1
Variability and Validity of Polymorphism Association Studies in Parkinson’s Disease
(For NEUROLOGY On-Line Journal)
Correspondence:
Tetsuo Ashizawa, MD
Department of Neurology
Baylor College of Medicine
6550 Fannin, Smith 1801
Houston, Texas 77030, USA
Tel: 713 798 3953, Fax: 713 798 3128
E mail:
References
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Tables
E-1. DRD2 polymorphisms
Study / year / race / type and site of polymorphism / PD(no.) / controls
(no.) / association
Yes/No / results
Pastor et al1
Oliveri et al2
Plante-Bordeneuve et al3
Nanko et al4 / 1999
1999
1997
1994 / Caucasian
Caucasian
Caucasian
Japanese / dinucleotide repeat in 2nd intron of DRD2, chromosome 11q22-23 / 154
136
118
71 / 125
224
100
67 / No
Yes
Yes
No / The overall results of studies 1 to 4 were not combined because of insufficient data. Frequencies of allele 15 (study 2) and allele 122bp (study 3) were significantly higher in PD than controls.
Higuchi et al5 / 1995 / Japanese / Ser311/Cys311 in DRD2 / 70 / 70 / No / PD:controls
5:3
Comings et al6 / 1991 / Caucasian / Taq1 polymorphism of DRD2 / 17 / 108 / No / A1 allele
PD:controls
3:24
E-2. DRD4 polymorphisms
Study / year / race / type and site of polymorphism / PD(no.) / Controls
(no.) / Association Yes/No / Results
Wan et al7
Kronenberg et al8
Ricketts et al9
Higuchi et al5
Nanko et al10 / 1999
1999
1998
1995
1993 / Chinese
Caucasian
Caucasian
Japanese
Japanese / 48 base-pair tandem repeat sequences in exon 3 of DRD4, chromosome 11p / 101
122
95
70
60 / 105
127
47
70
81 / No
No
Yes, repeat number 6 to 7 was higher in PD, odds ratio=2.1,
No
No / total alleles
(studies 5,7-9,10)
PD:controls
896:860
repeat number
PD:controls
repeat 2 to 5-756:775
repeat 6 to 7-140:85
Overall results did not show any significant association
E-3. DAT polymorphisms
study / year / race / type and site of polymorphism / PD(no.) / controls
(no.) / association
Yes/No / results
1.Mercier et al11
2.LeCouteur et al12
3.Leighton et al13
4. Plante-Bordeneuve et al3
5. Higuchi et al5 / 1999
1997
1997
1997
1995 / Caucasian
Australian
Chinese
Caucasian
Japanese / 40 base-pair tandem repeat sequences in exon 3 of DAT, chromosome 11p / 75
100
203
78
70 / 78
200
230
60
70 / No
Yes, repeat 11 was higher in PD, odds ratio=10.2, however absolute frequency of the repeats in PD was low (0.025)
No
No
No / total alleles
(studies 3,5,11-13)
PD:controls
1052:1276
repeat number
PD:controls
Repeat3- 2:0
5- 1:0
6- 1:0
7- 10:8
8- 0:2
9- 170:241
10- 848:1013
11- 19:12
12- 1:0
Overall results did not show any significant association
E-4. MAOA polymorphisms
study / year / race / type and site of polymorphism / PD(no.) / controls
(no.) / association
Yes/No / results
Plante-Bordeneuve et al3
Hotamisligil
et al14 / 1997
1994 / Caucasian
Caucasian / (GT)n dinucleotide repeat in intron 1of MAOA in
X chromosome p11.3 / ?*
91 / ?*
129 / No
Yes / In studies 3 & 14, allele sizes ranged from 112bp to 130bp
In study 14, allele 122bp was significantly higher in PD than controls.
Nakatome et al15 / 1998 / Japanese / (GT)n dinucleotide repeat in intron 1 of MAOA in
X chromosome
p11.3 / 68 / 228 / Yes / “allele 119” significantly higher in PD.
Kurth et al16 / 1993 / Caucasian / RLFP with EcoRV / 66 / 181 / No / no significant difference between allele 1 and 2
Nanko et al17 / 1996 / Japanese / (GT)n dinucleotide repeat in intron 2 of MAOA in
X chromosome p11.3 / 68 / 68 / No / sizes of alleles not indicated
?*Only the number of chromosomes were given, but females have two X chromosomes, and males one; the number of studied subjects cannot be determined.
E-5. MAOB Polymorphisms
study / year / race / type andsite of polymorphism / PD
(no.) / controls
(no.) / association
Yes/No / results
1.Mellick et al18
Checkoway et al19
**Costa et al20
Ho et al21
Morimoto et al22
Kurth et al16 / 1999
1998
1997
1995
1995
1993 / Australian
Caucasian
Caucasian
Caucasian
Japanese
Caucasian / G/A polymorphism in intron 13 of MAOB on
X chromosome / 204
82
62
124
54
64 / 285
118
79
60
56
77 / No
No
Yes, allele G higher in PD, odds ratio=2.1
No
No
Yes,allele A higher in PD,odds ratio=2.0 / total alleles (studies 16,18,20-22)
PD:controls
685:839
allele PD:controls
A 363:435
G 322:404
Overall results did not show any significant association
Mellick et al18
Nakatome et al15
Plante-Bordeneuve et al3
Hotamisligil
et al14 / 1999
1998
1997
1994 / Australian
Japanese
Caucasian
Caucasian / (GT)n dinucleotide repeat in intron 2 of MAOB on X chromosome / 204
68
122
91 / 285
196
93
129 / Yes, alleles 186 and 188 higher in PD, odds ratio=1.97
No
No
Yes, allele 180 higher in PD, odds ratio=2.0 / total alleles
(studies 3,14,15,18)
PD:controls
595:912
allele PD:controls
178 156:263
180 106:136
182 138:202
184 111:212
186 54:79
188 30:20*
Overall results showed that frequency of allele188 significantly higher in PD
Nanko et al17 / 1996 / Japanese / (GT)n dinucleotide repeat in intron 2 of MAOB on X chromosome / 71 / 70 / No / sizes of alleles not indicated
P=0.003, OR=2.58, 95%CI; 1.38 to 4.82 for allele 188. ** Study 20 was extended from study 19, and hence only results from study 20 were included in the analysis
E-6. COMT polymorphisms
study / year / race / type and site of polymorphism / PD(no.) / controls
(no.) / association
Yes/No / Results
Yoritaka et al23
Xie et al24
Kunugi et al25
Hoda et al26
Syvanen et al27 / 1997
1997
1997
1996
1997 / Japanese
Chinese
Japanese
Caucasian
Caucasian / G to A (-108Val/Met) polymorphism in exon 4 of COMT in chromosome 22q11 / 176
70
109
139
158 / 156
62
153
173
76 / Yes, allele108Val higher in PD, odds ratio=1.31
No
Yes, allele
108Met higher in PD, odds ratio=1.4
No
No / total alleles
(studies 23-27)
PD:controls
1304:1240
allele PD:controls
-108Val 796:755
-108Met 508:485
Genotype
Met/Met 111:97
Met/Val 280:289
Val/Val 261:234
Overall results did not show any significant association
E-7. NAT2 polymorphisms
study / Year / race / type and site of polymorphism / PD(no.) / controls
(no.) / association
Yes/No / results
Dupret et al28
Harhangi et al29
Nicholl et al30
Agundez et al31
Nicholl et al32
Bandmann et al33
Ladero et al34
Igbokwe et al35 / 1999
1999
1999
1998
1998
1997
1989
1989 / Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
African / Polymorphisms of NAT2 in chromosome 8p21.3-23.1
Acetylator status determined by sulphamthazine / 68
80
203
121
223
200
100
20 / 211
161
205
121
?
100
93
21 / No
No
No
Yes, slow acetylator genotype higher in young onset PD, odds ratio=2.92
No
Yes, slow acetylator genotype higher in familial PD,odds ratio=3.79
No
No / total patients
(studies 28-31, 33-35)
PD:control
792:912
Acetylator status
PD:controls
Slow 480:490**
Fast 312:422
Overall results showed the slow acetylator genotype was significantly higher in PD
** P=0.006, OR=1.33, 95%CI: 1.08 to 1.62
E-8. ApoE Polymorphisms
Study / Year / race / type and site of polymorphism / PD(no.) / controls
(no.) / association
Yes/No / results
Bon et al36
Kruger et al37
F-Fernandez et al38
Inzelberg et al39
Mattila et al40
Wakahayashi et al41
Arai et al42,43
French PD Group44
Ballering et al45
St Clair et al46
Egenspezer et al47
Whitehead et al48
Helisalmi et al49
Morris et al50
Podulso et al51
Martinoli et al52
Ibarreta et al53
Koller et al54
Benjamin et al55
Marder et al56
Harington et al57
Rubinsztein et al58
Hardy et al59 / 1999
1999
1998
1998
1998
1997
1997
1997
1997
1997
1996
1996
1996
1996
1995
1995
1995
1995
1994
1994
1994
1994
1994 / Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Japanese
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Mixed
Caucasian
Caucasian
Caucasian / 1. C/G-T/A transition converting codon 158 from arginine (E3) to cysteine (E2)
2.T/A-C/G transition converting codon 112 from cysteine (E3) to arginine (E4) / 199
193
105
125
11
22
73
103
50
50
20
189
23
23
54
13
64
113
23
79
51
34
24 / 96
177
105
93
59
50
77
387
107
447
54
162
60
99
77
243
228
78
55
44
58
34
35 / Yes allele E4 higher in demented PD
Yes, allele E4 higher in young PD
No
Yes, allele E4 higher in non demented PD
No
No
Yes, allele E4 higher in demented PD
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No / total alleles
(studies 36-59, except 41 and 55)
PD:control
3192:5440
allele PD:control
E2 &E3 2754:4707
E4 438:733
PD group demented:non-demented
E2 &E3 262:777
E4 51:123
Overall results did not show any significant association
Studies 42 & 43 shared some common data, hence only study 43 included. Study 41 was excluded because data from controls not available. Study 55 was excluded because similar results reported by same group in study 50.