Association of the IL16 Asn1147Lys polymorphism with intravenous immunoglobulin resistance in Kawasaki disease
Authors
Hea-Ji Kim ; Jae-Jung Kim ; Sin Weon Yun ; Jeong Jin Yu ; Kyung Lim Yoon ; Kyung-Yil Lee ; Hong-Ryang Kil ; Gi Beom Kim ; Myung-Ki Han ; Min Seob Song ; Hyoung Doo Lee ; Kee Soo Ha ; Young Mi Hong ; Gi Young Jang ; Jong-Keuk Lee
Citation
JOURNAL OF HUMAN GENETICS, Vol.65(4) : 421-426, 2020-04
Child ; Child, Preschool ; Drug Resistance / genetics* ; Female ; Genome-Wide Association Study ; Humans ; Immunoglobulins, Intravenous / administration & dosage* ; Infant ; Interleukin-16 / genetics* ; Male ; Mucocutaneous Lymph Node Syndrome* / drug therapy ; Mucocutaneous Lymph Node Syndrome* / genetics ; Mutation, Missense* ; Polymorphism, Single Nucleotide*
Abstract
Kawasaki disease (KD) is an acute, self-limited vasculitis, mainly affecting children younger than 5 years old, with accompanying fever and signs of mucocutaneous inflammation. Intravenous immunoglobulin (IVIG) is the standard treatment for KD; however, similar to 15% of patients are resistant to IVIG treatment. To identify protein coding genetic variants influencing IVIG resistance, we re-analyzed our previous genome-wide association study (GWAS) data from 296 patients with KD, including 101 IVIG non-responders and 195 IVIG responders. Five nonsynonymous SNPs (nsSNPs) in five immune-related genes, including a previously reported SAMD9L nsSNP (rs10488532; p.Val266Ile), were associated with IVIG non-response (odds ratio [OR] = 1.89-3.46, P = 0.0109-0.0035). In a replication study of the four newly-identified nsSNPs, only one in the interleukin 16 (IL16) gene (rs11556218, p.Asn1147Lys) showed a trend of association with IVIG non-response (OR = 1.54, P = 0.0078). The same IL16 nsSNP was more significantly associated with IVIG non-response in combined analysis of all data (OR = 1.64, P = 1.25 x 10(-4)). Furthermore, risk allele combination of the IL16 CT and SAMD9L TT nsSNP genotypes exhibited a very strong effect size (OR = 9.19, P = 3.63 x 10(-4)). These results implicate IL16 as involved in the mechanism of IVIG resistance in KD.