57 - GENOME-WIDE ASSOCIATION STUDY OF RISK FACTORS FOR NON-RESPONSE TO PRIMARY IMMUNOGLOBULIN PLUS PREDNISOLONE THERAPY

BACKGROUND/ AIM: A proportion of patients with KD are predicted to be resistant to standard IVIG treatment and receive intensified initial treatment remain resistant, or develop coronary artery lesions (CAL). Pathogenesis of this refractoriness has been unelucidated. We conducted an explorative study to investigate genetic risk factors for non-response to IVIG plus prednisolone (PSL) treatment, the most widely administered intensified initial treatment for patients with severe KD.

Methods: Genome-wide SNP typing was performed using the Illumina Asian Screening Array in 349 KD cases enrolled in the Kawasaki Disease Genome Consortium (JKDGC) who received initial IVIG plus PSL treatment. Outcomes were defined as follows: 1) axillary temperature > 37.5 ℃ persisted for more than 24 hours after completion of the initial treatment (27 non-responders and 322 responders); 2) administration of additional treatment (106 administered and 243 not administered); 3) CAL formation (49 with CAL, 300 without CAL). We performed whole genome imputation, Genome-wide association study (GWAS), and Gene Set Enrichment (GSE) analysis.

Results: GWAS showed no SNP with a significant association (p < 5.0×10^-8). Marginal association trends (p < 5.0×10^-5) were observed in 10 loci, including the IL-1 gene cluster for delayed defervescence, one for the administration of additional treatment, and three for CAL formation. No significant Gene Ontology, Reactome, or Human Phenotype Ontology term was identified in the GSE analysis. Among SNPs in eight previously identified susceptibility loci for KD, rs2254546 near BLK (CAL formation), rs6423677 in IGHV3-66 (defervescence delay), and rs4813003 near CD40 (CAL formation) showed positive trend of association (P < 0.01).

Conclusion: Several candidate loci for resistance to IVIG plus PSL as the intensified initial treatment for KD were identified. Follow-up studies in additional recruited patients treated with the same regimen are needed to conclude. Validation of the specificity of SNP effects to the IVIG plus PSL treatment is in progress by evaluating their associations in those treated with standard IVIG treatment.