MHC class II, tumour necrosis factor alpha, and lymphotoxin alpha gene haplotype associations with serological subsets of systemic lupus erythematosus

OBJECTIVE: To conduct a case-control study to investigate whether there are independent tumour necrosis factor alpha (TNFalpha) or lymphotoxin alpha (LTalpha) haplotype associations with SLE or with any of the major serological subsets of SLE. METHODS: 157 patients with SLE were genotyped for HLA-DRB1, HLA-DQB1, TNFalpha, and LTalpha alleles by polymerase chain reaction and compared with 245 normal white controls. For TNFalpha, six single nucleotide polymorphisms (SNPs) at positions -1031, -863, -857, -308, -238, and +488 and for LTalpha three SNPs at positions +720, +365, and +249 were studied to assign six TNFalpha haplotypes (TNF1-6) and four LTalpha haplotypes (LTA1-4). All SLE patients had full serological profiles on serial samples. RESULTS: The most significant association with SLE overall was with HLA-DR3 (p<0.001; odds ratio (OR) = 2.5 (95% confidence interval, 1.6 to 3.8)) and the extended haplotype HLA-DQB1*0201;DRB1*0301;TNF2;LTA2 (p<0.001; OR = 2.3 (1.4 to 3.7)). Associations were strongest in the anti-La positive group (13%) of SLE patients (HLA-DR3, OR = 71 (9 to 539); HLA-DQB1*0201, OR = 35 (5 to 267); TNF2, OR = 10 (2.8 to 36), and LTA2, OR = 4.9 (1.1 to 21)). There was an increase in the HLA-DR2 associated extended haplotype (HLA-DQB1*0602;DRB1*1501;TNF1;LTA1) in patients with anti-Ro in the absence of anti-La (p<0.005; OR = 3.9 (1.5 to 10)). The HLA-DR7 extended haplotype (HLA-DQB1*0303;DRB1*0701/2;TNF5;LTA3) was decreased in SLE overall (p<0.02; OR = 0.2 (0.05 to 0.8)). CONCLUSIONS: The strongest association in this predominantly white population with SLE was between HLA-DR3 and anti-La, which seemed to account for any associations with TNFalpha alleles on an extended DR3 haplotype.     

Mannose binding lectin and FcgammaRIIa (CD32) polymorphism in Spanish systemic lupus erythematosus patients

OBJECTIVE: Mannose binding lectin (MBL) and FcgammaRII (CD32) polymorphisms have both been implicated as candidate susceptibility genes in systemic lupus erythematosus (SLE). The aim of this study was to evaluate the relationship of these polymorphisms with SLE. METHODS: We studied a cohort of 125 SLE patients from Barcelona, Spain and 138 geographically matched controls. Sequence-specific primer-polymerase chain reaction (SSP-PCR) amplification was used to determine CD32 and MBL structural polymorphisms. MBL haplotypes were established using sequence-specific oligonucleotide probing techniques. RESULTS: Patients carried the MBL codon 54 mutant allele more frequently than controls [odds ratio (OR) 2.2; 95% confidence interval (CI) 1.2-4.0; P=0.007] and the haplotype HY W52 W54 W57 was found to be significantly lower in cases compared with controls (OR 0.6; 95% CI 0.4-0.9; P=0.016). CONCLUSION: The MBL gene codon 54 mutant allele appears to be a risk factor for SLE, whilst haplotypes encoding for high levels of MBL are protective against the disease. Differences between controls and patients were not significant when considering the FcgammaRIIa polymorphisms; similar results were observed for renal affectation.     

Autoimmunity and tuberculosis. Opposite association with TNF polymorphism

OBJECTIVE: To examine the influence of the -308 and -238 single nucleotide polymorphisms (SNP) of tumor necrosis factor-a gene (TNF) on patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), primary Sjogren's syndrome (SS), and tuberculosis (TB). METHODS: Genomic DNA from patients with RA (n = 165), SLE (n = 100), primary SS (n = 67), and TB (n = 135) and ethnically matched controls (n = 430) was genotyped for TNF -308 and -238 SNP by PCR-RFLP. RESULTS: TNF -308A allele was associated with RA (odds ratio, OR 1.8, p = 0.002), SLE (OR 2.6, p < 0.0001), and primary SS (OR 2.9, p < 0.0001). TNF -308G was associated with TB (OR 1.8, p = 0.02). The -308 GG genotype was protective for autoimmunity (p < 0.003). TNF -238A allele was protective for autoimmunity but represented a susceptibility factor for TB (OR 2.2, p < 0.0001). Haplotype -308A-238G was a protective factor against TB, whereas it carried susceptibility for RA, SLE, and primary SS (p < 0.0001). CONCLUSION: The results show an opposite association of TNF polymorphism with autoimmunity and TB, and suggest the existence of heterozygote advantage, sustaining the hypothesis that autoimmune diseases are a consequence of natural selection for enhanced TB resistance. Data also provide genetic evidence supporting the common variants/multiple disease hypothesis, which emphasizes that many disease genes may not be disease-specific, and that similar immunogenetic mechanisms underlie autoimmune diseases.     

TNF polymorphisms in psoriasis: association of psoriatic arthritis with the promoter polymorphism TNF*-857 independent of the PSORS1 risk allele

OBJECTIVE: Single-nucleotide polymorphisms (SNPs) of the tumor necrosis factor gene TNF at positions -238 and -308 have been associated with psoriasis vulgaris and psoriatic arthritis (PsA). The strong linkage disequilibrium (LD) at chromosome region 6p21, a region known to harbor risk factors for psoriasis susceptibility (PSORS1) other than just SNPs of the TNF gene, renders the interpretation of these findings difficult. The aim of this study was to analyze several SNPs of the TNF gene and its neighboring LTA gene for independent and dependent carriage of the PSORS1 risk allele. METHODS: SNPs in the promoter of the TNF (-238G/A, -308G/A, -857C/T, and -1031T/C), LTA (+252A/G), TNLFRSF1A (+36A/G), and TNLFRSF1B (+676T/G) genes were genotyped in 375 psoriasis patients, 375 PsA patients, and 376 controls. The Trp- Trp-Cys-Cys haplotype of the CCHCR1 gene (CCHCR1*WWCC) was used as an estimate of the risk allele PSORS1. RESULTS: Whereas we were able to confirm the previously described strong association of allele TNF*-238A with psoriasis, our study revealed that this association was completely dependent on carriage of the PSORS1 risk allele. For PsA, but not psoriasis vulgaris without joint involvement, a strong association with the allele TNF*-857T (odds ratio 1.956 [95% confidence interval 1.334-2.881]; corrected P = 0.0025) was also detected in patients negative for the PSORS1 risk allele. CONCLUSION: Our results indicate that there are genetic differences between psoriasis vulgaris patients with and without joint manifestations. While the previously reported association between TNF*-238A and psoriasis seems to primarily reflect LD with PSORS1, TNF*-857T may represent a risk factor for PsA that is independent of the PSORS1 allele.     

Mannose-binding lectin polymorphisms and susceptibility to infection in systemic lupus erythematosus.

OBJECTIVE: To determine whether variant alleles in the coding portion of the mannose-binding lectin (MBL) gene are associated with increased susceptibility to systemic lupus erythematosus (SLE) and concomitant infections. METHODS: MBL alleles and serum concentrations were determined by polymerase chain reaction and enzyme-linked immunosorbent assay, respectively, in 91 Danish patients with SLE and in 250 controls. RESULTS: Homozygosity for MBL variant alleles was observed in 7.7% of the SLE patients compared with 2.8% of the controls (P = 0.06), while no difference was seen for heterozygosity (33.0% versus 34.4%). Homozygotes had an increased risk of acquiring serious infections compared with patients who were heterozygous or homozygous for the normal allele (odds ratio 8.6, 95% confidence interval 1.5-47.6, P = 0.01). The time interval from the diagnosis of SLE to the first infectious event was shorter (P = 0.017), and the annual number of infectious events was 4 times higher, among homozygotes (P = 0.00002). They were especially prone to acquire pneumonia (P = 0.00004). CONCLUSION; Homozygosity for MBL variant alleles may explain much of the increased risk of complicating infections seen in SLE patients. Additionally, it is a minor risk factor for acquiring SLE.     

MERTK polymorphisms associated with risk of haematological disorders among Korean SLE patients

OBJECTIVE: The MER receptor tyrosine kinase (MERTK) gene is critical for the efficient clearance of apoptotic cells and has implications for inflammation and autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the genetic polymorphisms in MERTK to evaluate it as a potential candidate gene for a host genetic study of SLE and clinical manifestations in patients with SLE. METHODS: By resequencing the coding and flanking regions of the MERTK gene in 24 unrelated Koreans, 37 polymorphisms were identified. Based on gene position, minor allele frequency and inter-single-nucleotide polymorphism (SNP) linkage disequilibrium, six of these polymorphisms were selected for subsequent genotyping and association analysis with the risk of SLE and haematological disorders in 350 Korean SLE patients and 330 controls. RESULTS: Although no significant associations with the risk of SLE were found, logistic regression analyses revealed that variants +465C > G (P = 0.05) and +130215insdelT (P = 0.0005) were significantly associated with decreased risk of leucopenia in SLE patients. Further, +465C > G, +95616G > A, +123157A > G and the haplotype ht1 also showed significant associations (P = 0.006-0.05) with a decreased risk of lymphopenia in SLE patients. CONCLUSION: Our findings suggest that polymorphisms in MERTK might be one of the genetic risk factors for presenting leucopenia and lymphopenia in SLE patients.     

The mannose-binding lectin gene polymorphisms and systemic lupus erythematosus: two case-control studies and a meta-analysis

OBJECTIVE: Mannose-binding lectin (MBL) enhances opsonization and activates complement. Dysfunctional alleles of MBL have been associated with low plasma concentrations of MBL and increased risk of systemic lupus erythematosus (SLE), but genotyping studies have shown inconsistent results. We performed case-control studies of the MBL polymorphisms in 2 Caucasian cohorts and a meta-analysis incorporating all published results of MBL genotyping in SLE to explore whether the MBL functional variants are associated with SLE. METHODS: MBL genotypes at 7 single-nucleotide polymorphisms were sequenced in 96 European American patients with SLE and 96 age-, race-, and sex-matched controls. MBL codons 52, 54, and 57 were genotyped in 285 German patients with SLE and 200 race-matched controls. Allele frequencies of all known variants were tallied for meta-analysis. RESULTS: Although there was a trend toward association with MBL polymorphisms in both patient cohorts evaluated, none of them was significantly associated with SLE on its own. Seventeen comparisons from 15 studies were included in the meta-analysis. Publication bias was excluded by Egger's regression test (P = 0.14). The overall odds ratio for MBL codon 54 variant B was 1.406 (95% confidence interval 1.221-1.608; P < 0.001). Stratification by ethnicity showed significantly increased odds ratios for association of the MBL codon 54 B variant with SLE in African, Asian, and Caucasian cohorts. CONCLUSION: Meta-analysis of all available studies on MBL polymorphisms and SLE shows that MBL variant alleles such as MBL exon 1 codon 54 B, promoter -550 L, and promoter -221 X are SLE risk factors. This association is robust and persists after incorporation of data from our 2 cohorts in which the association failed to reach significance.     

TNF-308A and HLA-DR3 alleles contribute independently to susceptibility to systemic lupus erythematosus

OBJECTIVE: To evaluate the respective contributions of tumor necrosis factor (TNF) promoter polymorphisms and HLA-DR alleles to susceptibility to systemic lupus erythematosus (SLE). METHODS: TNF-238G/A and 308G/A promoter polymorphisms and HLA-DRB1 alleles were determined in 99 consecutive Caucasian SLE patients and 177 Caucasian controls. Standard and Mantel-Haenszel odds ratios were calculated to assess the magnitude of the susceptibility factors. The presence or absence of the SLE classification criteria was determined and correlated with the TNF promoter and HLA-DRB1 genotypes. RESULTS: The frequency of the TNF-308A/A and 308G/A genotypes was significantly higher in SLE patients (odds ratio 5.0). Conversely, TNF-238G/A and 238A/A genotypes were equally prevalent in SLE patients and controls. The HLA-DR3 specificity (DRBI*0301 allele) was significantly more prevalent in the SLE population (odds ratio 4.4). Stratification to correct for interdependence of the 2 loci confirmed the association of both TNF-308A and HLA-DR3 with SLE (Mantel-Haenszel odds ratio 3.2 and 2.4, respectively). No correlation was found between TNF promoter and HLA-DRB1 genotypes and any SLE classification criterion or disease manifestation. CONCLUSION: TNF-308A and HLA-DR3 alleles are independent susceptibility factors for SLE.     

Single nucleotide polymorphisms and microsatellite alleles of tumor necrosis factor alpha and interleukin-10 genes and the risk of advanced chronic alcoholic liver disease

BACKGROUND: Only a minority of ethanol abusers develop advanced chronic alcoholic liver disease (CALD). In CALD there is a imbalance between TNF alpha and IL-10, which may be modulated by several polymorphisms at both genetic loci. Our aim has been to elucidate the possible relation between these polymorphisms and the risk of CALD. PATIENTS AND METHODS: 147 patients with advanced CALD and 355 healthy controls (all white Spaniards) were included. TNF alpha biallelic single nucleotide polymorphisms (SNP) at positions -238, -308, and -376 and IL-10 biallelic SNP at positions -597, - 824, and - 1087 were investigated by polymerase chain reaction (PCR) amplification and dot blot hybridization. Moreover, polymorphic microsatellites TNFa, TNFb, IL-10.R and IL-10.G were investigated in a multiplex PCR and alleles were estimated in an automatic sequencer. RESULTS: No differences were found in the distribution of any of the studied polymorphisms, except by an excess of the haplotype formed by the allele 11 of the microsatellite IL-10.G and the GCC arrangement of the SNPs at the promoter of IL-10 gene in patients (15.7 vs. 8.24%, odds ratio: 2.08, 95% C.I. = 1.31-3.31). CONCLUSIONS: The studied polymorphisms at TNF alpha and IL-10 genetic loci are not clearly related to the risk of CALD. The excess of G11-GCC haplotype found in CALD patients needs independent confirmation.     

Variants in Intron 4 of PD-1 Gene are Associated with the Susceptibility to SLE in an Iranian Population

Background: Programmed cell death protein 1 (PD-1) is a negative costimulatory molecule with immunomodulatory properties. Recently, PD-1 gene defects have attracted attention in the pathogenesis of SLE. Objective: Here, we assessed the association of PD-1 gene polymorphisms in intron 4 and haplotypes with the susceptibility to SLE. Method: Seventy-six SLE patients and 159 healthy controls were included. We screened the polymorphisms by amplifying the intron 4 of the PD-1 gene with the specific primers followed by sequencing. Results: Two distinct SNPs were identified (rs6705653 and rs41386439) within the intron 4 of the PD-1 gene. The AA genotype of +7499 (G/A) SNP was associated with the higher risk of SLE [OR=3.31, 95% CI (1.25-8.76), p-value=0.045], while A allele was identified as a risk allele [OR=1.75, 95% CI (1.10-2.76), p-value=0.015]. However, no significant association was observed between the allele and the genotype frequencies of +7209 (C/T) polymorphic region of the PD-1 gene and susceptibility to SLE. Haplotype analysis showed the significantly higher presence of H2 haplotype (AC; +7499/+7209) [OR=1.70, 95% CI (1.24-2.33), p-value=0.0012] in SLE patients. Conclusion: To the best of our knowledge, this is the first report of the significant association of PD-1 +7499 (G/A) SNP with the SLE susceptibility and the first detection of both polymorphic loci in a population from Iran. However, more investigations are necessary to confirm these findings.     

TNF-alpha promoter gene polymorphisms in Spanish children with persistent oligoarticular and systemic-onset juvenile idiopathic arthritis

OBJECTIVE: To explore the possible association/s of the first reported tumour necrosis factor (TNF-alphaTNF-) alpha promoter gene polymorphisms -308, -238, -376 and -163 (G-->A) with systemic (SoJIA) and oligoarticular subtypes of juvenile idiopathic arthritis (JIA); and to test the association between these polymorphisms and the class I/class II HLA alleles in our population. METHODS: The patient group comprised 29 oligoarticular and 26 systemic Caucasian Spanish children with JIA; 68 healthy volunteers from the same ethnic group and geographical region served as controls. HLA alleles were determined using low-resolution polymerase chain reaction (PCR). TNF-alpha promoter gene polymorphisms were screened using PCR denaturing gradient gel electrophoresis (PCR-DGGE), followed, if positive, by restriction fragment length polymorphism (RFLP) analysis for identification. RESULTS: No statistical association was found between the four polymorphisms studied and JIA. However, the -308 G-->A polymorphism (TNF A2) tended to be more frequent in patients with SoJIA than in the oligoarticular group. TNF A2 was strongly associated with the extended haplotype A1B8DR3 (p = 0.003), and the tandem polymorphism -238/-376 in the presence of B18 and DR3. CONCLUSION: The TNF A2 allele was more frequent in SoJIA than in the oligoarticular group. TNF A2 can help to create a more inflammatory milieu in this JIA subtype, in combination with other polymorphisms involved in regulatory sequences of key molecules in the inflammatory response. The association of the -308 and -238/-376 polymorphisms with specific alleles of the HLA is reconfirmed.     

Fcgamma receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: contribution of FCGR2B to genetic susceptibility

OBJECTIVE: Human low-affinity Fcgamma receptors (FcgammaR) constitute a clustered gene family located on chromosome 1q23, that consists of FcgammaRIIA, IIB, IIC, IIIA, and IIIB genes. FcgammaRIIB is unique in its ability to transmit inhibitory signals, and recent animal studies demonstrated a role for FcgammaRIIB deficiency in the development of autoimmunity. Genetic variants of FcgammaRIIA, IIIA, and IIIB and their association with systemic lupus erythematosus (SLE) have been extensively studied in various populations, but the results were inconsistent. To examine the possibility that another susceptibility gene of primary significance exists within the FcgammaR region, we screened for polymorphisms of the human FCGR2B gene, and examined whether these polymorphisms are associated with SLE. METHODS: Variation screening of FCGR2B was performed by direct sequencing and polymerase chain reaction (PCR)-single-strand conformation polymorphism methods using complementary DNA samples. Genotyping of the detected polymorphism was done using genomic DNA, with a specific genotyping system based on nested PCR and hybridization probing. Association with SLE was analyzed in 193 Japanese patients with SLE and 303 healthy individuals. In addition, the same groups of patients and controls were genotyped for the previously known polymorphisms of FCGR2A, FCGR3A, and FCGR3B. RESULTS: We detected a single-nucleotide polymorphism in FCGR2B, (c.695T>C), coding for a nonsynonymous substitution, Ile232Thr (I232T), within the transmembrane domain. The frequency of the 232T/T genotype was significantly increased in SLE patients compared with healthy individuals. When the same patients and controls were also genotyped for FCGR2A-131R/H, FCGR3A-176V/F, and FCGR3B-NA1/2 polymorphisms, FCGR3A-176F/F showed significant association. Two-locus analyses suggested that both FCGR2B and FCGR3A may contribute to SLE susceptibility, while the previously reported association of FCGR3B was considered to be secondary and derived from strong linkage disequilibrium with FCGR2B. CONCLUSION: These results demonstrate the association of a new polymorphism of FCGR2B (I232T) with susceptibility to SLE in the Japanese.     

Genetic background of Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis: association of HLA-DRB1*0901 with microscopic polyangiitis

OBJECTIVE: To examine association of 8 candidate genes with susceptibility to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japanese patients. Little is known on the genetic background of AAV in Japanese patients mainly because of the difficulty in collecting a sufficient number of samples for the genetics study. METHODS: Sixty-nine patients, including 50 with microscopic polyangiitis (MPA), were recruited in a multicenter study. Among them, 64 patients were positive for myeloperoxidase (MPO)-ANCA. Associations of HLA-DRB1, tumor necrosis factor-alpha promoter (TNF), TNF receptor 2 (TNFR2), Fcgamma receptor IIa (FCGR2A), IIb (FCGR2B), IIIa (FCGR3A), IIIb (FCGR3B), and CTLA-4 (CTLA4) polymorphisms were examined in a case-control analysis. RESULTS: A significant association of HLA-DRB1*0901 with MPA (p = 0.0037, OR 2.44, 95% CI 1.33-4.46), as well as with MPO-ANCA positivity (p = 0.0014, OR 2.44, 95% CI 1.41-4.22), was detected. There was no difference in the TNF promoter haplotype frequencies between patients with MPA and controls, excluding the possibility that the association of DRB1*0901 was secondarily caused by linkage disequilibrium with TNF. No association was observed for TNFR2, FCGR, or CTLA4 with MPA, nor with the presence of MPO-ANCA, although the combined genotype FCGR2A-131H/H and 3A-176F/F was increased in patients with MPA (p = 0.025). CONCLUSION: There was an association of HLA-DRB1*0901 with MPA and MPO-ANCA positive vasculitis in Japanese patients.     

Systemic lupus erythematosus and genetic variation in the interleukin 1 gene cluster: a population based study in the southeastern United States

BACKGROUND: Interleukin (IL)1alpha and IL1beta, and their endogenous receptor antagonist (IL1Ra), have been related to the pathology of systemic lupus erythematosus (SLE), but the role of IL1 polymorphisms in the aetiology of SLE is unknown. OBJECTIVE: To examine polymorphisms at IL1alpha -889(C-->T), IL1alpha +4845(C-->T), IL1beta -511(C-->T), IL1beta +3953(G-->T), and IL1Ra (86 bp VNTR) in a population based study of SLE in North Carolina and South Carolina. METHODS: Genotypes from 230 cases who met ACR classification criteria, and from 275 controls matched for age, sex, and state, were analysed separately for African Americans and whites. Odds ratios (ORs) were estimated by logistic regression models for each locus alone and also after adjusting for polymorphisms at adjacent loci. RESULTS: An increased risk of SLE for the IL1alpha -889C/C genotype compared with carriage of the -889T allele was found in both African Americans (OR = 3.1, p = 0.001) and whites (OR = 2.9, p = 0.005). In African Americans, carriage of the IL1beta -511T allele was associated with a higher risk of SLE than carriage of the -511C/C genotype (OR = 2.4, p = 0.017), independent of variation at IL1alpha -889. CONCLUSIONS: The observed associations support the hypothesis that genetic variation in IL1 is involved in the aetiology of SLE and merit further investigation.     

Systemic lupus erythematosus as a first presentation of common variable immunodeficiency associated with infrequent mannose-binding lectin gene polymorphisms

The association of common variable immunodeficiency (CVID) and systemic lupus erythematosus (SLE) is infrequent. Mannose-binding lectin (MBL) has been shown to play a role in CVID and SLE. The purpose of this study is to describe two cases of CVID who presented as SLE and also evaluate the presence of MBL polymorphisms and MBL serum levels in those patients. In both patients, SLE was the first manifestation of CVID. In these patients the SLE immunological markers and disease activity disappeared after the development of CVID. They carried the very infrequent MBL haplotype 4Q-57Glu. One of them had a homozygous genotype, whereas the other patient was heterozygous and also presented the haplotype 4P-57Glu that had never been previously detected. Interestingly, this last patient was presenting frequent respiratory tract infections, developed bronchiectasis and had low levels of circulating MBL. These results may support the role of MBL in the development of autoimmunity in CVID. Further genetic studies are needed to clarify the role of the MBL polymorphisms in the development of autoimmunity in CVID.     

Association of mannose binding lectin (MBL) gene polymorphism and serum MBL concentration with characteristics and progression of systemic lupus erythematosus

OBJECTIVE: To determine whether occurrence, characteristics, and progression of systemic lupus erythematosus (SLE) are associated with polymorphism of the mannose binding lectin (MBL) gene and with serum MBL concentration. METHODS: Codon 54 MBL gene polymorphism of 147 patients with SLE and 160 healthy controls was determined by polymerase chain reaction-restriction fragment length polymorphism. Serum concentration of MBL was measured by enzyme immunoassay. Fluctuations of serum MBL were analysed with respect to disease characteristics and activity. RESULTS: Frequency of homozygosity for codon 54 minority allele was 6% (9/147) in patients with SLE, and significantly higher than in controls (p = 0.0294, Fisher's exact test). MBL polymorphism in patients with SLE was not significantly associated with disease characteristics or immunological phenotypes. Patients homozygous for the B allele tended to have a higher risk of infection during treatment. Levels of C3 and CH(50) were slightly, but significantly, associated with serum MBL concentration in patients with SLE homozygous for the majority allele. During the course of SLE, serum MBL concentration increased in 6/14 patients, and decreased in 7 after initiation of immunosuppressive treatment. CONCLUSIONS: MBL gene polymorphism influences susceptibility to SLE, but has no direct effect on disease characteristics. Serum MBL levels fluctuate during the course of SLE in individual patients. MBL genotyping may be useful in assessing the risk of infection during treatment of SLE.     

Association of a transmembrane polymorphism of Fcgamma receptor IIb (FCGR2B) with systemic lupus erythematosus in Taiwanese patients

OBJECTIVE: To investigate the possible association of the Fcgamma receptor IIb (FcgammaRIIb) Ile/Thr187 transmembrane domain polymorphism, which significantly affects receptor signaling, with susceptibility to systemic lupus erythematosus (SLE) in Taiwanese patients. METHODS: We used matrix-assisted laser desorption ionization-time-of-flight mass spectrometry to genotype 351 Taiwanese SLE patients and 372 age- and sex-matched healthy individuals from the same geographic area. Allele frequencies and genotype distributions were compared between the patients and controls, both as an aggregate and as stratified by sex, autoantibody profile, and clinical parameters. A combined analysis was conducted to assess the FCGR2B Thr187 allele as a common risk factor in different ethnic populations. RESULTS: The minor Thr187 allele was significantly associated with SLE in Taiwanese subjects (P = 0.017, odds ratio [OR] 1.989 [95% confidence interval (95% CI) 1.119-3.553]). Interestingly, male SLE patients showed enrichment of the Thr/Thr187 genotype (24%; 7 of 29) as compared with female SLE patients (10%; 32 of 322) (P = 0.043, OR 2.884 [95% CI 1.028-7.839]). Additionally, SLE patients with Thr/Thr187 and Ile/Thr187 genotypes were more likely to have pleural effusions (P = 0.038, OR 1.874 [95% CI 1.033-3.411]) and anti-SSA/Ro antibody production (P = 0.046, OR 2.221 [95% CI 1.013-4.897]). Combined analysis of 4 groups of Asian patients strongly supported the association of the FCGR2B Thr187 allele with the lupus phenotype (P = 0.000159). CONCLUSION: The FcgammaRIIb transmembrane polymorphism is a strong disease susceptibility candidate in epistasis with other genetic effects in Taiwanese and other Asian populations. It may also play a more prominent role in male patients with SLE.     

Mannose-binding lectin is a disease-modifying factor in North American patients with systemic lupus erythematosus

OBJECTIVE: To investigate whether development of systemic lupus erythematosus (SLE), its clinical manifestations, and autoantibody production are associated with polymorphisms of the mannose-binding lectin (MBL) gene in North American patients with SLE. METHODS: MBL gene polymorphisms in codons 52 (designated variant D, with the wild-type designated A), 54 (variant B), and 57 (variant C) were determined by polymerase chain reaction-sequence specific priming in 130 patients with SLE and 142 healthy controls. Autoantibodies against double-stranded DNA (dsDNA), Smith antigen, phospholipids, Ro/SSA, La/SSB, and RNP were tested at certified clinical pathology laboratories. RESULTS: A statistically significant increased likelihood of anti-Smith antibody production was observed in SLE patients with the heterozygous A/B genotype [odds ratio (OR) 5.1; 95% confidence interval (CI) 1.6-16.6; the A/A genotype as the reference group] or A/C genotype (OR 8.2; 95% CI 2.0-33.9). SLE patients with the homozygous or compound heterozygous variant genotype (O/O; O, a common designation for variant alleles) had an increased likelihood of mounting autoantibody responses against dsDNA, Ro/SSA, and La/SSB, and were more likely to have a history of renal disease (OR 4.8; 95% CI 0.9-25.2). However, differences in the frequencies of MBL variant alleles and genotypes observed between patients with SLE and controls did not reach statistical significance. CONCLUSION: A significantly increased prevalence of anti-Smith antibody was associated with the heterozygous genotypes A/B and A/C. Although MBL structural gene polymorphism was not a risk factor for SLE development in this study population, homozygosity of MBL variant alleles may be a weak disease-modifying factor, particularly for renal involvement, in North American patients with SLE.     

无关供者异基因造血干细胞移植中急性移植物抗宿主病与肿瘤坏死因子基因多态性的关系

目的 探讨无关供者异基因造血干细胞移植(allo-HSCT)患者及其干细胞供者的肿瘤坏死因子(TNF)单核苷酸多态性(SNP)与急性移植物抗宿主病(aGVHD)之间的关系.方法 回顾性分析浙江大学医学院附属第一医院移植中心接受无关供者allo-HSCT患者及其供者,共76对,采用多重单碱基延伸SNP分型技术检测TNF基因5个位点的SNP(TNFα-238、TNFα-857、TNFα-863、TNFα-1031、TNFβ+252),分析与aGVHD的发生风险、临床严重程度之间的关系.结果 在23例发生Ⅱ-Ⅳ度aGVHD患者中,其干细胞供者基因型TNFα-857 CC的频率(91.3%)高于基因型CT(8.7%)(P=0.039);TNFβ+252(A/G)位点未检出从基因型,19例患者为GA基因型(82.6%),4例患者为GG基因型(17.4%),3组之间比较差异有统计学意义(P=0.006).而患者与干细胞供者TNFα-238(G/A)、TNFα-863(C/A)和TNFα-1031(T/C)位点的基因多态性均未发现与aGVHD的发生风险相关.结论 干细胞供者TNFα-857 CC基因型与Ⅱ～Ⅳ度aGVHD的发生密切相关,而TNFβ+252为AA基因型的患者不易发生Ⅱ～Ⅳ度aGVHD.     

Association of the CT60 marker of the CTLA4 gene with systemic lupus erythematosus

OBJECTIVE: To investigate the possible association of the CT60A/G marker with systemic lupus erythematosus (SLE) in Spanish patients, and to identify the possible CTLA4 haplotype responsible for the association, taking into account other polymorphisms described at positions -1722T/C, -319C/T, +49A/G, and the microsatellite (AT)(n) in the 3'-untranslated region (3'-UTR) of the CTLA4 gene. METHODS: Genotyping of CT60 was performed in 395 patients with SLE and 293 healthy controls using polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis. Genotyping of the rest of the dimorphisms has been previously reported. Genotyping of microsatellite polymorphism (AT)(n) in the 3'-UTR was performed using PCR with a fluorescence-labeled primer. RESULTS: With regard to CT60A/G, the frequency of the AA genotype was significantly decreased among the SLE patients (18.7% versus 28.3% in the control group; P = 0.003, corrected P [P(corr)] = 0.009, odds ratio [OR] = 0.58, 95% confidence interval [95% CI] 0.40-0.85). In other words, the frequency of individuals bearing the G phenotype was increased in the patient group compared with the control group (81.2% versus 71.7%; P = 0.003, P(corr) = 0.006, OR = 1.71, 95% CI 1.18-2.49). The distribution of allele frequency was also significantly different between patients and controls (P = 0.01, P(corr) = 0.02, OR [for allele G] = 1.32, 95% CI 1.06-1.65). After combining the data on the different polymorphisms, 2 neutral haplotypes were found: +49A;(AT)(7);CT60A and +49G;(AT)(8-19);CT60G. In addition, a susceptibility haplotype was found: +49A;(AT)(>19);CT60G. CONCLUSION: The 3'-UTR of the CTLA4 gene is involved in susceptibility to SLE.