Germ-line genetic variation in the immunoglobulin heavy chain creates stroke susceptibility in the spontaneously hypertensive rat

Abstract

The risk of cerebrovascular disease in stroke-prone spontaneously hypertensive rats (SHR-A3/SHRSP) arises from naturally occurring genetic variation. In the present study we show the involvement of SHR genetic variation that affects antibody formation and function in the pathogenesis of stroke. We have tested the involvement in susceptibility to stroke of genetic variation in IgH, the gene encoding the immunoglobulin heavy chain by congenic substitution. This gene contains functional natural variation in SHR-A3 that diverges from stroke-resistant SHR-B2. We created a SHR-A3 congenic line in which the IgH gene was substituted with the corresponding haplotype from SHR-B2. Compared with SHR-A3 rats, congenic substitution of the IgH locus [SHR-A3( IgH-B2)] markedly reduced cerebrovascular disease. Given the role in antibody formation of the IgH gene, we investigated the presence of IgG and IgM autoantibodies and their targets using a high-density protein array containing ~20,000 recombinant proteins. High titers of autoantibodies to key cerebrovascular stress proteins were detected, including FABP4, HSP70, and Wnt signaling proteins. Serum levels of these autoantibodies were reduced in the SHR-A3( IgH-B2) congenic line.

A Novel Framework for Characterizing Genomic Haplotype Diversity in the Human Immunoglobulin Heavy Chain Locus

“…To date, few diseases have been robustly associated to IGH (24,25,72,73). We previously suggested this was due to sparse locus coverage of genotyping arrays and an inability of array SNPs to tag functional IGH variants (2,3).…”

A novel framework for characterizing genomic haplotype diversity in the human immunoglobulin heavy chain locus

“…To date, few diseases have been robustly associated to IGH 22,23,70,71 . We previously suggested this was due to sparse locus coverage of genotyping arrays and an inability of array SNPs to tag functional IGH variants 4,20 .…”

Igh Locus Polymorphism May Dictate Topological Chromatin Conformation and V Gene Usage in the Ig Repertoire

“…Genetic differences, such as those observed between 129S1/SvImJ and C57BL/6 (Figures 2A, B), when considered alongside observations that have been made for regulatory elements elsewhere in the genome, raise important questions about the potential for Ig genetic diversity to impact V(D)J recombination. First, there are numerous examples for which germline V H variants have been shown to contribute to antigen specificity (75-79) and associate with disease and clinical phenotypes in the context of infection, inflammation, and vaccination (31,32,(80)(81)(82)(83). Second, both large structural variants and single nucleotide polymorphisms could modify key regulatory elements, such as CTCF sites and in promoters and enhancers, either through the disruption of these elements (e.g.…”