title: The HLA locus contains novel foetal susceptibility alleles for congenital heart block with significant paternal influence.
abstract: OBJECTIVE
  The main aim of this study was to identify foetal susceptibility genes on chromosome six for Ro/SSA autoantibody-mediated congenital heart block.
  
  
  METHODS
  Single nucleotide polymorphism (SNP) genotyping of individuals 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 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 association of CHB with 15 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 of association of SNP markers as well as distinct MHC class I and II alleles with CHB, HLA-DRB1*04 and HLA-Cw*05 variants were significantly more frequently transmitted to affected individuals (P < 0.03 and P < 0.05, respectively), whilst HLA-DRB1*13 and HLA-Cw*06 variants were significantly less often transmitted to affected children (P < 0.04 and P < 0.03). We further observed marked association of increased paternal (but not maternal) HLA-DRB1*04 transmission to affected offspring (P < 0.02).
  
  
  CONCLUSIONS
  HLA-DRB1*04 and HLA-Cw*05 were identified as novel foetal HLA allele variants that confer susceptibility to CHB in response to Ro/SSA autoantibody exposure, whilst DRB1*13 and Cw*06 emerged as protective alleles. Additionally, we demonstrated a paternal contribution to foetal susceptibility to CHB for the first time.
authors.affiliation: Department of Medicine, Karolinska Institutet, Uppsala University, Uppsala, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Meisgen
authors.forename: T
authors.initials: T
authors.lastname: Östberg
authors.forename: S
authors.initials: S
authors.lastname: Salomonsson
authors.forename: B
authors.initials: B
authors.lastname: Ding
authors.forename: H
authors.initials: H
authors.lastname: Eliasson
authors.forename: A
authors.initials: A
authors.lastname: Mälarstig
authors.forename: L
authors.initials: L
authors.lastname: Alfredsson
authors.forename: L
authors.initials: L
authors.lastname: Klareskog
authors.forename: A
authors.initials: A
authors.lastname: Hamsten
authors.forename: T
authors.initials: T
authors.lastname: Olsson
authors.forename: T
authors.initials: T
authors.lastname: Axelsson
authors.forename: F
authors.initials: F
authors.lastname: Gadler
authors.forename: A
authors.initials: A
authors.lastname: Jonzon
authors.forename: S-E
authors.initials: SE
authors.lastname: Sonesson
authors.forename: I
authors.initials: I
authors.lastname: Kockum
authors.forename: M
authors.initials: M
authors.lastname: Wahren-Herlenius
mesh_terms: D000328:Adult; D000974:Antibodies, Antinuclear; D002648:Child; D005192:Family Health; D005220:Fathers; D005260:Female; D005787:Gene Frequency; D005802:Genes, MHC Class II / Q000235:genetics; D020022:Genetic Predisposition to Disease; D015236:HLA-C Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006327:Heart Block / Q000151:congenital* / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D013548:Sweden / Q000453:epidemiology
chemical_list: D000974:Antibodies, Antinuclear; D015236:HLA-C Antigens; C037505:HLA-C*05 antigen; D059811:HLA-DRB1 Chains; C527195:HLA-DRB1*04 antigen; C035356:SS-A antibodies
keywords: HLA-DRB1*04; MHC; autoantibodies; congenital heart block; neonatal lupus erythematosus