intervals (95% CI) were calculated from 2 x 2 contingency tables by {chi}2-test. The mean age at onset and age of clinical and ACR diagnosis were compared using independent sample t-test or ANOVA, and the amount of proteinuria using the Mann–Whitney U-test or Kruskal–Wallis test. Here we used SPSS 10.0 for Windows for statistical analysis.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Baseline characteristics
We used the same data for SLE patients that we used in our previous report [29]. These are summarized in Table 1.


View this table:
[in this window]
[in a new window]
 
TABLE 1. Baseline characteristics of the 299 SLE patients

 
Distribution of Fc{gamma}RIIa and Fc{gamma}RIIIa between SLE patients and controls
There was significant skewing in the distribution of the three Fc{gamma}RIIa genotypes between the SLE patients and the controls, but not in Fc{gamma}RIIIa genotypes (Table 2): Fc{gamma}RIIa R/R131 homozygote was a significant predictor of SLE [P = 0.002 for R/R131 vs R/H131 and H/H131, OR 2.6 (95% CI 1.3–5.2)], but Fc{gamma}RIIa R131 allele (R/R131 or R/H131) was not. The frequency of any genotype and allele of both Fc{gamma}RIIa and IIIa was not significantly different between SLE with nephritis and SLE without nephritis, and between SLE with nephritis and controls.


View this table:
[in this window]
[in a new window]
 
TABLE 2. Distribution of Fc{gamma}RIIa and Fc{gamma}RIIIa genotypes and gene frequencies in Korean SLE patients and controls

 
To analyse the protective effect of haplotype including high-binding alleles or to analyse the susceptibility of disease of haplotype including low-binding alleles of Fc{gamma}RIIa and IIIa, we observed the frequency of Fc{gamma}RIIa/Fc{gamma}RIIIa haplotype R131/F176, R131/V176, H131/F176, H131/V176 in SLE with or without nephritis and controls. In this analysis, we observed that the high-binding allele combination H131/V176 showed a protective effect for the development of lupus nephritis [P = 0.018 for H131/V176 vs R131/F176, R131/V176, and H131/F176, relative risk (RR) 0.6 (95% CI 0.4–0.9)], but the low-binding allele combination R131/F176 was not associated with SLE and SLE nephritis (Table 2). Testing for the presence of LD between alleles at the two Fc{gamma}R loci showed no significant association ({triangleup} = –0.0057, c2 = 0.3, P = 0.58).

Distribution of HLA-DR type between SLE patients and controls
HLA-DRB1*15 allele was significantly more prevalent among SLE patients than the control population [P = 0.015 for HLA-DRB1*15 allele vs non-HLA-DRB1*15 allele, RR 1.7 (95% CI 1.1–2.6)] (Table 3). No HLA-DR genotype or allele of the SLE patients with nephritis differed significantly from those of the SLE patients without nephritis. However, comparing the lupus nephritis patients with controls, DRB1*07 was more prevalent among the lupus nephritis group [RR = 2.2 (1.2–4.3), P < 0.002] (Table 3). The frequency of HLA-DRB1*01 and *04 allele was lower in SLE patients than controls. With respect to clinical manifestations and autoantibody profiles of SLE, the frequencies of neurological disorder and anti-RNP antibody in SLE patients with HLA-DRB1*15 allele were significantly increased compared with controls (Table 4). Besides HLA-DRB1*15, the other HLA-DR types were also associated with some clinical manifestations or laboratory findings. Increased frequency of arthritis and bacterial infection in patients with HLA-DRB1*04, increased serum creatinine level in patients with HLA-DRB1*01, haemolytic anaemia in patients with HLA-DRB1*13 or DRB1*07, anti-RNP antibody in patients with HLA-DRB1*11, anti-La antibody in patients with HLA-DRB1*07 or DRB1*08, lupus anticoagulant in patients with HLA-DRB1*12, and Raynaud’s phenomenon and low C4 in patients with HLA-DRB1*09 were observed (Table 4).


View this table:
[in this window]
[in a new window]
 
TABLE 3. Distribution of HLA-DRB1 alleles in SLE patients and controls

 

View this table:
[in this window]
[in a new window]
 
TABLE 4. HLA-DR type showing significant associations (P < 0.05) with specific clinical manifestations or laboratory findings

 
Interaction of the Fc{gamma}RIIa and HLA-DR polymorphism in the risk of SLE
To evaluate the combined effect of the Fc{gamma}RIIa and HLA-DR polymorphism, we calculated the risk of developing SLE conferred by either the Fc{gamma}RIIa-R/R131 genotype or HLA-DRB1*15 allele, and then calculated the risk conferred by both high-risk genes together [25, 38, 39] (Table 5). At first, the risk associated with the presence of the HLA-DRB1*15 allele (homozygote or heterozygote) in the absence of the Fc{gamma}RIIa-R/R131 genotype compared with the reference group with neither Fc{gamma}RIIa-R/R131 nor HLA-DRB1*15 allele was determined. The risk was statistically significant in SLE patients [RR = 2.1 (1.2–3.7), corrected P < 0.008]. Similarly, the effect of the Fc{gamma}RIIa-R/R131 homozygote in the subgroup of individuals who were HLA-DRB1*15 allele negative was statistically significant [RR = 5.3 (1.9–15.4), corrected P < 0.001]. The corrected P value of the above partitioning 2 x 2 comparison test was 0.05 and 0.006, respectively. The combined effect of these two polymorphic genes was then calculated, but individuals with both genes did not show a significant increase in SLE development compared with the reference group with neither Fc{gamma}RIIa-R/R131 nor HLA-DRB1*15 allele (Table 5).


View this table:
[in this window]
[in a new window]
 
TABLE 5. The combined effect of both candidate genes on SLE development

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
SLE is a disease of polygenic inheritance and therefore interactions between candidate genes that participate in separate genetic pathways in SLE pathogenesis may be important [3]. Based on genome-wide scans, animal studies and many association studies, a multitude of candidate genes have been noticed recently [4, 5]. They contain genes related to triggering the loss of immune tolerance to nuclear autoantigens and mediating the initiation of autoimmunity. Also genes participating in the disruption of the normal immune system and genes mediating specific organ damage were important in SLE pathogenesis. These genes may co-operate in the development of SLE in concert [3].

Fc{gamma}R genes in chromosome 1q23 and MHC class II genes in chromosome 6p are among candidate genes of SLE. There are various proposals for the mechanism underlying the higher association of these polymorphisms in SLE patients. HLA class II molecules elicit the T-helper cell response after presentation of specific antigens by antigen-presenting cells. Therefore, autoantibody production mediated by T-helper cells specific to autoantigens, a characteristic feature in SLE, can be attributed to HLA class II molecules [3, 40]. The role of Fc{gamma}R polymorphisms in the pathogenesis of SLE has been focused on their dysregulation of immune complex handling and enhanced immune complex-mediated organ injury [25, 38, 39]. Despite this reasonable theoretical background and many positive results, a significant debate in interpreting these association data is posed by the significant LD across the region. In fact, reported associations of SLE with several MHC class III genes such as TNF-{alpha}, TAP genes, HSP70 and complement genes as well as DQ alleles may reflect LD with HLA-DR allele or the epistatic effects of several genes on extended haplotypes [4145]. Also, the Fc{gamma} receptors are very tightly clustered at 1q23, and the interpretation of the association result of one locus is potentially complicated by LD in the region [25, 38, 46].

This study showed similar results to previous reports on Korean populations: Fc{gamma}RIIa-R/R131 homozygote and HLA-DRB1*15 allele were significantly prevalent in SLE patients, but not Fc{gamma}RIIIa polymorphism or HLA-DR3 [23, 24, 29]. In addition, several non-HLA-DRB1*15 alleles were associated with some clinical manifestations and some autoantibodies as shown in Table 4. Among these associations, increased frequency of arthritis in patients with HLA-DR4—which has been reported as a susceptible allele in rheumatoid arthritis—was interesting and suggested that HLA-DR4 allele participates in the development of arthritis in SLE as in RA. We further analysed the effects of Fc{gamma}RIIa polymorphism on arthritis in SLE patients. There was no association between the two variables (data not shown). Although we showed there are many associations between various HLA-DRB1 alleles and clinical manifestations or laboratory findings, interpretations about their protective or predictive effects in SLE are obscure and further study is needed to clarify their associations.

We analysed the combined effects of both candidate genes on SLE, HLA-DRB1 and Fc{gamma}RIIa-R/R131. HLA-DRB1*15 allele was a significant predictor of SLE in Fc{gamma}RIIa-R/R131 homozygote-negative individuals, and Fc{gamma}RIIa-R/R131 homozygote vice versa. Also, ORs of HLA-DRB1*15 and Fc{gamma}RIIa-R/R131 homozygote for SLE in Fc{gamma}RIIa-R/R131 homozygote-negative and HLA-DRB1*15-negative individuals, respectively, are more increased than initial ORs in total individuals. These results suggest that the two susceptible genes may not have an additive or synergistic effect on OR for SLE, but rather each gene has independent association with SLE. Also one candidate gene may have a more pathogenic role, especially within the individuals without the other susceptible gene, suggesting HLA-DRB1 and Fc{gamma}RIIa are probably involved in different pathogenic pathways. There are a few reports that have analysed the association of these two genes in SLE development. Manger et al. [25] analysed the distribution of Fc{gamma}RIIa polymorphism and HLA-DR3 in Caucasian SLE patients. Although they did not present the data in detail, they suggested that HLA-DR3 haplotypes did not seem to represent additional risk factors for the association of the Fc{gamma}RIIa-R131 allele polymorphism with SLE. We also obtained the results about LD between Fc{gamma}RIIa and Fc{gamma}RIIIa in Korean populations, which showed no significant associations. These results were consistent with other ethnic groups [28].

In addition, we analysed the combination effect between HLA-DRB1*07 and Fc{gamma}RIIa polymorphism, and HLA-DRB1*15 and Fc{gamma}RIIIa polymorphism, and obtained no significant combination effects (data not shown).

Our study had some limitations to interpretation. Control groups were ethnically matched with SLE patients, but not sex and age matched. Also the size of the control group was too small to conclude the exact role of the combination of two candidate genes in SLE susceptibility.

In conclusion, our results suggest that Fc{gamma}RIIa-R/R131 homozygote and HLA-DRB1*15 allele are independent risk factors in Korean SLE patients without additive and synergistic effects.


    Acknowledgments
 
This research was supported in part by the Center for Functional Analysis of Human Genome FG 2–3.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Reveille JD, Bias WB, Winkelstein JA, Provost TT, Dorsch CA, Arnett FC. Familial systemic lupus erythematosus: immunogenetic studies in eight families. Medicine (Baltimore) 1983;62:21–35.[ISI][Medline]
  2. Lawrence JS, Martins CL, Drake GL. A family survey of lupus erythematosus. 1. Heritability. J Rheumatol 1987;14:913–21.[ISI][Medline]
  3. Wakeland EK, Liu K, Graham RR, Behrens TW. Delineating the genetic basis of systemic lupus erythematosus. Immunity 2001;15:397–408.[ISI][Medline]
  4. Moser KL, Neas BR, Salmon JE et al. Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees. Proc Natl Acad Sci USA 1998;95:14869–74.[Abstract/Free Full Text]
  5. Gray-McGuire C, Moser KL, Gaffney PM et al. Genome scan of human systemic lupus erythematosus by regression modeling: evidence of linkage and epistasis at 4p16-15.2. Am J Hum Genet 2000;67:1460–9.[CrossRef][ISI][Medline]
  6. Gaffney PM, Kearns GM, Shark KB et al. A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families. Proc Natl Acad Sci USA 1998;95:14875–9.[Abstract/Free Full Text]
  7. Gaffney PM, Ortmann WA, Selby SA et al. Genome screening in human systemic lupus erythematosus: results from a second Minnesota cohort and combined analyses of 187 sib-pair families. Am J Hum Genet 2000;66:547–56.[CrossRef][ISI][Medline]
  8. Shai R, Quismorio FP Jr, Li L et al. Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families. Hum Mol Genet 1999;8:639–44.[Abstract/Free Full Text]
  9. Lindqvist AK, Steinsson K, Johanneson B et al. A susceptibility locus for human systemic lupus erythematosus (hSLE1) on chromosome 2q. J Autoimmun 2000;14:169–78.[CrossRef][ISI][Medline]
  10. Sobel ES, Mohan C, Morel L, Schiffenbauer J, Wakeland EK. Genetic dissection of SLE pathogenesis: adoptive transfer of Sle1 mediates the loss of tolerance by bone marrow-derived B cells. J Immunol 1999;162:2415–21.[Abstract/Free Full Text]
  11. Morel L, Croker BP, Blenman KR et al. Genetic reconstitution of systemic lupus erythematosus immunopathology with polycongenic murine strains. Proc Natl Acad Sci USA 2000;97:6670–5.[Abstract/Free Full Text]
  12. Morel L, Mohan C, Yu Y et al. Functional dissection of systemic lupus erythematosus using congenic mouse strains. J Immunol 1997;158:6019–28.[Abstract]
  13. Mohan C, Morel L, Yang P et al. Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies. J Clin Invest 1999;103:1685–95.[Abstract/Free Full Text]
  14. Mohan C, Yu Y, Morel L, Yang P, Wakeland EK. Genetic dissection of Sle pathogenesis: Sle3 on murine chromosome 7 impacts T cell activation, differentiation, and cell death. J Immunol 1999;162:6492–502.[Abstract/Free Full Text]
  15. Harley JB, Moser KL, Gaffney PM, Behrens TW. The genetics of human systemic lupus erythematosus. Curr Opin Immunol 1998;10:690–6.[CrossRef][ISI][Medline]
  16. Clayton D, McKeigue PM. Epidemiological methods for studying genes and environmental factors in complex diseases. Lancet 2001;358:1356–60.[CrossRef][ISI][Medline]
  17. Rood MJ, van Krugten MV, Zanelli E et al. TNF-308A and HLA-DR3 alleles contribute independently to susceptibility to systemic lupus erythematosus. Arthritis Rheum 2000;43:129–34.[CrossRef][ISI][Medline]
  18. Bekker-Mendez C, Yamamoto-Furusho JK, Vargas-Alarcon G, Ize-Ludlow D, Alcocer-Varela J, Granados J. Haplotype distribution of class II MHC genes in Mexican patients with systemic lupus erythematosus. Scand J Rheumatol 1998;27:373–6.[CrossRef][ISI][Medline]
  19. Tarassi K, Carthy D, Papasteriades C et al. HLA-TNF haplotype heterogeneity in Greek SLE patients. Clin Exp Rheumatol 1998;16:66–8.[ISI][Medline]
  20. Lu LY, Ding WZ, Fici D et al. Molecular analysis of major histocompatibility complex allelic associations with systemic lupus erythematosus in Taiwan. Arthritis Rheum 1997;40:1138–45.[Medline]
  21. Vargas-Alarcon G, Salgado N, Granados J et al. Class II allele and haplotype frequencies in Mexican systemic lupus erythematosus patients: the relevance of considering homologous chromosomes in determining susceptibility. Hum Immunol 2001;62:814–20.[CrossRef][ISI][Medline]
  22. Schur PH. Genetics of systemic lupus erythematosus. Lupus 1995;4:425–37.[ISI][Medline]
  23. Hong GH, Kim HY, Takeuchi F et al. Association of complement C4 and HLA-DR alleles with systemic lupus erythematosus in Koreans. J Rheumatol 1994;21:442–7.[ISI][Medline]
  24. Kim HY, Lee SH, Yang HI et al. TNFB gene polymorphism in patients with systemic lupus erythematosus in Korea. Korean J Intern Med 1995;10:130–6.[Medline]
  25. Manger K, Repp R, Spriewald BM et al. Fc{gamma} receptor IIa polymorphism in Caucasian patients with systemic lupus erythematosus: association with clinical symptoms. Arthritis Rheum 1998;41:1181–9.[CrossRef][ISI][Medline]
  26. Norsworthy P, Theodoridis E, Botto M et al. Overrepresentation of the Fc{gamma} receptor type IIA R131/R131 genotype in caucasoid systemic lupus erythematosus patients with autoantibodies to C1q and glomerulonephritis. Arthritis Rheum 1999;42:1828–32.[CrossRef][ISI][Medline]
  27. Salmon JE, Ng S, Yoo DH, Kim TH, Kim SY, Song GG. Altered distribution of Fc{gamma} receptor IIIA alleles in a cohort of Korean patients with lupus nephritis. Arthritis Rheum 1999;42:818–9.[ISI][Medline]
  28. Zuniga R, Ng S, Peterson MG et al. Low-binding alleles of Fc{gamma} receptor types IIA and IIIA are inherited independently and are associated with systemic lupus erythematosus in Hispanic patients. Arthritis Rheum 2001;44:361–7.[CrossRef][ISI][Medline]
  29. Yun HR, Koh HK, Kim SS et al. FcgammaRIIa/IIIa polymorphism and its association with clinical manifestations in Korean lupus patients. Lupus 2001;10:466–72.[CrossRef][ISI][Medline]
  30. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725.
  31. Salmon JE, Millard S, Schachter LA et al. Fc{gamma} RIIA alleles are heritable risk factors for lupus nephritis in African Americans. J Clin Invest 1996;97:1348–54.[Abstract/Free Full Text]
  32. Wu J, Edberg JC, Redecha PB et al. A novel polymorphism of Fc{gamma}RIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest 1997;100:1059–70.[Abstract/Free Full Text]
  33. Bingnon JD, Fernandez V, Cheneau ML et al. HLA DNA class II typing by PCR-SSOP: 12th International Histocompatibility Workshop Experience. In: Charron D, ed. HLA volume 1: Genetic diversity of HLA functional and medical implication. Paris: EDK, 1997.
  34. Xie X, Ott J. Testing linkage disequilibrium between a disease gene and marker loci. Am J Hum Genet 1993;53:1107.
  35. Terwilliger J, Ott J. Handbook for human genetic linkage. Baltimore: Johns Hopkins University Press, 1994.
  36. Svejgaard A, Hauge M, Jersild C et al. The HLA system. An introductory survey. Monogr Hum Genet 1975;7:1–100.[Medline]
  37. Everitt BS. The analysis of contingency tables. London: Chapman & Hall, 1979.
  38. Seligman VA, Suarez C, Lum R et al. The Fc{gamma} receptor IIIA-158F allele is a major risk factor for the development of lupus nephritis among Caucasians but not non-Caucasians. Arthritis Rheum 2001;44:618–25.[CrossRef][ISI][Medline]
  39. Tsao BP. Lupus susceptibility genes on human chromosome 1. Int Rev Immunol 2000;19:319–34.[Medline]
  40. Azizah MR, Ainol SS, Kong NC, Normaznah Y, Rahim MN. HLA antigens in Malay patients with systemic lupus erythematosus: association with clinical and autoantibody expression. Korean J Intern Med 2001;16:123–31.[Medline]
  41. Granados J, Vargas-Alarcon G, Andrade F, Melin-Aldana H, Alcocer-Varela J, Alarcon-Segovia D. The role of HLA-DR alleles and complotypes through the ethnic barrier in systemic lupus erythematosus in Mexicans. Lupus 1996;5:184–9.[ISI][Medline]
  42. Jarjour W, Reed AM, Gauthier J, Hunt S 3rd, Winfield JB. The 8.5-kb PstI allele of the stress protein gene, Hsp70-2: an independent risk factor for systemic lupus erythematosus in African Americans? Hum Immunol 1996;45:59–63.[CrossRef][ISI][Medline]
  43. Folomeeva OM. [Subgroups of patients with systemic lupus erythematosus.] Ter Arkh 1989;61:26–31.
  44. Goldstein R, Arnett FC, McLean RH, Bias WB, Duvic M. Molecular heterogeneity of complement component C4-null and 21-hydroxylase genes in systemic lupus erythematosus. Arthritis Rheum 1988;31:736–44.[ISI][Medline]
  45. Stoppa-Lyonnet D, Gougerot A, Poirier JC, Schmid M, Busson M, Marcelli A. [Familial studies of systemic lupus erythematosus. HLA markers and complotypes.] Pathol Biol (Paris) 1986;34:773–7.[ISI][Medline]
  46. Dijstelbloem HM, Bijl M, Fijnheer R et al. Fc{gamma} receptor polymorphisms in systemic lupus erythematosus: association with disease and in vivo clearance of immune complexes. Arthritis Rheum 2000;43:2793–800.[CrossRef][ISI][Medline]
Submitted 28 March 2003; Accepted 17 April 2003





This Article
Abstract
Full Text (PDF)
All Versions of this Article:
42/12/1501    most recent
keg404v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (2)
Disclaimer
Request Permissions
Google Scholar
Articles by Lee, H. S.
Articles by Yoo, D. H.
PubMed
PubMed Citation
Articles by Lee, H. S.
Articles by Yoo, D. H.