Regional evaluation of childhood acute lymphoblastic leukemia genetic susceptibility loci among Japanese

Kevin Y Urayama,Daisuke Hasegawa,Johji Inazawa,Yujin Sekinaka,Takashi Kaneko,Dai Keino,Yoko Ayukawa,Masatoshi Takagi ,Daisuke Toyama,Kozue Nakamura,Katsuyoshi Koh,Yozo Nakazawa,Akira Ohara,Hiroaki Goto,Motohiro Kato,Yuichi Taneyama,Yasushi Ishida,Takahisa Kawaguchi,Yasushi Noguchi,Yuki Yuza,Fumihiko Matsuda,Koichi Moriwaki,Daisuke Morita,Shuki Mizutani,Yoïchi Tanaka ,Toshihiro Tanaka,Kenichi Koike ,Takeshi Inukai,Hidemitsu Kurosawa,Yuki Arakawa,Masakatsu Yanagimachi,Keitaro Matsuo,Setsuo Ota,Junko Takita,Atsushi Manabe

doi:10.1038/s41598-017-19127-7

Abstract

Genome-wide association studies (GWAS) performed mostly in populations of European and Hispanic ancestry have confirmed an inherited genetic basis for childhood acute lymphoblastic leukemia (ALL), but these associations are less clear in other races/ethnicities. DNA samples from ALL patients (aged 0–19 years) previously enrolled onto a Tokyo Children’s Cancer Study Group trial were collected during 2013–2015, and underwent single nucleotide polymorphism (SNP) microarray genotyping resulting in 527 B-cell ALL for analysis. Cases and control data for 3,882 samples from the Nagahama Study Group and Aichi Cancer Center Study were combined, and association analyses across 10 previous GWAS-identified regions were performed after targeted SNP imputation. Linkage disequilibrium (LD) patterns in Japanese and other populations were evaluated using the varLD score based on 1000 Genomes data. Risk associations for ARID5B (rs10821936, OR = 1.84, P = 6 × 10−17) and PIP4K2A (rs7088318, OR = 0.76, P = 2 × 10−4) directly transferred to Japanese, and the IKZF1 association was detected by an alternate SNP (rs1451367, OR = 1.52, P = 2 × 10−6). Marked regional LD differences between Japanese and Europeans was observed for most of the remaining loci for which associations did not transfer, including CEBPE, CDKN2A, CDKN2B, and ELK3. This study represents a first step towards characterizing the role of genetic susceptibility in childhood ALL risk in Japanese.

Highlights

In childhood acute lymphoblastic leukemia (ALL), six regions that have replicated in several populations are considered known susceptibility loci, with the majority of the evidence supported through studies conducted in populations of European and Hispanic descent[1,2]
In our targeted evaluation of 16 previous genome-wide association studies (GWAS)-reported single nucleotide polymorphisms (SNPs), we observed that the risk associations of those in ARID5B and PIP4K2A directly transfer to the Japanese population
Examination of regional variation in LD (varLD) scores showed that significant differences in linkage disequilibrium (LD) between Japanese and the population in which the association was first reported were commonly observed in genes where the risk association did not transfer

Summary

Introduction

Using available SNP data across all 10 genetic loci including 10-kb flanking regions on both ends of the target genes, B-cell ALL risk associations were identified for alternate SNPs in IKZF1 (rs1451367, OR = 1.52, 95% CI = 1.28–1.80, P = 1.9 × 10−6) (Table 3 and Fig. 1). With the exception of LHPP and WWOX, the four additional genetic loci in which the association did not transfer to Japanese showed strong evidence of regional LD structure differences based on varLD evaluations.

Results

Conclusion