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The HLA locus contains novel foetal susceptibility alleles for congenital heart block with significant paternal influence.

Authors :
Meisgen, S
Ostberg, T
Salomonsson, S
Ding, B
Eliasson, H
Mälarstig, A
Alfredsson, L
Klareskog, L
Hamsten, A
Olsson, T
Axelsson, T
Gadler, F
Jonzon, A
Sonesson, S-E
Kockum, I
Wahren-Herlenius, M
Swedish Congenital Heart Block Study Group
Source :
Journal of Internal Medicine; Jun2013, Vol. 273 Issue 6, p640-651, 12p
Publication Year :
2013

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. SUBJECTS AND DESIGN: 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 x 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
09546820
Volume :
273
Issue :
6
Database :
Complementary Index
Journal :
Journal of Internal Medicine
Publication Type :
Academic Journal
Accession number :
103950427
Full Text :
https://doi.org/10.1111/joim.12179