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Objective The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared rituximab to cyclophosphamide as induction therapy for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We undertook the current study to determine whether known single-nucleotide polymorphisms (SNPs) for Fcγ receptors (FcγR) or cytochrome P450 (CYP) enzymes were associated with the response to treatment with rituximab and cyclophosphamide, respectively. Methods Functional SNPs for FcγR (FcγRIIa 519G>A, FcγRIIb 695T>C, FcγRIIIa 559T>G) and CYP enzymes (CYP2B6 1459C>T, CYP2C19 681G>A) were analyzed by direct sequencing of polymerase chain reaction-amplified genomic DNA. Each SNP was tested as a predictor of complete remission at 6 months or remission with continued prednisone administration using logistic regression and including the covariates of baseline Birmingham Vasculitis Activity Score for Wegener's Granulomatosis, ANCA type, and new versus relapsing disease. The associations of these SNPs with the secondary outcomes of time to complete remission, time to relapse, or time to B cell reconstitution were analyzed by Cox proportional hazard tests. Results No significant associations were identified between complete remission and any FcγR genotype in the rituximab group or any CYP genotype in the cyclophosphamide group. However, when the treatment groups were combined, an association was found between the 519AA genotype of FcγRIIa and complete remission ( P = 0.01). The 519AA genotype predicted complete remission ( P = 0.006) and a shorter time to complete remission ( P < 0.001). Conclusion The finding that the homozygous FcγRIIa 519AA variant was associated with complete response and a shorter time to complete response in the RAVE trial, independent of treatment type, implies that FcγRIIa may be broadly involved in disease pathogenesis and response to therapy. [ABSTRACT FROM AUTHOR]

It is generally believed that susceptibility to both organ-specific and systemic autoimmune diseases is under polygenic control. Although multiple genes have been implicated in each type of autoimmune disease, few are known to have a significant impact on both. Here, we investigated the significance of polymorphisms in the human gene CD24 and the susceptibility to multiple sclerosis (MS) and systemic lupus erythematosus (SLE). We used cases/control studies to determine the association between CD24 polymorphism and the risk of MS and SLE. In addition, we also considered transmission disequilibrium tests using family data from two cohorts consisting of a total of 150 pedigrees of MS families and 187 pedigrees of SLE families. Our analyses revealed that a dinucleotide deletion at position 1527∼1528 (P1527del) from the CD24 mRNA translation start site is associated with a significantly reduced risk (odds ratio = 0.54 with 95% confidence interval = 0.34-0.82) and delayed progression (p = 0.0188) of MS. Among the SLE cohort, we found a similar reduction of risk with the same polymorphism (odds ratio=0.38, confidence interval=0.22-0.62). More importantly, using 150 pedigrees of MS families from two independent cohorts and the TRANSMIT software, we found that the P1527del allele was preferentially transmitted to unaffected individuals (p=0.002). Likewise, an analysis of 187 SLE families revealed the dinucleotide-deleted allele was preferentially transmitted to unaffected individuals (p = 0.002). The mRNA levels for the dinucleotide-deletion allele were 2.5-fold less than that of the wild-type allele. The dinucleotide deletion significantly reduced the stability of CD24 mRNA. Our results demonstrate that a destabilizing dinucleotide deletion in the 39 UTR of CD24 mRNA conveys significant protection against both MS and SLE. [ABSTRACT FROM AUTHOR]

A genomic region on distal mouse chromosome 1 and its syntenic human counterpart 1q23-42 show strong evidence of harboring lupus susceptibility genes. We found evidence of linkage at 1q32.2 in a targeted genome scan of 1q21-43 in 126 lupus multiplex families containing 151 affected sibpairs (nonparametric linkage score 2.52, P = 0.006). A positional candidate gene at 1q32.2, complement receptor 2 (CR2), is also a candidate in the murine Sle1c lupus susceptibility locus. To explore its role in human disease, we analyzed 1,416 individuals from 258 Caucasian and 142 Chinese lupus simplex families and demonstrated that a common three-single-nucleotide polymorphism CR2 haplotype (rs3813946, rs1048971, rs17615) was associated with lupus susceptibility (P = 0.00001) with a 1.54-fold increased risk for the development of disease. Single-nucleotide polymorphism 1 (rs3813946), located in the 5′ untranslated region of the CR2 gene, altered transcriptional activity, suggesting a potential mechanism by which CR2 could contribute to the development of lupus. Our findings reveal that CR2 is a likely susceptibility gene for human lupus at 1q32.2, extending previous studies suggesting that CR2 participates in the pathogenesis of systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]