Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
HLA-DRB104 Is a Novel Fetal Susceptibility Allele in Congenital Heart Block.
Ostberg2, Therese, Salomonsson2, Stina, Ding4, Bo, Eliasson4, Håkan, Alfredsson4, Lars, Klareskog5, Lars, Hamsten2, Anders
Department of Medicine, Karolinska Institutet, Stockholm
Department of Medicine, Karolinska Institutet
Department of Women and Child Health, Karolinska Instituet
Karolinska University Hospital, Stockholm, Sweden
Congenital heart block may develop in the fetus of Ro52 autoantibody positive women. The reported recurrence rate for autoantibody associated congenital heart block is however only 1025%, indicating that other factors than maternal autoantibodies influence the disease development and fetal outcome. The most potent genetic influence on susceptibility to autoimmune diseases is the HLA locus, and as there is a strong and well-known HLA-DR*03 allele association with SLE, Sjögren's syndrome and production of Ro/SSA autoantibodies, we hypothesized that specific alleles of the HLA locus may render the fetus susceptible to congenital heart block induced by maternal autoantibodies.
Genotyping was performed for 561,490 SNPs in DNA from 348 individuals of 88 Swedish Caucasian families with a Ro/SSA autoantibody positive mother and with at least one case of congenital heart block (83 mothers and 72 fathers, 92 index cases and 101 unaffected siblings). Full HLA-A, -C and HLA-DRB1 allele typing was performed by SSP-PCR in 60 families with complete trios. Swedish Caucasian population-based healthy controls from the EIRA (n=1056) and PROCARDIS (n=654) studies were used in case-control association analysis. Genetic linkage was analyzed by transmission disequilibrium test (TDT).
A case-control analysis between the index cases and population-based controls revealed an association of congenital heart block with 6 SNPs in the 6p21 MHC locus at a genome-wide significance of p<5×10-8 (OR 2.573.12). In family-based TDT analysis of distinct MHC class I and II alleles we observed an association of the HLA-DR*04 allele with congenital heart block, and that this variant was significantly more often transmitted to children that developed congenital heart block (p=0.01). No difference in the transmission frequency of the DRB1*04 allele from mothers (maternal DRB1*04 allele frequency 7.6%) compared with fathers (paternal DRB1*04 allele frequency 20.8%) was observed. No other HLA-DRB1, -A or -C association with congenital heart block was found. The previously described HLA-DRB1*03 association in the mothers compared with controls was observed also in our cohort, and 79.7% of the mothers carried DRB1*03.
Our study identifies HLA-DRB1*04 as a novel fetal genetic variant that confers susceptibility to develop congenital heart block in response to exposure to Ro/SSA autoantibodies, and indicates equal maternal and paternal genetic influence on fetal susceptibility to maternal autoantibody exposure.
To cite this abstract, please use the following information:
Ostberg, Therese, Salomonsson, Stina, Ding, Bo, Eliasson, Håkan, Alfredsson, Lars, Klareskog, Lars, et al; HLA-DRB104 Is a Novel Fetal Susceptibility Allele in Congenital Heart Block. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :832