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A7.23 The HLA Locus Contains Novel Foetal Susceptibility Alleles for Congenital Heart Block with Significant Paternal Influence
  1. Sabrina Görgen1,*,
  2. Therese Östberg1,*,
  3. Stina Salomonsson1,
  4. Bo Ding2,
  5. Håkan Eliasson3,
  6. Anders Mälarstig1,
  7. Lars Alfredsson2,
  8. Lars Klareskog1,
  9. Anders Hamsten1,
  10. Tomas Olsson4,
  11. Tomas Axelsson5,
  12. The Swedish Congenital Heart Block Study Group6,
  13. Fredrik Gadler1,
  14. Anders Jonzon7,
  15. Sven-Erik Sonesson3,
  16. Ingrid Kockum4,
  17. Marie Wahren-Herlenius1
  1. 1Department of Medicine
  2. 2Department of Environmental Medicine
  3. 3Department of Women’s and Children’s Health
  4. 4Department of Neuroscience, Karolinska Institutet, Stockholm
  5. 5Department of Medical Sciences, Uppsala University
  7. 7Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden


Objective To identify foetal susceptibility genes in Ro/SSA autoantibody-mediated congenital heart block on chromosome six.

Methods Single nucleotide polymorphism (SNP) genotyping of individuals included in the Swedish Congenital Heart Block (CHB) study population was performed. Low resolution HLA-A, -Cw and -DRB1 allele typing was carried out in 86 families of the study population comprising 339 individuals (86 Ro/SSA autoantibody positive mothers, 71 fathers, 87 CHB index cases and 95 unaffected siblings).

Results A case-control comparison between index cases and population-based out of study controls (n = 1710) revealed an association of CHB with fifteen SNPs in the 6p21.3 MHC locus at a chromosome-wide significance of p < 2.59 × 10–6 (OR 2.21–3.12). In a family-based analysis between SNP markers as well as distinct MHC class I and II alleles with CHB we observed associations to HLA-DRB1*04 and HLA-Cw*05 variants that were significantly more often transmitted to affected individuals (p < 0.03 and p < 0.05, respectively), and HLA-DRB1*13 and HLA-Cw*06 variants which were significantly less often transmitted to affected children (p < 0.05 and p < 0.04). We further observed a significant association of increased paternal, but not maternal, HLA-DRB1*04 transmissions to the affected offspring (p < 0.02).

Conclusions Our study identifies HLA-DRB1*04 and HLA-Cw*05 as novel foetal HLA-allele variants that confer susceptibility to develop CHB in response to exposure to Ro/SSA autoantibodies, while DRB1*13 and Cw*06 emerged as protective alleles. For the first time, we also demonstrate paternal contribution to foetal susceptibility to CHB.

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