Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Congenital heart block (CHB) may affect children of women with anti-Ro/SSA and anti-La/SSB autoantibodies. The most recognized manifestation of CHB is an atrioventricular (AV) block, but atrial and ventricular arrhythmias, a prolonged isovolumetric contraction time and cardiomyopathies also affect a substantial proportion of the babies. The potentially lethal cardiac manifestations develop in utero during gestational weeks 18-24, and the risk of giving birth to a child with CHB is 1-2% in anti-Ro/SSA-positive pregnancies. A recurrence rate of only 12% despite persisting maternal autoantibodies suggests that additional factors influence disease development. The purpose of this study was to identify fetal genetic susceptibility factors for CHB, and to understand their functional impact on pathogenesis.
We performed a genome-wide association study of >500,000 single nucleotide polymorphisms (SNP) in a population-based cohort of families with children diagnosed with CHB and analyzed transmission of SNPs based on genotypes of index cases (n=92) and first degree relatives (n=256). CHB-associated SNPs (p≤ 1×10-4) were replicated in a population-based case-control analysis (ncontrols=1122). Expression quantitative trait loci (eQTL) analysis was performed in cardiac tissue of genes present in the regions surrounding replicating SNPs (±500 kb) across both data sets. Human and mouse tissue expression of genes and proteins was assessed by qPCR, RNAseq, Western blot, immunohistochemistry and immunofluorescence staining. Functional analysis in vitro using primary cultured cardiomyoctes from genetically modified neonatal mouse pups was performed with time lapse Ca2+ recordings. Doppler echocardiography was used to assess cardiac disease phenotypes in utero.
Results: We discovered DNAJC6 as a novel fetal susceptibility gene associated with CHB, with decreased cardiac expression of DNAJC6 associated with the disease risk genotype. Auxilin, the putative tyrosine-protein phosphatase encoded by DNAJC6, was remarkably higher expressed in the fetal compared to the adult heart both before and during the risk period for CHB (>10 fold, p< 0.001). In human fetal cardiomyocytes we observed auxilin in the cytoplasm in a vesicular pattern, co-localized with clathrin, suggesting that the cellular function of auxilin in cardiomyocytes, as already described for neurons, is within the clathrin-mediated endocytic process. Analysis of auxilin-deficient cardiomyocytes of neonatal mice revealed abnormal connectivity and Ca2+ homeostasis in culture. Doppler echocardiography of auxilin-deficient fetal mice in utero revealed several CHB-related manifestations in vivo, including AV-block, abnormal heart rhythm with atrial and ventricular ectopias and a prolonged isovolumetric contraction time as a sign of decreased myocardial performance.
In conclusion, our study identifies auxilin as the first susceptibility gene in CHB modulating cardiac function, and connects the decreased auxilin expression observed for the susceptibility allele with clinical fetal CHB features.
To cite this abstract in AMA style:Meisgen S, Hedlund M, Ambrosi A, Folkersen L, Dzikaite-Ottosson V, Ding B, Strandberg L, Biavati L, Ramsköld D, Forsberg D, Bergin L, Ruhrmann S, Study Group TSCHB, Hamilton RM, Franco-Cereceda A, Hamsten A, Olsson T, Greene L, Eriksson P, Gemzell-Danielsson K, Salomonsson S, Kuchroo VK, Herlenius E, Kockum I, Sonesson SE, Wahren-Herlenius M. Auxilin Is a Novel Susceptibility Gene for Congenital Heart Block Modulating Cardiac Function [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/auxilin-is-a-novel-susceptibility-gene-for-congenital-heart-block-modulating-cardiac-function/. Accessed January 29, 2020.
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