Kawasaki disease (alternate names: Mucocutaneous Lymph Node Syndrome, Infantile Polyarteritis) is an acute necrotizing vasculitis thought to be of autoimmune origin. It affects large- to medium-sized blood vessels, with frequent involvement of the coronary arteries. Though most often reported in Asian populations, the incidence of Kawasaki disease is increasing around the world. Kawasaki disease primarily affects infants and children less than 4 years old with a male-to-female ratio of 1.8-1.5 to 1. (1) The course of the disease is usually self-limited, but serious sequelae may develop; it is the leading cause of acquired cardiovascular disease in children, with up to 20% of untreated patients developing such complications. With aspirin administration and intravenous immunoglobulin treatment, only 4% of patients will develop serious cardiovascular sequelae. As early treatment is essential and no specific diagnostic molecular markers are currently available, identification of SNPs associated with an increased risk of the disease may prove clinically useful. In particular, risk SNPs may add supporting evidence to a differential diagnosis of Kawasaki disease, particularly in cases of atypical Kawasaki, which do not present with as many classic signs and symptoms.(2-5)
PRESENTATION & ETIOLOGY:
The classic presentation of the disease is a high fever that may last up to two weeks despite treatment with standard doses of acetaminophen or ibuprofen. Other symptoms may include cervical lymphadenopathy, conjunctival, oral, palmar, and plantar erythema, a desquamative rash, and edema of the hands and feet. Though the etiology is unclear, Kawasaki disease is thought to arise from a type IV hypersensitivity reaction to an unknown infection, resulting in the production of cross-reactive antibodies to endothelial and smooth muscle cells of the vasculature. These autoantibodies precipitate the characteristic pathological inflammatory reaction seen in Kawasaki disease.(1-5) Despite concerted efforts to identify the infectious trigger, no causal link has been established. However, numerous epidemiological studies have found evidence of a strong genetic influence on disease susceptibility. Most notably, familial aggregation has been demonstrated(6,7) and emigration from Asia does not appear to diminish the disproportionately high risk of the disease observed in Asian populations.(8,9) One possibility is that a relatively ubiquitous, normally harmless infectious agent causes disease only in genetically susceptible individuals.
KAWASAKI RISK-ASSOCIATED SNPS, discussed below:
Other SNPs discussed below:
A 2012 case-control GWAS by Lee et al. identified three SNPs at two particularly biologically-plausible loci that reached genome-wide significance (p < 5 x 10-8) in a combined GWAS / replication set analysis. In this study, the initial GWAS cohort consisted of 622 cases and 1107 controls of Han Chinese descent, while the replication cohort consisted of an additional 261 cases and 550 controls, also of Han Chinese descent. Two SNPs (rs2736340 (T) p = 9.01 x 10-10, OR = 1.54 (95% CI = 1.34-1.77); rs2618476 (G) p = 1.96 x 10-9, OR = 1.52 (95% CI = 1.33-1.75)) in strong linkage disequilibrium (D’ = 0.988; r2 = 0.971) were localized to a 12.2-kb LD block at 8p23.1 that contains the promoter and first intron of B-lymphoid tyrosine kinase (BLK). BLK is a Src-related tyrosine kinase involved in signal transduction from the B cell receptor, a key transmembrane receptor protein involved in the immune response to specific antigens.(10) A genetic lesion at this locus could result in disregulation of B cell function, a biological mechanism consistent with the working hypothesis that Kawasaki disease results at least in part from an anti-body mediated immune response. This is certainly plausible, as rs2736340 is also associated with other immune-mediated disorders like rheumatoid arthritis(10,11) and is in linkage disequilibrium (D’=1, r2 = 0.957) with systemic lupus erythematosus-associated SNP rs13277113 in the HapMap JPT and CHB populations.(10,12) Also of note is the fact that data from the 1000 Genomes Project indicates that the rs2736340 risk allele (T) is far more frequent in Asian populations (0.68-0.77) than in Western Europeans (0.239), consistent with the higher incidence of Kawasaki disease in Asian populations.(10)
The second Kawasaki-associated locus identified by Lee et al. (2012) consists of a 17.2-kb LD block upstream of the CD40 gene at 20q13.12. In this case, the A risk allele of rs1569723 has a p-value of 5.67 x 10-9 with an odds ratio of 1.42 (95% CI: 1.26-1.59) in the combined GWAS / replication set analysis.(10) This SNP is located within a haplotype block that includes a part of the CD40 exonic region.(16) CD40 is a cell surface receptor that is part of the larger TNF receptor superfamily. It is found on B cells and other antigen-presenting cells, and is not only required for B and T cell activation, but also promotes the inflammatory response through the production of cytokines and chemokines. As a result of its important role in immune regulation, CD40 has also emerged as a potential pathogenic candidate in a number of other immune-mediated diseases such as Sjogren’s disease, systemic lupus erythematosus, and rheumatoid arthritis, among others.(13) Lee et al. (2012) also note that the rs1569723 SNP identified in the study is in strong linkage disequilibrium (D’ = 0.96, r2 = 0.93) with a SNP (rs1883832) located 1 bp from the start codon of CD40. Rs1883832 has been shown to alter CD40 translation efficiency and is associated with Graves’ disease, an autoimmune disorder.(10,17) A 2009 study by the Australia and New Zealand Multiple Sclerosis Genetics Consortium also found an association (p = 2.9 x 10-7) between rs1569723 and multiple sclerosis in a GWAS that included 3,874 cases and 5,723 controls.16 The association of rs1569723 with multiple sclerosis, an autoimmune disease of the central nervous system, lends additional support to the possibility of the CD40 locus’ involvement in an autoimmune disorder such as Kawasaki disease. Moreover, the CD40 ligand (CD40LG) has also been loosely implicated in Kawasaki disease. A study by Wang et al. (2003) demonstrated that expression levels of CD40LG in serum and on CD4+ and CD8+ T cells was significantly higher (p < 0.001) in a set of 43 patients with Kawasaki disease when compared with 43 age-matched febrile controls. These studies suggest a role for CD40 pathway dysfunction in Kawasaki.
In summary, the three risk SNPs (rs2736340, rs2618476, and rs1569723) associated with Kawasaki disease identified by Lee et al. (2012) all pass the genome-wide significance threshold and feature relatively substantial odds ratios. The SNPs are close to genes (BLK and CD40) with roles in immune function. The immunological roles of these genes makes them biologically plausible candidate loci for pathological disturbance in Kawasaki. Moreover, several of the SNPs have either been associated directly with autoimmune disorders, or are in strong linkage disequilibrium with SNPs that have been associated with such disorders. These SNPs and their associated loci merit further investigation to better understand how they may contribute to the development and/or progression of Kawasaki disease.
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