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European families reveal MHC class I and II associations with autoimmune-mediated congenital heart block
  1. Nikolaos C Kyriakidis1,
  2. Ingrid Kockum2,
  3. Heikki Julkunen3,
  4. Ariela Hoxha4,
  5. Stina Salomonsson1,
  6. Lauro Meneghel1,
  7. Cathrine Ebbing5,
  8. The Swedish Congenital Heart Block Study Group6,
  9. Alexander Dilthey6,
  10. Marianne Eronen7,
  11. Sara De Carolis8,
  12. Torvid Kiserud5,9,
  13. Amelia Ruffatti4,
  14. Juha Kere10,11,12,
  15. Sabrina Meisgen1,
  16. Marie Wahren-Herlenius1
  1. 1 Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  2. 2 Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
  3. 3 Department of Internal Medicine and Rheumatology, Helsinki University Central Hospital, Helsinki, Finland
  4. 4 Rheumatology Unit, Department of Medicine, University of Padua, Padua, Italy
  5. 5 Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
  6. 6 The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  7. 7 Health Department, Social Insurance Institution of Finland, Helsinki, Finland
  8. 8 Department of Obstetrics and Gynecology, Catholic University of Sacred Heart, Rome, Italy
  9. 9 Department of Clinical Science, University of Bergen, Bergen, Norway
  10. 10 Department of Biosciences and Nutrition, Centre for Innovative Medicine, Karolinska Institutet, Stockholm, Sweden
  11. 11 School of Basic and Medical Biosciences, King’s College London, London, UK
  12. 12 Folkhälsan Institutet of Genetics, and Molecular Neurology Research Program, University of Helsinki, Helsinki, Finland
  1. Correspondence to Professor Marie Wahren-Herlenius, Department of Medicine, Karolinska Institutet, Stockholm 171 76, Sweden ; marie.wahren{at}

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Congenital heart block (CHB) may develop in the fetus of Ro/SSA autoantibody-positive women. A population-based recurrence rate of only 12% however suggests that factors other than maternal autoantibodies influence the risk of developing CHB.1 In the present study, we aimed to identify genetic contribution to the disease by analysing HLA associations in European families with a Ro/SSA antibody-positive mother and at least one child affected by CHB.

HLA allele genotypes were imputed for 173 families comprising 635 individuals (291 parents, 173 cases and 167 unaffected siblings) from Sweden, Norway, Finland and Italy (online supplementary table 1) based on 5636 tag SNPs. Parental HLA allele transmission frequencies to patients with CHB were assessed and OR and significance of the association with CHB calculated. We considered nominal P values <0.05 suggestive of significance, and P values below the threshold of Bonferroni correction for multiple testing, or if the association had been previously reported at P<0.05, significant. Detailed information on patients and methods are available online (online supplementary methods).

Supplementary file 1


Supplementary file 2


In the MHC class I gene locus, we replicated the previously identified2 protective association of HLA-Cw*06 (OR 0.22 (0.07–0.67), P=0.003) …

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  • SM and MW-H contributed equally.

  • Handling editor Josef S Smolen

  • Contributors SM, NK, IK and MWH conceived the study. AH, LM, SS, HK, CE, SCHBSG, ME, SDC, TK, AR, and JK identified and provided samples from CHB patients and family members. AD imputed HLA allele genotypes. NK and SM analyzed the data with input from IK and MWH. SM and NK wrote the manuscript together with IK and MWH. All authors edited and approved the final manuscript.

  • Funding The study was supported by grants from the Swedish Research Council, the Heart-Lung Foundation, the Stockholm County Council, Karolinska Institutet, the Swedish Rheumatism Association, the King Gustaf Vth 80-year Foundation and the Freemason’s in Stockholm Foundation for Children’s Welfare.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The Regional Ethic’s Committees in Stockholm, Helsinki, Bergen, Padua and Rome.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Collaborators Amanda Skog; Anders Ekbom; Anders Jonzon; Annika Rydberg; Annika Öhman; Elke Theander; Eva Fernlund; Fredrik Gadler; Gunnar Bergman; Håkan Eliasson; Ingrid Kockum; Joanna Tingström; Katarina Bremme; Kristina Gemzell Danielsson; Linda Lagnefeldt; Malin Hedlund; Marie Wahren-Herlenius; Mats Mellander; Ola Winqvist; Sabrina Meisgen; Stina Salomonsson; Sven-Erik Sonesson; Thomas Skogh; Vijole Ottosson.