Background/Purpose:  Anti-Ro associated congenital heart block (CHB) exhibits a 33% concordance rate in monozygotic twins, 17.5% recurrence of disease and a high sibling risk ratio (lamda s=3000). Given the strong maternal genetic influence on anti-Ro antibody production and the proposed pathogenesis of injury which implicates fetal innate immune responses, the Immunochip (SNP array for fine mapping 186 genomic regions previously connected to at least one of 12 autoimmune diseases) was selected to explore associations between immune-related variants and CHB. Pedigrees inclusive of affected and unaffected children and their parents were included in an attempt to untangle maternal from fetal contributions.

Methods: Caucasian CHB children (n=170) and nuclear family members (n=435) from three Registries (U.S., France, Italy) were genotyped. Sera from the mothers of all probands were confirmed to react with either 52kD SSA/Ro, 60kD SSA/Ro, or 48kD SSB/La. In 96%, 2nd or 3rd degree block was present; the remaining 4% had an isolated cardiomyopathy. Out-of-study controls (n=1087) were called together with CHB pedigree data. After standard QC, association analyses were computed using logistic regression for case-control and pedigree disequilibrium tests (PDT) for pedigree-based tests; the latter accounts for genetic maternal immune load. P-values were genomic control adjusted and genome-wide significance was assessed using the false discovery rate P-value (FDR-P<0.05). Primary inference is based on the FDR-P for the case-control analysis, conditional on the PDT/TDT P-value being <0.05.  

Results: There were 18 SNPs inside and 25 SNPs outside the HLA region that met the dual criteria, case-control FDR-P<0.05 (i.e., genome-wide significance) and PDT/TDT P<0.05.  The strongest association was inside the extended HLA region within an intronic region of GABBR1 (rs29252: FDR-P=2x10E-10, OR=6.2) which encodes an inhibitory neurotransmitter receptor whose ligation resists ischemia/reperfusion-injury and fibrosis. Detailed imputation-based four digit HLA analyses are underway. Outside the HLA region the primary associations included rs3739706 [FDR-P=0.0009, OR=1.9] within LPAR1 which encodes a lysophosphatidic acid G-protein-coupled receptor with a role in endothelial cell differentiation; rs62092154 [FDR-P=0.0026, OR=4.8] within SLC14A2 (encodes a urea transporter, which in addition to being expressed in the kidney, is also expressed in the heart and increased in heart failure); rs8063008 [FDR-P=0.00598, OR=0.46] with an intergenic on 16q24 and numerous associations on 2p14 within FLJ16124 (e.g., rs7575614: FDR-P=0.02, OR=2.7), a region rich in regulatory elements. Interestingly, rs473024 showed evidence of association [FDR-P=0.01, OR=1.8] and is located within MAGI2, a gene identified in an imprinted gene expressed in human placenta. 

Conclusion: Analysis with the Immunochip yielded numerous regions strongly associated with CHB, even after accounting for potential parental load. These associations corroborate the genetic influence on CHB and suggest a link between immune responses and exuberant fibrotic replacement of the atrioventricular node and in some cases a cardiomyopathy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/accounting-for-parental-load-and-identification-of-multiple-risk-variants-for-anti-ro-congenital-heart-block-through-high-density-genotyping-of-immune-related-loci/