Brief Report: Enrichment of associations in genes with fibrosis, apoptosis, and innate immunity functions with cardiac manifestations of neonatal lupus

Abstract

Objective The proposed pathogenesis of the cardiac manifestations of neonatal lupus (cardiac-NL) involves maternal autoantibodies to the ribonucleoproteins SSA/Ro and SSB/La enhanced by as yet unknown factors likely to involve the dysregulation of both inflammatory and fibrotic fetal responses. This study was designed to improve the power to detect specific associations in genes with candidate biological functions. Methods Using data from our genome-wide association study (GWAS) in 116 cardiac-NL Caucasian children and 3,351 Caucasian controls, we tested for enrichment of SNP associations in genes with candidate biological functions related to fibrosis, immune, 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 in genes related to fibrosis (P=2.27×10−9), apoptosis (P=7.67×10−7), innate immune cell (P=2.53×10−6), immune (P=5.01×10−4), T cell (P=2.23×10−4), and interferon functions (P=1.64×10−3). The most significant non-HLA associations included the sialyltransferase ST8SIA2 (rs1487982, P=3.38×10−5, OR [95%CI]=2.20 [1.52–3.19]), the integrin ITGA1 (rs2432143, P=4.54×10−5, OR [95%CI]=2.31 [1.54–3.45]), and the complement regulator CSMD1 (rs7002001, P=6.33×10−5, OR [95%CI]=2.41 [1.57–3.72]). Conclusion This study identified novel candidate genes associated with cardiac-NL and highlights the value of this cohort in advancing our 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.

Epigenetics and Systemic Lupus Erythematosus: Unmet Needs

“…In addition, a pro-fibrotic TGF beta1 genotype was detected in the twin with CHB and not in the healthy twin in one series but not in another one [84]. This finding is in line with the hypothesis that a profibrotic response to damaged tissues by cardiac macrophages can play a role in favoring the appearance of CHB [85].…”

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cellRNAsequencing

“…ITGA1, part of the integrin signaling and virus entry via endocytic pathways as identified by IPA, is involved in cell proliferation (Macias‐Perez et al ., 2008) and invasion (Yang et al ., 2015), as well as inflammation (Becker et al ., 2013) and fibrosis (Ramos et al ., 2012), which have all been previously linked to APE1 (Aamann et al ., 2016; Shah et al ., 2017). …”

Pediatric systems medicine: evaluating needs and opportunities using congenital heart block as a case study

“…How can we use such carefully selected public data to elucidate mechanisms of CHB or find predictive biomarkers? Similar to other pediatric diseases, genetic variants (singlenucleotide polymorphisms) have been associated with CHB, but it is yet unclear how to identify CHB-relevant genes from such disease loci because tag single-nucleotide polymorphisms only provides markers of loci and cannot identify individual genes (18). Because CHB is a rare disease, the study cohorts are as a rule small, and the availability of samples is limited, rendering omics approaches challenging.…”