Faculty Bibliography

OBJECTIVE: The proposed pathogenesis of the cardiac manifestations of neonatal lupus (cardiac-NL) involves maternal autoantibodies to the RNPs SSA/Ro and SSB/La, enhanced by as-yet-unknown factors that likely involve dysregulation of both inflammatory and fibrotic fetal responses. This study was designed to improve the power to detect specific associations in genes with candidate biologic functions. METHODS: Using data from our genome-wide association study of 116 Caucasian children with cardiac-NL and 3,351 Caucasian controls, we tested for enrichment of single-nucleotide polymorphism (SNP) associations in genes with candidate biologic functions related to fibrosis, immune function, apoptosis, T cell function, cell infiltration, innate immune cell function, interferon, Toll-like receptors, and calcium channels. After linkage disequilibrium pruning and exclusion of the extended HLA region, a total of 15,103 SNPs in 3,068 genes remained. RESULTS: A highly significant enrichment of P values was observed for genes related to fibrosis (P = 2.27 x 10(-9) ), apoptosis (P = 7.67 x 10(-7) ), and innate immune cell (P = 2.53 x 10(-6) ), immune (P = 5.01 x 10(-4) ), T cell (P = 2.23 x 10(-4) ), and interferon functions (P = 1.64 x 10(-3) ). The most significant non-HLA associations included the sialyltransferase gene ST8SIA2 (rs1487982; odds ratio 2.20 [95% confidence interval 1.52-3.19], P = 3.37 x 10(-5) ), the integrin gene ITGA1 (rs2432143; odds ratio 2.31 [95% confidence interval 1.54-3.45], P = 4.54 x 10(-5) ), and the complement regulator gene CSMD1 (rs7002001; odds ratio 2.41 [95% confidence interval 1.57-3.72], P = 6.33 x 10(-5) ). CONCLUSION: This study identified novel candidate genes associated with cardiac-NL and highlights the value of studying this cohort for advancing knowledge regarding the genetic etiology of this syndrome. Identification of causal alleles is expected to provide critical insight into the molecular mechanisms responsible for linking maternal autoantibodies to cardiac scarring in these fetuses/neonates.

OBJECTIVE: To determine the value of cell-bound complement activation products in combination with antinuclear antibody (ANA), anti-double-stranded DNA antibody (anti-dsDNA), and anti-mutated citrullinated vimentin antibody (anti-MCV) for the diagnosis of systemic lupus erythematosus (SLE). METHODS: This was a multicenter cross-sectional study in which 593 subjects were enrolled (210 SLE patients, 178 patients with other rheumatic diseases, and 205 healthy subjects). Complement receptor 1 levels on erythrocytes (ECR1) together with complement C4d levels on erythrocytes (EC4d), platelets (PC4d), and B cells (BC4d) were determined using fluorescence-activated cell sorting. Serologic markers were measured by enzyme-linked immunosorbent assay. Statistical analyses were performed using area under the curve (AUC), logistic regression, and calculations of diagnostic sensitivity and specificity. RESULTS: Anti-dsDNA was an insensitive (30%) but specific (>95%) marker for SLE. Levels of EC4d, BC4d, and PC4d were several times higher, and levels of ECR1 lower, in SLE patients compared to patients with other rheumatic diseases and healthy subjects. Among 523 anti-dsDNA-negative subjects, multivariate logistic regression analysis revealed that SLE was associated with ANA positivity (>/=20 units), anti-MCV negativity (90%. The combination of anti-dsDNA and index score positivity yielded 80% sensitivity for SLE and 87% specificity against other rheumatic diseases. CONCLUSION: An assay panel combining anti-dsDNA, ANA, anti-MCV, EC4d, and BC4d is sensitive and specific for the diagnosis of SLE.

OBJECTIVE: Variation in the interferon regulatory factor 5 (IRF5) gene has been associated with risk of developing systemic lupus erythematosus (SLE), and this association is largely dependent upon anti-Ro autoantibodies. This study was undertaken to determine if the IRF5 genotype is associated with maternal diagnosis or progression of autoimmunity. METHODS: Genotyping of haplotype-tagging polymorphisms in IRF5 was performed in 93 subjects of European ancestry who were recruited to the Research Registry for Neonatal Lupus. All subjects had high-titer anti-Ro autoantibodies and had a child with neonatal lupus (NL); allele frequencies were compared to those in nonautoimmune controls. The mothers had SLE, Sjogren's syndrome (SS), or undifferentiated autoimmune syndrome (UAS), or were asymptomatic. RESULTS: The SLE risk haplotype of IRF5 was enriched in all anti-Ro-positive subjects except in those with SS (odds ratio [OR] 2.55, P = 8.8 x 10(-4) ). The SLE risk haplotype was even enriched in asymptomatic individuals with anti-Ro antibodies (OR 2.69, P = 0.019). The same haplotype was more prevalent in subjects who were initially asymptomatic but developed symptomatic SLE during followup (OR 5.83, P = 0.0024). Interestingly, SS was associated with 2 minor IRF5 haplotypes, and these same haplotypes were decreased in frequency in mothers with SLE and those with UAS. CONCLUSION: The IRF5 SLE risk haplotype was associated with anti-Ro antibody positivity in asymptomatic individuals, as well as with progression to SLE in asymptomatic anti-Ro-positive individuals. SS in mothers of children with NL was associated with different IRF5 haplotypes. These data suggest that IRF5 polymorphisms play a role in serologic autoimmunity in humans and may promote the progression to clinical autoimmunity.