Brief report: enrichment of associations in genes with fibrosis, apoptosis, and innate immunity functions with cardiac manifestations of neonatal lupus.

Neonatal lupus (NL) is a syndrome whose clinical manifestations include transient cutaneous rash, hematologic and hepatic laboratory abnormalities, and irreversible cardiac damage. The cardiac manifestations of NL (cardiac-NL), which include atrioventricular conduction defects (heart block) and life-threatening cardiomyopathy, are associated with substantial mortality and morbidity (1). While maternal antibodies to components of the SSA/Ro-SSB/La ribonucleoprotein complex are necessary for the development of disease, the rarity of advanced injury at 2–5% suggests that fetal factors are highly contributory (2) to a complex pathogenic cascade which links autoantibody to scar. A fetal genetic contribution to the development of cardiac-NL is supported by a high sibling risk ratio (λs= 10–3000), recurrence rate of approximately 18%, concordance rates in monozygotic twins of 33% (reviewed in 3), as well as the results from our published genome-wide association study (GWAS) in cardiac-NL (4). While the precise pathogenic cascade is yet to be fully defined, one scenario posits that injury is initiated by increased apoptosis of the cardiocytes which exposes Ro/SSA antigens and associated ssRNA generating an immune complex phagocytosed by macrophages, which sustain both an inflammatory response and a fibrotic response, resulting in the scarring of the heart (5). This hypothesis is supported by the results from our GWAS (4), where several genome-wide significant variants were identified in the MHC region, as well as at 21q22.3, near the erythroblast transformation-specific transcription factor ERG, which is a regulator of embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis. Despite the significant associations identified in the GWAS (4), we hypothesize that there may be a global enrichment of specific pathways and genetic variation potentially overlooked if only the most significant statistical associations are considered. A judicious and efficient way to identify genetic variation predisposing to complex diseases is the application of a candidate gene framework that incorporates prior biological knowledge. Unlike agnostic GWAS, this approach narrows the hypothesis space to provide a more focused and powerful examination of the data. Indeed, several studies have shown that an essentially Bayesian approach of selecting candidate genes serves to increase the reliability and likelihood of finding genes that are truly associated with disease (6, 7). In accord with these considerations, we tested for a potential enrichment of significant associations in genes with candidate biological functions by mining the cardiac-NL GWAS. Given their potential contribution to inflammation, fibrosis, and conduction abnormalities in the heart, we selected genes with functions contributing to apoptosis, calcium electrogenesis, immune function, and fibrosis. Figure 1 illustrates our approach for the identification of cardiac-NL risk loci. Several associations within genes in candidate pathways relevant to the pathogenesis of cardiac-NL were identified supporting the potential of this approach for gene discovery. Figure 1 Approach for the identification of genes predisposing to cardiac manifestations of neonatal lupus (cardiac-NL). An approach that focuses the hypothesis space based on biological knowledge provides a more powerful and efficient way to identify disease-causing ...