Rheumatology Advance Access originally published online on May 22, 2006
Rheumatology 2006 45(8):1044-1046; doi:10.1093/rheumatology/kel160
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LETTER TO THE EDITOR |
Polymorphisms of the FCRL3 gene in a Spanish population of systemic lupus erythematosus patients
1 Instituto de Parasitología y Biomedicina, CSIC and 2 Servicio de Medicina Interna, Hospital San Cecilio, Granada, 3 Servicio de Reumatología, Hospital Virgen de la Victoria and 4 Servicio de Medicina Interna, Hospital Carlos-Haya, Malaga, and 5 Servicio de Medicina Interna, Hospital Virgen del Rocío, Sevilla, Spain, 6 Department of Biomedical Genetics, Utrecht University Medical Centre, Utrecht, the Netherlands and 7 Servicio de Inmunología. Hospital Virgen del Rocío, Sevilla, Spain
Correspondence to: María Francisca González-Escribano, PhD, Servicio de Inmunología, Hospital Universitario Virgen del Rocío, Avda Manuel Siurot s/n, 41013 Sevilla, Spain. E-mail: mariaf.gonzalez.sspa{at}juntadeandalicia.es
SIR, Receptors for the Fc portion of IgG (Fc
Rs) are essential mediators of the inflammatory effect of immune complexes and cytotoxic antibodies [1, 2]. FcRs are candidate genes to the susceptibility to autoimmune disease. A new family of FcRs, FcR-like (FcRL) or FcR homologous (FcRH) genes, with similarity in structure and sequence to the classical FcR genes, has been recently identified [3]. They map in the chromosomal region 1q21–32, which has showed evidence of linkage with systemic lupus erythematosus (SLE) and other autoimmune diseases [4, 5]. A very recent study reported an association of the FCRL3 gene with several autoimmune diseases [6]. The aim of this study was to investigate the association of the FCRL3 and SLE in a large cohort of SLE Spanish patients.
We analysed a Spanish Caucasian case-control panel consisting of 520 SLE patients meeting the American College of Rheumatology (ACR) criteria for SLE [7, 8], and recruited from five Spanish hospitals. Samples were obtained from subjects after they provided written informed consent. The study was approved by all local ethical committees of the corresponding hospitals. A total of 540 matched blood and bone marrow donors were included as healthy controls. Among the patients, 59.9% had anti-dsDNA antibodies, 35.9% developed lupus nephritis and 37.5% were DRB1*03 positive. No significant differences in the frequency of the different alleles of the three polymorphisms studied were observed among the patient groups or the control groups from different cohorts. Hence, we combined all cohorts to form a SLE case-control group, which was used in further analyses. The control study population was found to be in the Hardy–Weinberg equilibrium for all the polymorphisms studied.
Table 1 shows the distribution of genotypes and alleles of the three FCRL3 polymorphisms studied in SLE patients and controls. As described previously [6], the concordance between the polymorphisms fcr3_3 and fcr3_6 was almost total, and so they both are referred to as fcr3_3 Single Nucleotide Polymorphism (SNP) hereafter. There was a significant deviation in the distribution of the fcr3_3 genotypes between the patient and the control groups (P = 0.047 by chi-square test on a 3 x 2 contingency table). We tested the hypothesis of a recessive model of inheritante for the proposed causal allele fcr3_3 C. Frequency of homozygous CC was higher in SLE patients (18.5 vs 14.3% in the control group), but the difference did not reach statistical significance (P = 0.06). No statistically significant differences in the distribution of fcr3_4 genotypes were detected to compare SLE patients and controls (P = 0.8 by chi-square test on a 3 x 2 contingency table). Also no significant differences in the distribution of the allelic frequencies were observed to compare SLE patients and controls in any case.
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Table 1 shows data for the three most common fcr3_3/4/6 haplotypes (frequency >5%) found in our population. A significantly higher frequency of the CGA haplotype was found among patients (15.7 vs 12.4%, P = 0.04, OR = 1.32, 95% CI 1.00–1.75).
No significant differences in the distribution of these polymorphisms were observed when comparing individuals with vs without anti-dsDNA antibodies, having vs not having lupus nephritis and DRB1*03 positive vs negative (data not shown).
Validation of genetic association studies requires replication using independent data set in order to search for functional variants relevant to disease ethiology [9]. Results of the present work cannot completely confirm the recent finding that FCRL3 is associated with SLE [6]. We found a different genotype distribution of the proposed causal variant among SLE patients and controls. Although our results for CC genotype were not statistically significant (statistical power <78% to detect an OR = 1.49), they showed the same trend as the Japanese study. In fact, odds ratios (ORs) (1.36 vs 1.49) were very similar in both studies. The finding that no significant differences in the fcr3_3 allelic frequencies does not discard a recessive model as that proposed by Kochi et al. [6]. To analyse the haplotype distribution, we found that the CGA haplotype was the only FCRL3 haplotype that seemed to be associated with SLE. Of note, the study by Kochi et al. [6] did not perform haplotype analysis in SLE, but both haplotypes bearing the fcr3_3 C allele were associated with RA with similar OR. According to our results, the presence of the fcr3_3 C allele in neutral and risk haplotypes would discard the fcr3_3 C allele as the only SLE associated variant. Genetic heterogeneity, due to variability not only in the frequency of alleles but also in diverse effects of linkage disequilibrium for other important genetic markers, seems to be the most likely cause of the discrepancies between ours and the previous results. In fact, the frequency of CAA haplotype was higher in Caucasian (31% in European American and 26% in Spanish) than in Japanese controls (19% P < 0.0001 in both cases), whereas the frequency of the CGA haplotype was similar in Spanish (12.4%), Japanese (14%) and European American (14%, P > 0.05) populations. In conclusion, our results suggest that the FCRL3_3 SNP does not play a major role in SLE susceptibility in Spanish population. Potential association of the FCRL3 gene cannot be excluded.
The study is supported by grants: Plan Nacional de I+D (SAF03-3460), Fondo de Investigaciones Sanitarias (PI 04 0067) and Junta de Andalucía, grupos CTS-197 and CTS-180.
Notes
*These authors share senior authorship of this manuscript. 
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