Genome-wide association study using the ethnicity-specific Japonica array: identification of new susceptibility loci for cold medicine-related Stevens–Johnson syndrome with severe ocular complications
Journal of Human Genetics
Genome-wide association study using the ethnicity- specific Japonica array: identification of new susceptibility loci for cold medicine-related Stevens- Johnson syndrome with severe ocular complications
Mayumi Ueta 0 1
Hiromi Sawai 1
Ryosei Shingaki 2
Yusuke Kawai 3
Chie Sotozono 4
Kaname Kojima 3
Kyung-Chul Yoon 5
Mee Kum Kim 6
Kyoung Yul Seo 7
Choun-Ki Joo 8
Masao Nagasaki 3
Shigeru Kinoshita 0
Katsushi Tokunaga 1
0 Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine , Kyoto , Japan
1 Department of Human Genetics, Graduate School of Medicine, University of Tokyo , Tokyo , Japan
2 Life Science Business Department, Healthcare Medical Business Promotion Division, Toshiba Corporation Healthcare Company , Tokyo , Japan
3 Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University , Sendai , Japan
4 Department of Ophthalmology, Kyoto Prefectural University of Medicine , Kyoto , Japan
5 Department of Ophthalmology, Chonnam National University , Gwangju , Korea
6 Department of Ophthalmology, Seoul National University College of Medicine , Seoul , Korea
7 Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine , Seoul , Korea
8 Department of Ophthalmology and Visual Science, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea , Seoul, Korea Kawaramachi, Kamigyoku, Kyoto 602-0841 , Japan
A genome-wide association study (GWAS) for cold medicine-related Stevens-Johnson syndrome (CM-SJS) with severe ocular complications (SOC) was performed in a Japanese population. A recently developed ethnicity-specific array with genome-wide imputation that was based on the whole-genome sequences of 1070 unrelated Japanese individuals was used. Validation analysis with additional samples from Japanese individuals and replication analysis using samples from Korean individuals identified two new susceptibility loci on chromosomes 15 and 16. This study might suggest the usefulness of GWAS using the ethnicity-specific array and genome-wide imputation based on large-scale whole-genome sequences. Our findings contribute to the understanding of genetic predisposition to CM-SJS with SOC. Journal of Human Genetics (2017) 62, 485-489; doi:10.1038/jhg.2016.160; published online 19 January 2017
Stevens?Johnson syndrome (SJS) is an acute inflammatory
vesiculobullous reaction of the skin and mucosa. It tends to involve the ocular
surface, oral cavity and genitals. In patients with extensive skin
detachment and a poor prognosis, the condition is called toxic
epidermal necrolysis (TEN). Although these reactions are rare (annual
incidence 1?6 cases per 106 persons),1?3 the mortality rate is 3% for
SJS and 27% for TEN.4 Survivors often suffer severe sequelae such as
vision loss due to severe ocular complications (SOC).5
About 40% of SJS/TEN patients diagnosed by dermatologists develop
SOC.2 Among SJS and TEN patients, especially those with SJS/TEN with
SOC, cold medicines (CM), including multi-ingredient cold medications
and non-steroidal anti-inflammatory drugs, were identified as
causative.2,6?9 We reported that in the Japanese, CM-related SJS/TEN
(CM-SJS/TEN) with SOC was strongly associated with HLA-A*02:06 and
significantly associated with HLA-B*44:03.9 In our first genome-wide
association study (GWAS), we analyzed SJS/TEN with SOC patients using
the Affymetrix GeneChip Mapping 500 K array set (Affymetrix, Santa
Clara, CA, USA). We found an association between prostaglandin E receptor
3 (PTGER3) and SJS/TEN with SOC.6,10 We subsequently documented
that this association was stronger in CM-SJS/TEN patients with SOC than
in all SJS/TEN patients with SOC.11 Moreover, we identified an interaction
with additive effects between HLA-A*02:06 and the high-risk genotypes
PTGER3 rs1327464 GA or AA.11 A second GWAS using the Affymetrix
AXIOM Genome-Wide ASI 1 array (Affymetrix) identified the association
between IKAROS family zinc-finger 1 (IKZF1) and CM-SJS/TEN with SOC
in the Japanese.7 These findings were indicative of a genetic predisposition
for CM-SJS/TEN with SOC.
A single-nucleotide polymorphism (SNP) array (Japonica Array,
Toshiba, Japan) specifically designed for the genome-wide study of the
Japanese population was developed by Kawai et al.12 Its haplotype
collection was constructed from whole-genome sequences of 1070
Japanese individuals.13 We posited that whole-genome imputation
with the Japonica array would increase the statistical power for
detecting associated variants of CM-SJS/TEN with SOC than was
possible with the AXIOM Genome-wide ASI 1 array we reported
In the current study, we performed GWAS using the Japonica array
and imputation with the 1KJPN panel (Tohoku Medical Megabank
Organization constructed the reference panel) to look for additional
genetic predispositions for CM-SJS/TEN with SOC in the Japanese
MATERIALS AND METHODS
This study was approved by the institutional review board of Kyoto Prefectural
University of Medicine (KPUM), the University of Tokyo and other
collaborating research institutes (Seoul National University College of Medicine, Yonsei
University College of Medicine, Chonnam National University Medical School
and College of Medicine, The Catholic University of Korea in Korea).
We used the same samples from 117 Japanese individuals with CM-SJS/TEN
with SOC and 691 healthy Japanese volunteers as were used in our earlier
GWAS with the Affymetrix AXIOM Genome-Wide ASI 1 array.7
SOC patients were defined as those with ocular sequelae such as severe dry
eye, trichiasis, symblepharon and conjunctival invasion into the cornea in the
chronic stage,5 and as patients who manifested severe conjunctivitis with
pseudomembranes and epithelial defects on the ocular surface (cornea and/or
conjunctiva) in the acute stage.14 We have classified the patients who had taken
CMs such as non-steroidal anti-inflammatory drugs and multi-ingredient cold
medications for a few?several days before the disease onset for common-cold
symptoms as CM-SJS/TEN. The specific drugs they used were not named by all
patients (Supplementary Table 1). In Japan, doctors in hospital usually
prescribed CM such as non-steroidal anti-inflammatory drugs and
acetaminophen with some antibiotics. However, we previously reported that the use of CM
such as non-steroidal anti-inflammatory drugs and cold-remedies was
significantly associated with SJS/TEN with SOC, whereas the use of antibiotics was not
associated.2 Detailed information on the SJS/TEN patients and the controls we
analyzed are shown in Supplementary Methods in the Online Repository.
GWAS, imputation with 1KJPN and validation analysis
In the GWAS, we genotyped 808 samples from the same SJS/TEN patients
(n = 117) and the healthy Japanese controls (n = 691) used in our earlier study.7
We used the Japonica SNP array12 according to the manufacturer?s instructions.
All genotyped samples passed the recommended sample quality control metric
for the AXIOM arrays (dish QC40.82); we excluded three control samples
with an overall call rate o97%. We recalled the remaining 805 samples with
Genotyping Console 22.214.171.124 software (Affymetrix).
Because we had already performed identity-by-descent estimation and
principal component analysis for all 808 samples genotyped with the AXIOM
Genome-Wide ASI 1 array;7 all samples used in the current study were known
to be from unrelated individuals and the effect of population stratification was
negligible. A quantile?quantile plot of the distribution of test statistics for the
comparison of genotype frequencies in our patients and controls showed
that the inflation factor ? was 1.024 for all tested SNPs and decreased to
1.021 when SNPs in the human leukocyte antigen (HLA) region (chr 6:
29 645 038?33 360 787) were excluded (Supplementary Figure 1).
For imputation, the clustering plots were classified by the Ps classification
function in the SNPolisher package (version 1.5.2; Affymetrix). SNPs that were
assigned 'recommended' by the Ps classification were retained. Excluded were
SNPs with a call rate o99.0%, a Hardy?Weinberg equilibrium (HWE) test
result of Po0.0001 or a minor allele frequency (MAF) o0.5%. Prephasing was
conducted first with these SNPs using SHAPEIT (v.2.r644);15 the options were
?burn 10, ?prune 10 and ?main 25. Genotype imputation was performed on
the phased genotypes with IMPUTE2 (ver. 2.3.1)16 using a phased reference
panel of 1070 healthy Japanese individuals (1KJPN panel).13 For IMPUTE2, the
applied options were -Ne 2000, -k hap 1000, -k 120, -burnin 15, and -iter 50.
After genome-wide imputation genotyped with the Japonica array,
we applied a SNP call rate ? 95%, MAF ? 1%, and HWE P ? 0.001 for SNP
quality control for data cleaning of the samples. The 6,714,496 SNPs and
insertions and deletions (indels) on autosomal chromosomes that passed the
quality control filters were used for GWAS.
Confirmation of the genotypes at 6 candidate SNPs with Po10 ? 7 in the
GWAS and the replication study using Korean samples was with the TaqMan
SNP genotyping assay (Applied Biosystems, Foster City, CA). We genotyped
extended sample sets of Japanese SJS patients (n = 138) and controls (n = 883)
to validate the GWAS results. Samples from Korean patients (n = 31) and
controls (n = 110) were genotyped to replicate the GWAS results
(Supplementary Methods in the Online Repository).
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For the validation of GWAS and the replication study, we applied the ?2 or the
Fisher's exact test on a two-by-two contingency table of the allele frequency,
the dominant model and the recessive model. The odds ratio (OR) and the
confidence interval (CI) were calculated using the major alleles as references.
Meta-analysis was with the Mantel?Haenszel method. Heterogeneity among
studies was examined using the Breslow?Day test.
GWAS of CM-SJS/TEN with SOC in Japanese individuals using the
Japonica array and imputation with 1KJPN
Figure 1 presents a genome-wide view of the SNP association data
for 117 Japanese CM-SJS/TEN patients with SOC and 688 controls
(3 of the 691 control samples were excluded because their overall call
rate was o97%). We used the Japonica array and performed
genomewide imputation based on 1KJPN; the associations were based on
allele frequencies (MAF 40.01, HWE P40.001, 6 714 496 SNPs).
Imputation with 1KJPN clearly increased the number of candidate
SNPs because SNP association data acquired with the Japonica array
without imputation with 1KJPN included only 612 877 sites
(MAF40.01, HWE P40.001) (Supplementary Figure 2).
The HLA-A region exhibited the strongest association with
susceptibility to CM-SJS/TEN with SOC (P = 2.2 ? 10 ? 19, OR = 4.6).
This is consistent with findings reported in our earlier studies;
they had shown a strong association between SJS/TEN with SOC
Outside of the HLA region, there were 82 polymorphisms
manifesting associations with Po10 ? 7 in the allele frequency model. Of these,
four exhibited MAF40.05 and they were located on chromosome 16.
There was a strong linkage disequilibrium (LD) between rs6500265 and
rs9933632 and between rs9888871 and rs76213482. The other 78
polymorphisms manifested 0.024MAF40.01 and were located in a
single LD block on chromosome 15 (Supplementary Table 2). For
validation, we selected one to three SNPs from each LD block; three
SNPs (rs16957893, rs12324361, rs113301740) were from the LD block
on chromosome 15 and one (rs9888871) or two SNPs (rs6500265,
rs9933632) were from the LD blocks on chromosome 16. Validation
analysis of these six SNPs by applying the TaqMan assay to samples
from the 117 Japanese CM-SJS/TEN with SOC patients and the 691
controls showed genome-wide significant associations for three of these
six SNPs (Table 1).
Extended analysis with additional Japanese and Korean samples
A different additional Japanese sample set of 213 samples (21 Japanese
CM-SJS/TEN-SOC patients and 192 Japanese healthy controls) was
used in a subsequent extended analysis to further evaluate these six
SNPs. We found that despite the relatively small sample size, one of
the six SNPs exhibited a significant association after applying
Bonferroni correction (Table 1).
It was difficult to evaluate the three SNPs with MAF o0.01 because
of the low sample number (n = 21). The combined results of the
GWAS validation analysis and the analysis of additional sample sets
showed that four of the six SNPs exhibited significant genome-wide
associations (Table 1).
We also genotyped the 6 SNPs in 141 samples from a Korean
population (31 CM-SJS/TEN with SOC patients and 110 controls).
Because their number was small, we found no significant association
between Korean CM-SJS/TEN-SOC and the six SNPs after applying
Bonferroni correction (Supplementary Table 3). However, the OR of the
six SNPs exhibited the same direction of association as the OR of the
Japanese population. Furthermore, meta-analysis using the Japanese and
Korean samples revealed a significant genome-wide association with
rs16957893 ((C vs G), OR = 5.61, P = 1.72 ? 10 ? 8), with rs12324361 ((C
vs T), OR = 5.58, P = 2.63 ? 10 ? 8) and with rs113301740 ((A vs C),
OR = 5.58, P = 2.63 ? 10 ? 8) (Supplementary Table 4).
GWAS using the Japonica array, an ethnicity-specific array and
imputation with a Japanese 1070 whole-genome-sequenced panel
(1KJPN) revealed that outside of the HLA region there were 82
polymorphisms manifesting associations with Po10 ? 7 in the allele
frequency model. We found that four SNPs with Po10 ? 7 in two LD
blocks on chromosome 16 were present in an intergenic region
between ZNF423 and CNEP1R1; their functions are unclear. Of the
78 variants with Po10 ? 7 in a single LD block on chromosome 15, 47
(60.3%) were located in introns of the REC114 gene; 16 (20.5%) in
introns of the NPTN gene, 5 (6.4%) in an exon (no amino-acid
change) or an intron of LOC105370891, 4 (5.1%) in an intergenic
region between LOC105370891 and CD276 and the remaining 6
(7.7%) in introns of the CD276 gene. There was no variant with
amino-acid changes among the above genes.
REC114, a meiotic recombination protein, may have a role in meiotic
DNA double-strand breaks.20 The function of LOC105370891 has not
been studied in detail. Neuroplastin encodes a type I transmembrane
protein belonging to the immunoglobulin superfamily; it may be
involved in cell?cell interactions or cell?substrate interactions.21 CD276
is a member of the immunoglobulin superfamily and is thought to
participate in the regulation of the T-cell-mediated immune response.22
However, the molecular mechanisms involved in the associations with
CM-SJS/TEN-SOC remain to be identified.
Validation analysis of selected six SNPs by applying the TaqMan
assay to samples from the 138 (117 of GWAS and additional 21)
Japanese CM-SJS/TEN with SOC patients and the 883 (691 of GWAS
and additional 192) controls showed genome-wide significant
associations for four of these six SNPs. However, when we performed
logistic regression analysis adjusted for sex in Japanese 138 cases
and 883 controls because of the difference of sex, P-values of the four
SNPs observed slightly increased (adjusted P-values of rs16957893,
rs6500265, rs9888871 and rs9933632 was 4.66 ? 10 ? 6, 1.32 ? 10 ? 7,
6.62 ? 10 ? 8 and 7.17 ? 10 ? 8, respectively). Moreover, when we
performed logistic regression analysis adjusted for sex using genome-wide
imputed GWAS data, we detected two additional regions (chromosome
3 and 20) with P-values o10 ? 6. This finding is consistent with our
previous report.7 Thus, further investigation with more case and
control samples which are sex-matched might be needed.
While typing with the Japonica array detected 612 877 sites
(MAF40.01, HWE P40.001), in combination with imputation we
detected 6 101 619 more; that is, a total of 6 714 496 polymorphisms.
Thus, the combination identified ~ 10 times more polymorphisms
than did typing with the Japonica array alone. Moreover, among 82
variants with Po10 ? 7 in the allele frequency detected by GWAS using
the Japonica array and imputation with 1KJPN, only three (3.7%)
were identified when typing was with the Japonica array alone. The
combination of the Japonica array and imputation with the 1KJPN
panel identified new SNPs.
Elsewhere we reported that in Japanese individuals, HLA-A*02:06
was strongly associated with CM-SJS/TEN with SOC.9 We also
documented that HLA-A*02:06 with TLR3 polymorphisms exerted
more than additive effects23 and that HLA-A*02:06 with PTGER3
polymorphisms exhibited additive effects in CM-SJS/TEN with SOC.11
Although our sample numbers were small, we found that
HLA-A*02:06 with Rec114 rs16957893 CG might also exert more
than additive effects in CM-SJS/TEN with SOC (OR = 110,
P = 4.45 ? 10 ? 8) (Supplementary Table 5). The combination of
variants' effects between HLA-A*02:06 and Rec114 rs16957893 CG
might be independent of the interactions between HLA-A*02:06 and
TLR3 rs3775296 T/T because CM-SJS/TEN with SOC in Japanese
patients with both HLA-A*02:06 and Rec114 rs16957893 CG did not
harbor TLR3 rs3775296 T/T (data not shown).
In Japanese individuals, combined genotyping for the associated
variants thus far identified; that is, HLA-A*02:06, TLR3 rs3775296
T/T and Rec114 rs16957893 CG, may help to predict the risk for
CM-SJS/TEN with SOC. Based on our previous and current
observations, we suggest that besides microbial infections and CMs, the
combination of multiple gene polymorphisms and their interactions
contributes strongly to the onset of CM-SJS/TEN with SOC.
In the current GWAS, we used the Japonica array and
imputation with the 1KJPN panel to investigate CM-SJS/TEN-SOC
in Japanese individuals. We also performed replication studies
using Korean samples to identify host genetic factors that predispose
to CM-SJS/TEN with SOC. The findings reported here increase our
understanding of pathogenic pathways involved in the development of
CM-SJS/TEN with SOC.
CONFLICT OF INTEREST
MN and KK hold concurrent positions at the Department of Cohort
Genome Information Analysis endowed by Toshiba Corporation. KT,
MU and MN received research funding from Toshiba Corporation.
We thank the patients and volunteers who participated in our study. We also
thank Hiromi Nishigaki, Natsumi Baba, Kayoko Yamada, Kayoko Kato for
processing the blood samples and for genotyping, and Drs Sangchul Yoon, Hyo
Seok Lee and Kyu-Yeon Hwang for their assistance in collecting blood and
DNA samples and for providing clinical information. Computational resources
for genome-wide imputation were provided by the ToMMo supercomputer
system. This work was supported by a grant from Toshiba Corporation
Healthcare Company and also supported, in part, by grants in aid from the
Ministry of Education, Culture, Sports, Science and Technology of the Japanese
government (BioBank Japan Project), and supported, in part, by JSPS
Core-toCore Program, A Advanced Research Networks. This work was also supported,
in part, by the Tohoku Medical Megabank Project (Special account for
reconstruction from the Great East Japan Earthquake). This work was also
supported, in part, by the Promotion Project of Knowledge-Based Industrial
Clustering of Okinawa Prefecture. The funding agencies had no role in the
study design, data collection or analysis, the decision to publish or the
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