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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) …
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.
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