Association of an IGHV3-66 gene variant with Kawasaki disease

Abstract

In a meta-analysis of three GWAS for susceptibility to Kawasaki disease (KD) conducted in Japan, Korea, and Taiwan and follow-up studies with a total of 11,265 subjects (3428 cases and 7837 controls), a significantly associated SNV in the immunoglobulin heavy variable gene (IGHV) cluster in 14q33.32 was identified (rs4774175; OR = 1.20, P = 6.0 × 10 −9). Investigation of nonsynonymous SNVs of the IGHV cluster in 9335 Japanese subjects identified the C allele of rs6423677, located in IGHV3-66, as the most significant reproducible association (OR = 1.25, P = 6.8 × 10 −10 in 3603 cases and 5731 controls). We observed highly skewed allelic usage of IGHV3-66, wherein the rs6423677 A allele was nearly abolished in the transcripts in peripheral blood mononuclear cells of both KD patients and healthy adults. Association of the highexpression allele with KD strongly indicates some active roles of B-cells or endogenous immunoglobulins in the disease pathogenesis. Considering that significant association of SNVs in the IGHV region with disease susceptibility was previously known only for rheumatic heart disease (RHD), a complication of acute rheumatic fever (ARF), these observations suggest that common B-cell related mechanisms may mediate the symptomology of KD and ARF as well as RHD.

SARS-CoV-2–related MIS-C: A key to the viral and genetic causes of Kawasaki disease?

“…Significant genome-wide associations were also detected for SNPs in HLA class II genes in the Japanese population ( Onouchi et al, 2012 ), whereas analyses performed with specific HLA class I alleles yielded nonreproducible results ( Onouchi, 2009 ). Finally, a recent follow-up study of the three East Asian GWASs identified several additional significant loci ( Johnson et al, 2020 ; Lee et al, 2012 ; Onouchi et al, 2012 ; Table 2 ). In particular, a higher risk of KD was found to be associated with the high-expression alleles of SNPs located in the Ig heavy variable gene (IGHV) cluster.…”

“… This table lists variants reaching genome-wide significance (P < 5 × 10 −8 ) in the primary GWAS in which they were identified ( Khor et al, 2011 ; Kim et al, 2017 ; Lee et al, 2012 ; Onouchi et al, 2012 ) or in a follow up meta-analysis ( Johnson et al, 2020 ) of the three Asian GWASs ( Kim et al, 2017 ; Lee et al, 2012 ; Onouchi et al, 2012 ). Chr, chromosome; SNP, single nucleotide polymorphism; UTR, untranslated region.…”

Profiling Germline Adaptive Immune Receptor Repertoire with gAIRR Suite

“…In a simian immunodeficiency virus infection model, the TR alleles response for the potent CD8+ T cell response was recently determined 10 . Germline AIRR alleles have started to be found associated with human diseases, including celiac disease 11 , Alzheimer disease 12 , rheumatic heart disease 13 , and Kawasaki disease 14 ; 15 . However, the known examples of germline AIRR effects on human immune-related phenotypes and diseases are likely only the tip of the iceberg because determining germline AIRR for any given individual is currently insurmountable.…”

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.…”