Open AccessBrief Report: Enrichment of associations in genes with fibrosis, apoptosis, and innate immunity functions with cardiac manifestations of neonatal lupus
Author(s) -
Ramos Paula S.,
Marion Miranda C.,
Langefeld Carl D.,
Buyon Jill P.,
Clancy Robert M.
Publication year - 2012
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.34663
Subject(s) - immunology , odds ratio , single nucleotide polymorphism , candidate gene , biology , innate immune system , immune system , medicine , genetics , gene , genotype
Abstract 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 × 10 −9 ), apoptosis ( P = 7.67 × 10 −7 ), and 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 gene ST8SIA2 (rs1487982; odds ratio 2.20 [95% confidence interval 1.52–3.19], P = 3.37 × 10 −5 ), the integrin gene ITGA1 (rs2432143; odds ratio 2.31 [95% confidence interval 1.54–3.45], P = 4.54 × 10 −5 ), and the complement regulator gene CSMD1 (rs7002001; odds ratio 2.41 [95% confidence interval 1.57–3.72], P = 6.33 × 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.