Table 1. Demographics, methotrexate treatment and the phenotype subgroups
|
JIA
|
JIA patients, n
|
121
|
Girls: Boys, n
|
82:39
|
Caucasian: not Caucasian, n
|
117:4
|
Age at enrolment (years)
|
13.3 (11.3 – 15.1)
|
Duration of MTX treatment (days)
|
340 (142-766)
|
MTXo: MTXSC, n
|
45:76
|
MTX dose (mg/m2/week)
|
9.7 (9.0 – 10.9)
|
Patients with completed MISS, n
MISS total score (0-36)
MTXintolerant subgroup1, n
MTXtolerant subgroup, n
|
120
8 (3-14)
73
47
|
Patients with ≥7 completed diary entries, n
“MTX-nausea” subgroup2, n
|
77
56
|
Data on demographics, details of the methotrexate (MTX) treatment and the distribution of patients in the phenotype subgroups.
Values are expressed as median (IQR) unless otherwise stated. MTXSC; subgroup treated with MTX subcutaneously. MTXo; subgroup treated with MTX orally.
1The MTXintolerant subgroup: children with a total score of the Methotrexate Intolerance Severity Score (MISS) ≥6 and at least 1 point in the anticipatory and/or associative and/or behavioral symptoms. Otherwise categorised as MTXtolerant.
2The “MTX-nausea” subgroup: children with a nausea diary illustrating a nausea pattern timely related to the MTX administration.
Table 2. Genotypes for the selected single nucleotide polymorphisms
Gene
|
SNP
|
Ancestral
Allel
|
Genotypes
|
Total,
n
|
MTX
intolerant1
|
MTX
tolerant
|
p-value
|
MTX
Nausea2
|
Controls
|
p-value
|
ABCC2
|
rs2273697
|
G
|
GG
GA
AA
|
74
32
13
|
44
20
8
|
29
12
5
|
χ2= 0.05
p= 0.98
|
32
16
8
|
14
5
2
|
0.81
|
ABCC2
|
rs37400663
|
G
|
GG
GA
AA
|
38
65
15
|
23
38
10
|
15
27
4
|
0.74
|
19
29
7
|
7
12
2
|
1.00
|
ABCC2
|
rs717620
|
G
|
GG
GA
AA
|
73
39
7
|
47
21
4
|
26
17
3
|
0.64
|
35
18
3
|
13
7
1
|
1.00
|
ABCB1
|
rs2032582
|
G
|
GG
GT
GA
TA
TT
|
38
58
2
3
18
|
23
34
0
3
12
|
15
24
2
0
5
|
0.28
|
18
27
1
2
8
|
6
10
1
1
3
|
0.95
|
ABCB1
|
rs1045642
|
C
|
CC
CT
TT
|
18
68
33
|
9
44
19
|
9
24
13
|
χ2=1.34
p=0.51
|
8
34
14
|
4
11
6
|
0.82
|
SLCO1B1
|
rs4149056
|
T
|
TT
TC
CC
|
84
32
3
|
49
21
2
|
34
11
1
|
0.86
|
39
16
1
|
15
6
0
|
1.00
|
SLCO1B1
|
rs4149081
|
G
|
GG
GA
AA
|
80
36
3
|
47
23
2
|
32
13
1
|
0.86
|
38
17
1
|
14
7
0
|
1.00
|
SLCO1B3
|
rs2117032
|
C
|
CC
CT
TT
|
17
53
49
|
12
28
32
|
5
24
17
|
χ2= 2.16
p=0.34
|
10
23
23
|
4
6
11
|
0.63
|
SLC19A1
|
rs10512663
|
G
|
GG
GA
AA
|
33
66
19
|
18
42
11
|
15
24
7
|
χ2= 0.76
p= 0.68
|
17
28
10
|
6
12
3
|
0.89
|
HTR3A
|
rs1062613
|
C
|
CC
CT
TT
|
80
37
2
|
52
20
0
|
28
16
2
|
0.13
|
36
19
1
|
16
5
0
|
0.58
|
HTR3A
|
rs1985242
|
A
|
AA
AT
TT
|
7
55
57
|
3
30
39
|
4
24
18
|
0.23
|
4
28
24
|
1
7
13
|
0.34
|
HTR3A
|
rs1176713
|
C
|
CC
CT
TT
|
6
37
76
|
3
21
48
|
3
16
27
|
0.68
|
3
19
34
|
1
3
17
|
0.18
|
HTR3B
|
rs1776744
|
T
|
TT
TG
GG
|
50
58
11
|
30
32
10
|
20
25
1
|
0.09
|
24
27
5
|
10
8
3
|
0.58
|
MTHFR
|
rs18011313
|
A
|
AA
AC
CC
|
52
53
13
|
34
30
7
|
18
22
6
|
χ2=0.93
p= 0.63
|
24
21
10
|
9
11
1
|
0.29
|
MTHFR
|
rs1801133
|
C
|
CC
CT
TT
|
58
51
10
|
33
29
10
|
25
21
0
|
0.02
|
27
24
5
|
10
10
1
|
1.00
|
The genotype distribution for the selected single nucleotide polymorphisms (SNPs) – including the distribution of genotypes within the phenotype subgroups defined by the methotrexate intolerance severity score and the nausea diary.
SNP; Single Nucleotide Polymorphism.
1The MTXintolerant subgroup: children with a total score of the Methotrexate Intolerance Severity Score (MISS) ≥6 and at least 1 point in the anticipatory and/or associative and/or behavioral symptoms (n=72). Otherwise categorised as MTXtolerant (n=46).
2The “MTX-nausea” subgroup: children with a nausea diary illustrating a nausea pattern timely related to the MTX administration (n=56). The remaining children grouped as “Controls” (n=21).
3SNP variant not available for one child.
Table 3. Single nucleotide polymorphisms in association with the phenotype “MTX intolerance”
|
Gene
|
SNP
|
Alleles,
Major>minor
|
MTXintolerant1
Allel count
|
MTXtolerant
Allel count
|
OR (95% CI)
|
p
|
Chr.
|
Genomic
position
|
Consequence
|
Hepatic
|
ABCC2
|
rs2273697
|
G>A
|
36
|
22
|
1.05 (0.61-1.80)
|
0.87
|
10
|
99804058
|
Missense
|
Efflux
|
ABCC2
|
rs37400662
|
G>A
|
58
|
35
|
1.15 (0.64-2.07)
|
0.64
|
10
|
99844450
|
Missense
|
Transporter
|
ABCC2
|
rs717620
|
G>A
|
29
|
23
|
0.77 (0.42-1.41)
|
0.40
|
10
|
99782821
|
5’UTR variant
|
|
ABCB1
|
rs2032582
|
G>T
G>A
|
61
3
|
34
2
|
1.28 (0.73-2.24)
0.96 (0.15-5.96)
|
0.39
0.96
|
7
|
87531302
|
Missense
|
|
ABCB1
|
rs1045642
|
T>C
|
62
|
42
|
0.88 (0.49-1.57)
|
0.67
|
7
|
87509329
|
Synonymous
|
Hepatic
|
SLCO1B1
|
rs4149056
|
T>C
|
25
|
13
|
1.28 (0.62-2.66)
|
0.51
|
12
|
21178615
|
Missense
|
Influx
|
SLCO1B1
|
rs4149081
|
G>A
|
27
|
15
|
1.19 (0.59-2.43)
|
0.62
|
12
|
21225087
|
Intron variant
|
Transporter
|
SLCO1B3
|
rs2117032
|
T>C
|
52
|
34
|
0.97 (0.57-1.64)
|
0.90
|
12
|
20921188
|
Down stream 3’UTR
|
|
SLC19A1
|
rs10512662
|
G>A
|
64
|
38
|
1.20 (0.67-2.13)
|
0.54
|
21
|
45537880
|
Missense
|
Nausea
|
HTR3A
|
rs1062613
|
C>T
|
20
|
20
|
0.55 (0.27-1.14)
|
0.11
|
11
|
113975284
|
5’UTR variant
|
Receptor
|
HTR3A
|
rs1985242
|
T>A
|
36
|
32
|
0.58 (0.31-1.09)
|
0.09
|
11
|
113977551
|
5’UTR variant
|
|
HTR3A
|
rs1176713
|
T>C
|
27
|
22
|
0.74 (0.40-1.39)
|
0.35
|
11
|
113989703
|
Synonymous
|
|
HTR3B
|
rs1176744
|
T>G
|
52
|
27
|
1.36 (0.78-2.54)
|
0.26
|
11
|
113932306
|
Missense
|
MTHFR
|
MTHFR
|
rs18011312
|
A>C
|
44
|
34
|
0.77 (0.44-1.33)
|
0.35
|
1
|
11794419
|
Missense
|
Enzyme
|
MTHFR
|
rs1801133
|
C>T
|
49
|
21
|
1.77 (0.96-3.28)
|
0.07
|
1
|
11796321
|
Missense
|
The additive effect of the minor allele on parent-assessed MTX-induced nausea – the methotrexate intolerance severity score. Listed for every single nucleotide polymorphism (SNP) are the respective gene, the alleles, the relevant chromosome (Chr.), the genomic position, and the consequence of the SNP.
N=118, due to missing SNP data for two patients and MISS data for one.
OR; Odds Ratio.
1The MTXintolerant subgroup: children with a total score of the Methotrexate Intolerance Severity Score (MISS) ≥6 and at least 1 point in the anticipatory and/or associative and/or behavioral symptoms (n=72). Otherwise categorised as MTXtolerant (n=46).
2SNP variant not available for one child.
Table 4. Single nucleotide polymorphisms in association with the phenotype “MTX-nausea”
|
Gene
|
SNP
|
Alleles,
Major>minor
|
MTX-nausea1
Allel count
|
Controls
Allel count
|
OR (95% CI)
|
p
|
Chr.
|
Genomic
Position
|
Consequence
|
Hepatic
|
ABCC2
|
rs2273697
|
G>A
|
32
|
9
|
1.35 (0.64-2.84)
|
0.44
|
10
|
99804058
|
Missense
|
Efflux
|
ABCC2
|
rs37400662
|
G>A
|
43
|
16
|
1.05 (0.48-2.30)
|
0.90
|
10
|
99844450
|
Missense
|
Transporter
|
ABCC2
|
rs717620
|
G>A
|
24
|
9
|
1.00 (0.43-2.34)
|
1.00
|
10
|
99782821
|
5’UTR variant
|
|
ABCB1
|
rs2032582
|
G>T
G>A
|
45
3
|
17
2
|
0.99 (0.46-2.10)
0.54 (0.08-3.47)
|
0.94
0.51
|
7
|
87531302
|
Missense
|
|
ABCB1
|
rs1045642
|
T>C
|
50
|
19
|
0.97 (0.44-2.14)
|
0.94
|
7
|
87509329
|
Synonymous
|
Hepatic
|
SLCO1B1
|
rs4149056
|
T>C
|
18
|
6
|
1.16 (0.41-3.31)
|
0.78
|
12
|
21178615
|
Missense
|
Influx
|
SLCO1B1
|
rs4149081
|
G>A
|
19
|
7
|
1.02 (0.37-2.80)
|
0.96
|
12
|
21225087
|
Intron variant
|
Transporter
|
SLCO1B3
|
rs2117032
|
T>C
|
43
|
14
|
1.20 (0.61-2.39)
|
0.60
|
12
|
20921188
|
Down stream 3’UTR
|
|
SLC19A1
|
rs10512662
|
G>A
|
48
|
18
|
1.04 (0.49-2.18)
|
0.93
|
21
|
45537880
|
Missense
|
Nausea
|
HTR3A
|
rs1062613
|
C>T
|
21
|
5
|
1.82 (0.60-5.47)
|
0.29
|
11
|
113975284
|
5’UTR variant
|
Receptor
|
HTR3A
|
rs1985242
|
T>A
|
36
|
9
|
1.85 (0.76-4.50)
|
0.17
|
11
|
113977551
|
5’UTR variant
|
|
HTR3A
|
rs1176713
|
T>C
|
25
|
5
|
2.03 (0.73-5.60)
|
0.17
|
11
|
113989703
|
Synonymous
|
|
HTR3B
|
rs1176744
|
T>G
|
37
|
14
|
0.99 (0.46-2.12)
|
0.97
|
11
|
113932306
|
Missense
|
MTHFR
|
MTHFR
|
rs18011312
|
A>C
|
41
|
13
|
1.30 (0.62-2.71)
|
0.49
|
1
|
11794419
|
Missense
|
Enzyme
|
MTHFR
|
rs1801133
|
C>T
|
34
|
12
|
1.10 (0.49-2.45)
|
0.82
|
1
|
11796321
|
Missense
|
The additive effect of the minor allele on child-assessed MTX-induced nausea – the nausea diary. Listed for every single nucleotide polymorphism (SNP) are the respective gene, the alleles, the relevant chromosome (Chr.), the genomic position, and the consequence of the SNP.
N=77, the patients who had completed at least seven diary entries.
OR; Odds Ratio.
1The “MTX-nausea” subgroup: children with a nausea diary illustrating a nausea pattern timely related to the MTX administration (n=56). Controls (n=21).
2SNP variant not available for one child.
Table 5. The specific haplotypes and the phenotype “MTX-intolerance”
Chr
|
Markers
|
Haplotype
|
F cases
|
F controls
|
Score
|
p-value
|
p-sim
|
1
|
rs1801131-rs1801133
|
A-C
|
0.348
|
0.402
|
-0.916
|
0.360
|
0.329
|
1
|
rs1801131-rs1801133
|
A-T
|
0.340
|
0.228
|
1.852
|
0.064
|
0.06
|
1
|
rs1801131-rs1801133
|
C-C
|
0.312
|
0.370
|
-0.914
|
0.361
|
0.324
|
1
|
rs1801131-rs1801133
|
C-T
|
0.000
|
0.000
|
NA
|
NA
|
NA
|
|
|
|
|
|
|
|
|
7
|
rs1045642-rs2032582
|
C-A
|
0.021
|
0.022
|
-0.048
|
0.962
|
1
|
7
|
rs1045642-rs2032582
|
C-G
|
0.401
|
0.435
|
-0.530
|
0.596
|
0.557
|
7
|
rs1045642-rs2032582
|
C-T
|
0.008
|
0.000
|
NA
|
NA
|
NA
|
7
|
rs1045642-rs2032582
|
T-G
|
0.154
|
0.174
|
-0.432
|
0.666
|
0.694
|
7
|
rs1045642-rs2032582
|
T-T
|
0.415
|
0.370
|
0.758
|
0.448
|
0.422
|
|
|
|
|
|
|
|
|
10
|
rs717620-rs2273697-rs3740066
|
A-A-A
|
0.000
|
0.000
|
NA
|
NA
|
NA
|
10
|
rs717620-rs2273697-rs3740066
|
A-G-A
|
0.201
|
0.250
|
-0.852
|
0.394
|
0.427
|
10
|
rs717620-rs2273697-rs3740066
|
A-G-G
|
0.000
|
NA
|
NA
|
NA
|
NA
|
10
|
rs717620-rs2273697-rs3740066
|
G-A-A
|
0.023
|
0.018
|
NA
|
NA
|
NA
|
10
|
rs717620-rs2273697-rs3740066
|
G-A-G
|
0.227
|
0.221
|
0.070
|
0.944
|
0.961
|
10
|
rs717620-rs2273697-rs3740066
|
G-G-A
|
0.182
|
0.112
|
1.465
|
0.143
|
0.153
|
10
|
rs717620-rs2273697-rs3740066
|
G-G-G
|
0.367
|
0.399
|
-0.466
|
0.641
|
0.639
|
10
|
rs717620-rs2273697
|
A-A
|
0.000
|
0.000
|
NA
|
NA
|
NA
|
10
|
rs717620-rs2273697
|
A-G
|
0.201
|
0.250
|
-0.852
|
0.394
|
0.36
|
10
|
rs717620-rs2273697
|
G-A
|
0.250
|
0.239
|
0.168
|
0.867
|
0.84
|
10
|
rs717620-rs2273697
|
G-G
|
0.549
|
0.511
|
0.537
|
0.591
|
0.572
|
10
|
rs2273697-rs3740066
|
A-A
|
0.021
|
0.017
|
NA
|
NA
|
NA
|
10
|
rs2273697-rs3740066
|
A-G
|
0.229
|
0.223
|
0.110
|
0.913
|
0.936
|
10
|
rs2273697-rs3740066
|
G-A
|
0.386
|
0.364
|
0.376
|
0.707
|
0.732
|
10
|
rs2273697-rs3740066
|
G-G
|
0.364
|
0.397
|
-0.526
|
0.599
|
0.587
|
|
|
|
|
|
|
|
|
11
|
rs1176744-rs1062613-rs1985242-rs1176713
|
G-C-A-C
|
0.071
|
0.043
|
0.558
|
0.577
|
0.569
|
11
|
rs1176744-rs1062613-rs1985242-rs1176713
|
G-C-T-T
|
0.029
|
0.008
|
NA
|
NA
|
NA
|
11
|
rs1176744-rs1062613-rs1985242-rs1176713
|
G-T-A-T
|
0.220
|
0.156
|
1.153
|
0.249
|
0.265
|
11
|
rs1176744-rs1062613-rs1985242-rs1176713
|
T-C-A-C
|
0.041
|
0.035
|
0.066
|
0.948
|
0.972
|
11
|
rs1176744-rs1062613-rs1985242-rs1176713
|
T-C-T-T
|
0.000
|
0.051
|
NA
|
NA
|
NA
|
11
|
rs1176744-rs1062613-rs1985242-rs1176713
|
T-T-A-C
|
0.001
|
NA
|
NA
|
NA
|
NA
|
11
|
rs1176744-rs1062613-rs1985242-rs1176713
|
T-T-A-T
|
0.029
|
0.063
|
-1.030
|
0.303
|
0.287
|
11
|
rs1176744-rs1062613-rs1985242
|
G-C-A
|
NA
|
0.016
|
NA
|
NA
|
NA
|
11
|
rs1176744-rs1062613-rs1985242
|
G-C-T
|
0.513
|
0.496
|
0.406
|
0.685
|
0.693
|
11
|
rs1176744-rs1062613-rs1985242
|
G-T-A
|
0.048
|
0.098
|
-1.430
|
0.153
|
0.153
|
11
|
rs1176744-rs1062613-rs1985242
|
T-C-A
|
0.034
|
0.034
|
-1.283
|
0.199
|
0.142
|
11
|
rs1176744-rs1062613-rs1985242
|
T-C-T
|
0.016
|
NA
|
NA
|
NA
|
NA
|
11
|
rs1176744-rs1062613-rs1985242
|
T-T-A
|
0.097
|
0.054
|
0.822
|
0.411
|
0.397
|
11
|
rs1176744-rs1062613-rs1985242
|
T-T-T
|
0.218
|
0.164
|
1.219
|
0.223
|
0.23
|
11
|
rs1062613-rs1985242-rs1176713
|
C-A-C
|
0.045
|
0.075
|
-1.052
|
0.293
|
0.276
|
11
|
rs1062613-rs1985242-rs1176713
|
C-A-T
|
0.001
|
NA
|
NA
|
NA
|
NA
|
11
|
rs1062613-rs1985242-rs1176713
|
C-T-T
|
0.030
|
0.077
|
-1.331
|
0.183
|
0.186
|
11
|
rs1062613-rs1985242-rs1176713
|
T-A-C
|
0.516
|
0.488
|
0.355
|
0.722
|
0.735
|
11
|
rs1062613-rs1985242-rs1176713
|
T-A-T
|
0.078
|
0.142
|
-1.947
|
0.052
|
0.054
|
11
|
rs1062613-rs1985242-rs1176713
|
T-T-T
|
0.015
|
NA
|
NA
|
NA
|
NA
|
11
|
rs1176744-rs1062613
|
G-C
|
0.099
|
0.106
|
-0.190
|
0.849
|
0.862
|
11
|
rs1176744-rs1062613
|
G-T
|
0.028
|
0.025
|
0.094
|
0.925
|
0.982
|
11
|
rs1176744-rs1062613
|
T-C
|
0.734
|
0.652
|
1.486
|
0.137
|
0.129
|
11
|
rs1176744-rs1062613
|
T-T
|
0.088
|
0.133
|
-1.048
|
0.295
|
0.302
|
11
|
rs1062613-rs1985242
|
C-A
|
0.034
|
0.084
|
-1.688
|
0.091
|
0.126
|
11
|
rs1062613-rs1985242
|
C-T
|
0.016
|
0.000
|
NA
|
NA
|
NA
|
11
|
rs1062613-rs1985242
|
T-A
|
0.323
|
0.224
|
1.489
|
0.137
|
0.137
|
11
|
rs1062613-rs1985242
|
T-T
|
0.038
|
0.070
|
-0.848
|
0.396
|
0.379
|
11
|
rs1985242-rs1176713
|
A-C
|
0.538
|
0.559
|
-0.078
|
0.937
|
0.953
|
11
|
rs1985242-rs1176713
|
A-T
|
0.101
|
0.148
|
-1.663
|
0.096
|
0.098
|
11
|
rs1985242-rs1176713
|
T-C
|
0.128
|
0.130
|
-0.136
|
0.892
|
0.868
|
11
|
rs1985242-rs1176713
|
T-T
|
0.734
|
0.652
|
1.488
|
0.137
|
0.126
|
|
|
|
|
|
|
|
|
12
|
rs2117032-rs4149056-rs4149081
|
C-C-A
|
0.082
|
0.045
|
0.914
|
0.361
|
0.392
|
12
|
rs2117032-rs4149056-rs4149081
|
C-C-G
|
0.000
|
0.000
|
NA
|
NA
|
NA
|
12
|
rs2117032-rs4149056-rs4149081
|
C-T-G
|
0.279
|
0.325
|
-0.596
|
0.551
|
0.554
|
12
|
rs2117032-rs4149056-rs4149081
|
C-T-T
|
0.092
|
0.097
|
0.172
|
0.864
|
0.855
|
12
|
rs2117032-rs4149056-rs4149081
|
T-C-A
|
0.014
|
0.022
|
NA
|
NA
|
NA
|
12
|
rs2117032-rs4149056-rs4149081
|
T-C-C
|
0.533
|
0.512
|
0.162
|
0.872
|
0.895
|
12
|
rs2117032-rs4149056-rs4149081
|
T-T-G
|
0.082
|
0.046
|
0.904
|
0.366
|
0.368
|
12
|
rs2117032-rs4149056
|
C-C
|
0.279
|
0.324
|
-0.593
|
0.553
|
0.566
|
12
|
rs2117032-rs4149056
|
C-T
|
0.091
|
0.096
|
0.177
|
0.860
|
0.828
|
12
|
rs2117032-rs4149056
|
T-C
|
0.547
|
0.535
|
0.039
|
0.969
|
0.984
|
12
|
rs2117032-rs4149056
|
T-T
|
0.174
|
0.141
|
0.660
|
0.509
|
0.586
|
12
|
rs4149056-rs4149081
|
C-A
|
0.014
|
0.022
|
NA
|
NA
|
NA
|
12
|
rs4149056-rs4149081
|
C-C
|
0.813
|
0.837
|
-0.490
|
0.624
|
0.681
|
12
|
rs4149056-rs4149081
|
C-G
|
0.082
|
0.045
|
0.914
|
0.361
|
0.392
|
12
|
rs4149056-rs4149081
|
C-T
|
0.000
|
0.000
|
NA
|
NA
|
NA
|
12
|
rs4149056-rs4149081
|
T-C
|
0.279
|
0.325
|
-0.596
|
0.551
|
0.554
|
12
|
rs4149056-rs4149081
|
T-G
|
0.092
|
0.097
|
0.172
|
0.864
|
0.855
|
12
|
rs4149056-rs4149081
|
T-T
|
0.014
|
0.022
|
NA
|
NA
|
NA
|
The haplotype-specific scores for the listed markers in association with the parent-assessed MTX-induced nausea – the methotrexate intolerance severity score.
N=118, due to missing SNP data for two patients and MISS data for one.
Chr; Chromosome. Markers; the SNPs in the haplotype. Haplotypes; the alleles for the SNPs in the haplotype. Cases; MTXintolerant (n=72). Controls; MTXtolerant (n=46). Fcases; Frequency of the haplotype among cases. Fcontrols; Frequency of the haplotype among controls. Score; the haplotype association test score for the specific haplotype. P-sim; the number of times the simulated score statistics exceeds the observed divided by the total number of simulations (1000).
Table 6. The specific haplotypes and the phenotype “MTX-nausea”
Chr
|
Markers
|
Haplotype
|
F cases
|
F controls
|
Score
|
p-value
|
p-sim
|
1
|
rs1801131-rs1801133
|
A-C
|
0.321
|
0.405
|
-1.067
|
0.286
|
0.333
|
1
|
rs1801131-rs1801133
|
A-T
|
0.304
|
0.286
|
0.222
|
0.825
|
0.837
|
1
|
rs1801131-rs1801133
|
C-C
|
0.376
|
0.310
|
0.730
|
0.465
|
0.523
|
1
|
rs1801131-rs1801133
|
C-T
|
0.000
|
0.000
|
NA
|
NA
|
NA
|
|
|
|
|
|
|
|
|
7
|
rs1045642-rs2032582
|
C-A
|
0.027
|
0.048
|
NA
|
NA
|
NA
|
7
|
rs1045642-rs2032582
|
C-G
|
0.420
|
0.405
|
0.184
|
0.854
|
0.929
|
7
|
rs1045642-rs2032582
|
C-T
|
0.000
|
0.000
|
NA
|
NA
|
NA
|
7
|
rs1045642-rs2032582
|
T-G
|
0.152
|
0.143
|
0.144
|
0.886
|
0.917
|
7
|
rs1045642-rs2032582
|
T-T
|
0.402
|
0.405
|
-0.035
|
0.972
|
0.931
|
|
|
|
|
|
|
|
|
10
|
rs717620-rs2273697-rs3740066
|
A-A-A
|
0.000
|
NA
|
NA
|
NA
|
NA
|
10
|
rs717620-rs2273697-rs3740066
|
A-A-G
|
0.214
|
0.214
|
0.000
|
1.000
|
0.964
|
10
|
rs717620-rs2273697-rs3740066
|
A-G-A
|
0.000
|
NA
|
NA
|
NA
|
NA
|
10
|
rs717620-rs2273697-rs3740066
|
G-A-A
|
0.014
|
0.000
|
NA
|
NA
|
NA
|
10
|
rs717620-rs2273697-rs3740066
|
G-A-G
|
0.272
|
0.214
|
0.735
|
0.463
|
0.478
|
10
|
rs717620-rs2273697-rs3740066
|
G-G-A
|
0.159
|
0.167
|
-0.011
|
0.991
|
0.977
|
10
|
rs717620-rs2273697-rs3740066
|
G-G-G
|
0.341
|
0.405
|
-0.802
|
0.423
|
0.385
|
10
|
rs717620-rs2273697
|
A-A
|
0.000
|
0.000
|
NA
|
NA
|
NA
|
10
|
rs717620-rs2273697
|
A-G
|
0.214
|
0.214
|
0.000
|
1.000
|
0.94
|
10
|
rs717620-rs2273697
|
G-A
|
0.286
|
0.214
|
0.783
|
0.434
|
0.44
|
10
|
rs717620-rs2273697
|
G-G
|
0.500
|
0.571
|
-0.748
|
0.454
|
0.469
|
10
|
rs2273697-rs3740066
|
A-A
|
0.013
|
0.000
|
NA
|
NA
|
NA
|
10
|
rs2273697-rs3740066
|
A-G
|
0.273
|
0.214
|
0.706
|
0.480
|
0.534
|
10
|
rs2273697-rs3740066
|
G-A
|
0.376
|
0.381
|
-0.014
|
0.989
|
0.966
|
10
|
rs2273697-rs3740066
|
G-G
|
0.338
|
0.405
|
-0.791
|
0.429
|
0.397
|
|
|
|
|
|
|
|
|
11
|
rs1176744-rs1062613-rs1985242-rs1176713
|
G-C-A-C
|
0.070
|
0.035
|
0.589
|
0.556
|
0.552
|
11
|
rs1176744-rs1062613-rs1985242-rs1176713
|
G-C-T-T
|
0.030
|
NA
|
NA
|
NA
|
NA
|
11
|
rs1176744-rs1062613-rs1985242-rs1176713
|
G-T-A-T
|
0.144
|
0.288
|
-1.331
|
0.183
|
0.171
|
11
|
rs1176744-rs1062613-rs1985242-rs1176713
|
T-C-A-C
|
0.060
|
NA
|
1.641
|
0.101
|
0.076
|
11
|
rs1176744-rs1062613-rs1985242-rs1176713
|
T-C-T-T
|
0.026
|
0.010
|
NA
|
NA
|
NA
|
11
|
rs1176744-rs1062613-rs1985242-rs1176713
|
T-T-A-C
|
0.035
|
0.064
|
-0.373
|
0.709
|
0.78
|
11
|
rs1176744-rs1062613-rs1985242-rs1176713
|
T-T-A-T
|
0.000
|
0.024
|
NA
|
NA
|
NA
|
11
|
rs1176744-rs1062613-rs1985242
|
G-C-A
|
NA
|
0.000
|
NA
|
NA
|
NA
|
11
|
rs1176744-rs1062613-rs1985242
|
G-C-T
|
0.534
|
0.470
|
0.151
|
0.880
|
0.87
|
11
|
rs1176744-rs1062613-rs1985242
|
G-T-A
|
0.059
|
0.020
|
0.943
|
0.346
|
0.38
|
11
|
rs1176744-rs1062613-rs1985242
|
T-C-A
|
0.042
|
0.060
|
0.086
|
0.931
|
0.917
|
11
|
rs1176744-rs1062613-rs1985242
|
T-C-T
|
NA
|
0.0282
|
NA
|
NA
|
NA
|
11
|
rs1176744-rs1062613-rs1985242
|
T-T-A
|
0.098
|
0.034
|
1.044
|
0.297
|
0.281
|
11
|
rs1176744-rs1062613-rs1985242
|
T-T-T
|
0.144
|
0.299
|
-1.300
|
0.194
|
0.197
|
11
|
rs1062613-rs1985242-rs1176713
|
C-A-C
|
0.089
|
0.000
|
1.273
|
0.203
|
0.234
|
11
|
rs1062613-rs1985242-rs1176713
|
C-T-C
|
0.036
|
0.089
|
-0.798
|
0.425
|
0.455
|
11
|
rs1062613-rs1985242-rs1176713
|
C-T-T
|
0.535
|
0.459
|
0.128
|
0.898
|
0.898
|
11
|
rs1062613-rs1985242-rs1176713
|
T-A-C
|
0.099
|
0.091
|
0.893
|
0.372
|
0.4
|
11
|
rs1062613-rs1985242-rs1176713
|
T-A-T
|
NA
|
0.028
|
NA
|
NA
|
NA
|
11
|
rs1062613-rs1985242-rs1176713
|
T-T-T
|
0.104
|
0.099
|
0.184
|
0.854
|
0.864
|
11
|
rs1176744-rs1062613
|
G-C
|
0.030
|
0.025
|
NA
|
NA
|
NA
|
11
|
rs1176744-rs1062613
|
G-T
|
NA
|
0.000
|
NA
|
NA
|
NA
|
11
|
rs1176744-rs1062613
|
T-C
|
0.679
|
0.757
|
-1.075
|
0.282
|
0.255
|
11
|
rs1176744-rs1062613
|
T-T
|
0.119
|
0.020
|
1.760
|
0.078
|
0.09
|
11
|
rs1062613-rs1985242
|
C-A
|
0.068
|
0.070
|
-0.053
|
0.958
|
0.997
|
11
|
rs1062613-rs1985242
|
C-T
|
0.000
|
0.028
|
NA
|
NA
|
NA
|
11
|
rs1062613-rs1985242
|
T-A
|
0.252
|
0.333
|
-0.579
|
0.563
|
0.564
|
11
|
rs1062613-rs1985242
|
T-T
|
0.078
|
0.000
|
1.293
|
0.196
|
0.162
|
11
|
rs1985242-rs1176713
|
A-C
|
0.560
|
0.548
|
-0.264
|
0.792
|
0.802
|
11
|
rs1985242-rs1176713
|
A-T
|
0.109
|
0.119
|
0.494
|
0.621
|
0.592
|
11
|
rs1985242-rs1176713
|
T-C
|
0.134
|
0.124
|
0.256
|
0.798
|
0.826
|
11
|
rs1985242-rs1176713
|
T-T
|
0.679
|
0.757
|
-1.072
|
0.284
|
0.241
|
|
|
|
|
|
|
|
|
12
|
rs2117032-rs4149056-rs4149081
|
C-C-A
|
0.105
|
0.000
|
1.143
|
0.253
|
0.26
|
12
|
rs2117032-rs4149056-rs4149081
|
C-C-G
|
0.279
|
0.333
|
0.009
|
0.993
|
0.978
|
12
|
rs2117032-rs4149056-rs4149081
|
C-T-G
|
0.056
|
0.143
|
-0.827
|
0.408
|
0.419
|
12
|
rs2117032-rs4149056-rs4149081
|
T-C-A
|
0.009
|
0.024
|
NA
|
NA
|
NA
|
12
|
rs2117032-rs4149056-rs4149081
|
T-T-G
|
0.551
|
0.500
|
-0.041
|
0.968
|
0.968
|
12
|
rs2117032-rs4149056
|
C-C
|
0.105
|
0.000
|
1.135
|
0.256
|
0.257
|
12
|
rs2117032-rs4149056
|
C-T
|
0.279
|
0.333
|
0.011
|
0.991
|
0.96
|
12
|
rs2117032-rs4149056
|
T-C
|
0.056
|
0.143
|
-0.824
|
0.410
|
0.5
|
12
|
rs2117032-rs4149056
|
T-T
|
0.560
|
0.524
|
-0.200
|
0.841
|
0.843
|
12
|
rs4149056-rs4149081
|
C-A
|
0.161
|
0.143
|
0.285
|
0.776
|
0.617
|
12
|
rs4149056-rs4149081
|
C-G
|
0.009
|
0.024
|
NA
|
NA
|
NA
|
12
|
rs4149056-rs4149081
|
T-G
|
0.830
|
0.833
|
-0.047
|
0.963
|
0.869
|
The haplotype-specific scores for the listed markers in association with the child-assessed MTX-induced nausea – the nausea diary.
N=77, the patients who had completed at least seven diary entries.
Chr; Chromosome. Markers; the SNPs in the haplotype. Haplotypes; the alleles for the SNPs in the haplotype. Cases; MTXnausea (n=56). Controls (n=21). Fcases; Frequency of the haplotype among cases. Fcontrols; Frequency of the haplotype among controls. Score; the haplotype association test score for the specific haplotype. P-sim; the number of times the simulated score statistics exceeds the observed divided by the total number of simulations (1000).