Prediction for Intravenous Immunoglobulin Resistance by Using Weighted Genetic Risk Score Identified From Genome-Wide Association Study in Kawasaki Disease

Ho-Chang Kuo; Henry Sung-Ching Wong; Wei-Pin Chang; Ben-Kuen Chen; Mei-Shin Wu; Kuender D Yang; Kai-Sheng Hsieh; Yu-Wen Hsu; Shih-Feng Liu; Xiao Liu; Wei-Chiao Chang

doi:10.1161/CIRCGENETICS.116.001625

Prediction for Intravenous Immunoglobulin Resistance by Using Weighted Genetic Risk Score Identified From Genome-Wide Association Study in Kawasaki Disease

Circ Cardiovasc Genet. 2017 Oct;10(5):e001625. doi: 10.1161/CIRCGENETICS.116.001625.

Authors

Affiliations

¹ From the Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy (H.-C.K., W.-C.C.), Department of Clinical Pharmacy, School of Pharmacy (H.S.-C.W., M.-S.W., W.-C.C.), School of Health Care Administration, College of Management (W.-P.C.), and PhD Program in Biotechnology Research and Development, College of Pharmacy (W.-C.C.), Taipei Medical University, Taiwan; Department of Pediatrics and Kawasaki Disease Center (H.-C.K., K.-S.H.), Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine (S.-F.L.), and Department of Respiratory Therapy (S.-F.L.), Kaohsiung Chang Gung Memorial Hospital, Taiwan; Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan (B.-K.C.); Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan (B.-K.C.); Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan (K.D.Y.); Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan (K.D.Y.); The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taiwan (Y.-W.H.); Section of Hematology/Oncology, Department of Medicine, The University of Chicago, IL (X.L.); Department of Pharmacy, Taipei Medical University-Wanfang Hospital, Taiwan (W.-C.C.); and Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Taiwan (W.-C.C.).
² From the Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy (H.-C.K., W.-C.C.), Department of Clinical Pharmacy, School of Pharmacy (H.S.-C.W., M.-S.W., W.-C.C.), School of Health Care Administration, College of Management (W.-P.C.), and PhD Program in Biotechnology Research and Development, College of Pharmacy (W.-C.C.), Taipei Medical University, Taiwan; Department of Pediatrics and Kawasaki Disease Center (H.-C.K., K.-S.H.), Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine (S.-F.L.), and Department of Respiratory Therapy (S.-F.L.), Kaohsiung Chang Gung Memorial Hospital, Taiwan; Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan (B.-K.C.); Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan (B.-K.C.); Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan (K.D.Y.); Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan (K.D.Y.); The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taiwan (Y.-W.H.); Section of Hematology/Oncology, Department of Medicine, The University of Chicago, IL (X.L.); Department of Pharmacy, Taipei Medical University-Wanfang Hospital, Taiwan (W.-C.C.); and Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Taiwan (W.-C.C.). wcc@tmu.edu.tw.

Abstract

Background: Intravenous immunoglobulin (IVIG) is the treatment of choice in Kawasaki disease (KD). IVIG is used to prevent cardiovascular complications related to KD. However, a proportion of KD patients have persistent fever after IVIG treatment and are defined as IVIG resistant.

Methods and results: To develop a risk scoring system based on genetic markers to predict IVIG responsiveness in KD patients, a total of 150 KD patients (126 IVIG responders and 24 IVIG nonresponders) were recruited for this study. A genome-wide association analysis was performed to compare the 2 groups and identified risk alleles for IVIG resistance. A weighted genetic risk score was calculated by the natural log of the odds ratio multiplied by the number of risk alleles. Eleven single-nucleotide polymorphisms were identified by genome-wide association study. The KD patients were categorized into 3 groups based on their calculated weighted genetic risk score. Results indicated a significant association between weighted genetic risk score (groups 3 and 4 versus group 1) and the response to IVIG (Fisher's exact P value 4.518×10^-⁰³ and 8.224×10^-¹⁰, respectively).

Conclusions: This is the first weighted genetic risk score study based on a genome-wide association study in KD. The predictive model integrated the additive effects of all 11 single-nucleotide polymorphisms to provide a prediction of the responsiveness to IVIG.

Keywords: alleles; genetics; genome-wide association study; odds ratio; pharmacogenetics.

MeSH terms

3' Untranslated Regions
Alleles
Area Under Curve
Child, Preschool
Chromosomes, Human, Pair 6
DNA, Intergenic / genetics
Female
Genetic Loci
Genome-Wide Association Study*
Genotype
Humans
Immunoglobulins, Intravenous / administration & dosage*
Infant
Kruppel-Like Factor 6 / genetics
Male
Membrane Proteins / genetics
MicroRNAs / genetics
Mucocutaneous Lymph Node Syndrome / drug therapy
Mucocutaneous Lymph Node Syndrome / genetics*
Mucocutaneous Lymph Node Syndrome / pathology
Odds Ratio
Polymorphism, Single Nucleotide
Principal Component Analysis
ROC Curve
Repressor Proteins / genetics
Risk Factors
Treatment Failure
Zinc Finger E-box-Binding Homeobox 1 / genetics

Substances

3' Untranslated Regions
ADTRP protein, human
DNA, Intergenic
Immunoglobulins, Intravenous
KLF6 protein, human
Kruppel-Like Factor 6
MIRN548 microRNA, human
Membrane Proteins
MicroRNAs
Repressor Proteins
ZEB1 protein, human
ZNF438 protein, human
ZPLD1 protein, human
Zinc Finger E-box-Binding Homeobox 1