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Received 9 November 2009 | Accepted 30 September 2010 | Published 5 October 2010
LOC387715/HTRA1 gene polymorphisms and susceptibility to agerelated macular degeneration: A HuGE review and meta-analysis
Yu Tong,1 Jing Liao,3 Yuan Zhang,4 Jing Zhou,5 Hengyu Zhang,6 Meng Mao2
(The first three authors are contributed equally to this work.)
1Laboratory
of Early Development and Injuries, Center for Research of Child Development and Disease, West China Second
University Hospital, Chengdu, China; 2Department of Pediatrics, Laboratory of Early Development and Injuries, Center for
Research of Child Development and Disease, West China Second University Hospital, Sichuan University, Chengdu, China;
3Department of Science and Technology, Sichuan People's Provincial Hospital, Chengdu, China; 4Department of Community
Health, Wuhou Health Bureau, Chengdu, China; 5Department of Laboratory Medicine, West China Hospital, Sichuan University,
Chengdu, China; 6Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China
Purpose: To examine the association of age-related macular degeneration (AMD) with HtrA serine peptidase 1
(HTRA1) gene rs11200638 GA polymorphism and LOC387715/ ARMS2 gene rs10490924 GT polymorphisms, and
to evaluate the magnitude of the gene effect and the possible genetic mode of action.
Methods: We searched the US National Library of Medicines PubMed, Embase, OMIM, ISI Web of Science, and CNKI
databases in a systematic manner to retrieve all genetic association studies on the HTRA1 (rs11200638) and LOC387715/
ARMS2 (rs10490924) gene polymorphisms and AMD. We performed a meta-analysis conducted with Stata software,
version 9.0.
Results: Individuals who carried the AA and AG genotypes of HTRA1 gene rs11200638 GA polymorphism had 2.243
and 8.669 times the risk of developing AMD, respectively, when compared with those who carry the GG genotype.
Individuals carrying the TT and TG genotypes of LOC387715/ ARMS2 gene rs10490924 GT polymorphism had 7.512
and 2.353 times the risk of developing AMD, respectively, compared with those who carry GG genotype. These results
suggested a moderate codominant, multiplicative genetic mode; that is, both HTRA1 rs11200638 GA polymorphism
and LOC387715/ARMS2 rs10490924 GT polymorphism play important roles in the pathogenesis of AMD. We found
no evidence of publication bias. Between-study heterogeneity was found in both allele-based analysis and genotype-based
analysis.
Conclusions: HTRA1 rs11200638 GA polymorphism and LOC387715/ARMS2 rs10490924 GT polymorphism play
important roles in AMD. Gene-gene and gene-environmental interactions, as well as precise mechanisms underlying
common variants in the HTRA1 gene and LOC387715/ ARMS2 gene, potentially increase the risk of AMD and need further
exploration.
1958
1959
1960
1961
2007
2007
2008
2008
2008
2008
[100]
[97]
[103]
[104]
[108]
2007
[106]
[96]
2007
[105]
2007
2007
[102]
[99]
2007
[98]
2007
2006
[101]
[95]
Year
Ref
1962
India
China
China
USA
UK
USA
France
USA
Japan
Japan
China
Austria
China
Region,
country
study
was
conducted
Indian Asian
East Asian
East Asian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
East Asian
East Asian
East Asian
Caucasian
East Asian
Ethnicity
Casecontrol
Casecontrol
Casecontrol
Casecontrol
Casecontrol
Casecontrol
Casecontrol
Casecontrol
Casecontrol
Casecontrol
Casecontrol
Casecontrol
Casecontrol
Study
design
NR
54
54
49.0/
52.5/
38.0/
44.4
40.6
NR
NR
NR
79.5
72.4
45.1
35.5
68
Sex
composition
in cases
(% males)
68.8
75.5
71.2
81.2/
78.9/
81.0/
78.3
>65.0
71.3
>65.0
>68.0
75.7
71.9
64.0/
78
74.9
Cases
64.4
73.3
71.5
74
>65.0
72.8
>65.0
>68.0
71.2
67.9
64
77.4
74.2
Controls
AMD, combined
Exudative AMD
bilateral wet
AMD, unilateral
wet AMD,
bilateral GA, and
unilateral GA.
Dry and wet
AMD
Wet AMD
Wet AMD
Exudative AMD
AMD, combined
Wet AMD
Exudative AMD
in AMD level 4
Wet AMD
Controls
250
163
95
776
401
134
200
535
73
123
164
242
96
Cases
250
183
90
294
266
134
116
288
94
133
106
157
130
Controls
TABLE 1. CHARACTERISTICS OF CASE-CONTROL STUDIES INCLUDED IN A META-ANALYSIS OF THE ASSOCIATION BETWEEN THE HTRA1 GENE POLYMORPHISMS AND AMD
2006
2007
2007
2007
2007
2007
2007
2008
[56]
??
??
[128]
[13]
[93]
[83]
2008
[3]
[133]
2008
[108]
2006
2007
[100]
[133]
2007
[96]
2005
2007
[99]
[84]
2007
[95]
2005
2007
[106]
[84]
Year
Ref
1963
USA
USA
Australia
USA
Japan
USA
Russia
USA
USA
Germany
Germany
China
India
UK
USA
France
USA
Japan
Region, country
study was
conducted
Caucasian
Caucasian
Caucasian
Caucasian
East Asian
Caucasian
Caucasian
Mixed
Caucasian
Caucasian
Caucasian
East Asian
Indian Asian
Caucasian
Caucasian
Caucasian
Caucasian
Ethnicity
East Asian
Case-control
Case-control
Cohort
Case-control
Case-control
Nested casecontrol
Case-control
Case-control
Case-control
Case-control
Case-control
Case-control
Case-control
Case-control
Case-control
Case-control
Case-control
Case-control
Study design
composition in
cases (% males)
NR
39.6
39.9
42.6
70.5
35.2
27.7
44
42
35.1
NR
58.7
NR
40.6
NR
NR
NR
Sex
79.5
NR
79.1
75.6
79
73.4
60.1
72.6
73.2
79.5
75.01
NR
66
68.8
>65.0
71.3
>65.0
>68.0
Cases
75.7
NR
72.9
74.9
72
73.6
60.2
71.1
70.3
76.5
68.25
NR
66.1
64.4
>65.0
72.8
>65.0
>68.0
Controls
71.2
Wet AMD+Dry
AMD
Wet AMD+Dry
AMD
Wet AMD
Wet AMD+Dry
AMD
Wet AMD+Dry
AMD
Wet AMD+Dry
AMD
Wet AMD+Dry
AMD
Wet AMD+Dry
AMD
Wet AMD+Dry
AMD
Wet AMD
Wet AMD+Dry
AMD
Wet AMD
Wet AMD+Dry
AMD
Wet AMD
Wet AMD
Wet AMD+Dry
AMD
Wet AMD
Cases
Wet AMD
Controls
Hospital-based controls without retinal
diseases and AMD on the base of full
ophthalmologic examination
Without AMD on the base of full
ophthalmologic examination
Without any type of drusen, geographic
atrophy, or exudative AMD.
Without AMD on the base of full
ophthalmologic examination
Without AMD on the base of full
ophthalmologic examination
Ethnic matched controls, without a
family history of AMD or any other
ocular or systemic diseases
Without any AMD and any other major
eye diseases aside from mild age-related
cataracts
Without any AMD and any other major
eye diseases
Unrelated controls without any AMD
and any other major eye diseases
Without AMD on the base of full
ophthalmologic examination
Without AMD on the base of full
ophthalmologic examination
Free of macular changes
TABLE 2. CHARACTERISTICS OF CASE-CONTROL STUDIES INCLUDED IN A META-ANALYSIS OF THE ASSOCIATION BETWEEN THE LOC387715 GENE POLYMORPHISMS AND AMD
87
164
278
399
95
445
155
120
693
361
759
121
193
401
134
118
431
Cases
73
232
155
557
329
99
1041
151
995
172
328
594
132
203
266
134
116
280
Controls
94
1964
1965
1966
2006
2007
2007
2007
2007
2007
2007
2007
2007
2008
2008
2008
2008
[99]
[96]*
[100]
[97]*
[103]
[104]
[108]
Total
95
163
229
3071
776
118
134
401
N
96
242
164
123
73
457
53
94
90
131
32
43
106
AA
44
67
68
45
29
102
33
51
89
400
57
54
172
AG
40
108
77
55
39
183
9
18
50
245
29
37
123
GG
18
67
19
26
5
172
0.53
0.0379
0.0111
0.327
0.937
0.0837
0.019
P value
for
HWE
0.266
0.247
0.924
0.488
0.239
<0.001
90
183
184
216
7
294
116
134
266
N
130
157
106
133
94
280
Year
Ref
[101]
[98]
[102]
[105]
[106]
[95]
cases
Genotype distribution
19
38
21
10
5
21
6
AA
14
8
15
22
16
11
12
8
47
90
85
41
43
91
AG
59
50
63
57
40
90
controls
GG
57
99
28
54
38
17
9
70
70
16
9
15
6
24
55
78
0.903
0.994
0.956
0.0282
0.948
0.0111
0.296
P value
for
HWE
0.976
0.877
0.104
0.582
0.627
0.997
7.439
7.559
6.686
8.341
15.448
3.874
24.274
OR1
9.952
12.375
6.681
4.248
13.775
9.65
2.940~18.819
3.398~14.509
3.695~12.098
4.253~16.360
5.476~43.582
2.009~7.469
10.327~57.057
95% CI
4.465~22.184
5.583~27.432
2.980~14.979
2.127~8.487
4.520~41.984
5.006~18.601
AA/GG
1.872
1.732
1.633
1.99
3.356
2.376
2.597
OR2
2.147
3.192
1.801
2.004
7.41
2.112
0.772~4.541
0.919~3.262
1.028~2.595
1.500~2.640
1.860~6.055
1.350~4.180
1.841~3.664
95% CI
1.104~4.174
2.022~5.039
0.921~3.523
1.103~3.640
2.642~20.786
1.525~2.937
AG/GG
3.046
3.31
2.701
2.042
3.734
2.358
3.826
OR
3.626
3.723
2.37
2.231
3.189
2.937
TABLE 3. THE ASSOCIATION BETWEEN THE HTRA1 GENE POLYMORPHISMS AND AMD- ALLELE AND GENOTYPE FREQUENCIES OF CASE-CONTROL STUDIES INCLUDED IN A META-ANALYSIS
1.973~4.703
2.403~4.559
2.033~3.589
1.652~2.525
2.498~5.583
1.657~3.347
2.963~4.942
95% CI
2.450~5.368
2.693~5.158
1.664~3.375
1.566~3.178
2.029~5.013
2.299~3.753
A/G
Year
2007
2007
2008
2008
2005
2005
2006
2006
2007
2007
2007
2007
2007
2007
2007
2007
2007
2008
Ref
[106]
[95]
[99]
[96]
[100]
[108]
[3]
[84]
[84]
[133]
[133]
[56]
??
??
[128]
[13]
[93]
[83]
Total
73
431
118
134
401
193
121
759
361
693
120
155
95
445
399
278
87
164
502
7
27
133
37
45
111
81
54
142
88
135
18
16
39
68
69
14
19
40
TT
40
180
55
51
170
77
49
349
156
341
49
66
34
182
182
120
38
74
TG
cases
6
118
26
38
120
35
18
268
117
217
53
73
22
195
148
144
30
50
GG
0.25
<0.001
0.811
0.0234
0.00992
0.101
0.472
0.327
0.0471
0.999
0.501
0.982
0.0398
0.0694
0.601
0.216
0.578
0.483
P value
for
HWE
94
280
116
134
266
203
132
594
328
172
995
151
99
1041
329
557
232
155
5878
N
15
12
5
22
10
25
22
27
16
4
43
10
10
41
12
16
13
10
TT
Genotype distribution
41
99
40
44
89
89
70
179
109
57
351
66
50
308
100
179
60
42
TG
controls
38
169
71
68
167
89
40
388
203
111
601
75
39
692
217
362
159
103
GG
0.783
0.992
0.978
0.013
0.908
0.932
0.651
0.558
0.962
0.567
0.654
0.669
0.58
0.661
0.994
0.547
0.092
0.108
P value
for
HWE
11.4
15.875
20.208
3.66
15.448
8.239
5.455
7.614
9.543
17.264
4.747
1.644
6.941
5.886
8.431
2.2
7.746
8.24
OR1
TT/GG
95% CI
3.920~33.155
8.405~29.979
7.169~56.962
1.918~6.985
7.761~30.746
4.544~14.937
2.589~11.491
4.904~11.822
5.347~17.030
6.223~47.893
2.559~8.804
0.700~3.859
2.898~16.491
3.872~8.948
4.412~16.112
1.047~4.623
3.459~17.346
3.812~17.813
6.179
2.604
3.755
2.074
2.658
2.2
1.556
2.823
2.483
3.06
1.583
1.027
1.205
2.097
2.669
1.685
3.357
3.63
OR2
2.354~16.217
1.854~3.658
2.048~6.886
1.178~3.653
1.878~3.763
1.340~3.613
0.800~3.026
2.225~3.582
1.778~3.468
2.131~4.395
1.050~2.386
0.643~1.643
0.610~2.380
1.645~2.673
1.935~3.679
1.247~2.278
1.911~5.896
2.185~6.029
95% CI
TG/GG
2.979
3.809
4.388
2.271
3.71
3.123
2.43
2.932
3.109
1.949
3.384
1.161
2.626
2.412
2.883
1.552
3.409
3.54
OR
TABLE 4. THE ASSOCIATION BETWEEN THE LOC387715 GENE POLYMORPHISMS AND AMDALLELE AND GENOTYPE FREQUENCIES OF CASE-CONTROL STUDIES INCLUDED IN A META-ANALYSIS
95% CI
1.901~4.668
2.995~4.845
2.928~6.576
1.600~3.223
2.884~4.774
2.336~4.175
1.697~3.480
2.459~3.495
2.453~3.940
1.466~2.592
2.532~4.523
0.821~1.641
1.742~3.958
2.023~2.876
2.265~3.670
1.221~1.974
2.331~4.986
2.488~5.038
T/G
1967
1968
2686/2000
1533/1206
4034/3212
16
7
8
7
16
14
16
7
8
8
8
7
16
14
16
7
8
Adjusted HWE
East Asian
Caucasian
HWE
1969
Adjusted HWE
East Asian
Caucasian
Wet AMD
HWE
Adjusted HWE
East Asian
Caucasian
2970/2160
835/868
4034/3212
3124/2784
1348/1212
2970/2160
835/868
4034/3212
3124/2784
4034/3212
1533/1206
2970/2160
835/868
4034/3212
3124/2784
14
HWE
4034/3212
Total sample
size (n)
16
No. of
studies
HTRA1 (rs11200638)
A allele versus G
allele
Total
Comparison
2.273
2.277
2.252
2.28
2.226
8.967
6.561
9.484
8.691
7.604
8.225
8.424
7.972
Odds ratio
1.982,
2.496
2.006,
2.589
2.011,
2.516
1.781,
2.866
1.916,
2.741
6.453,
9.778
6.667,
10.540
6.700,
10.030
5.541,
10.100
5.813,
13.600
6.834,
12.800
5.137,
8.270
5.964,
12.920
95% CI
2.205
2.202
2.192
2.193
2.168
8.534
6.138
9.205
7.258
7.273
7.423
7.515
7.21
3.059
2.589
2.847
2.701
2.754
2.664
1.944,
2.418
1.943,
2.475
1.966,
2.445
1.684,
2.878
1.948,
2.495
6.035,
8.614
6.201,
9.107
6.205,
8.880
5.390,
9.815
5.719,
9.211
6.941,
12.207
4.881,
7.719
6.411,
11.360
2.476,
2.867
2.542,
2.984
2.510,
2.907
2.473,
3.278
2.366,
2.833
2.717,
3.444
Fixed effects
2.221
2.219
2.204
2.232
2.18
9.309
6.138
9.843
8.687
7.273
7.928
8.16
7.737
3.053
2.8
2.847
2.827
2.909
2.803
Odds ratio
1.943,
2.447
1.935,
2.574
1.962,
2.477
1.665,
2.957
1.949,
2.531
6.096,
9.821
6.314,
10.546
6.286,
10.000
5.390,
9.815
5.556,
13.582
6.539,
14.817
4.881,
7.719
5.924,
14.682
2.486,
3.159
2.547,
3.324
2.519,
3.173
2.473,
3.278
2.289,
3.424
2.681,
3.478
95% CI
Random effects
Q
7.453
6.812
15.942
15.295
15.784
14.097
5.391
14.147
19.969
4.27
22.776
20.51
24.308
7.028
28.452
4.873
31.923
30.471
34.576
TABLE 5. AGE RELATED MACULAR DEGENERATION (AMD): HTRA1 SNPS VERSUS ARMS2 SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS).
0.383
0.339
0.386
0.289
0.397
0.029
0.612
0.049
0.006
0.64
0.089
0.083
0.06
0.318
0.56
0.007
0.004
0.003
P value
Heterogeneity
6.1
12.3
5.9
15.1
58.8
51.6
65.8
35.3
37.6
39.2
14.7
75.4
53
57.4
56.6
I2 (%)
0.386
0.387
0.386
0.403
0.381
0.441
0.359
2686/2000
1533/1206
8
7
18
17
18
3
13
7
HWE
Adjusted HWE
East Asian
Caucasian
Wet AMD
1970
HWE
Adjusted HWE
East Asian
Caucasian
1471/1225
4425/4355
289/325
5027/5878
4893/5744
5027/5878
0.4
2.392
1.959
2.692
Total
1348/1212
Wet AMD
Odds ratio
0.343,
0.430
0.340,
0.435
0.343,
0.429
0.311,
0.491
0.327,
0.438
0.373,
0.510
0.300,
0.419
0.331,
0.471
2.197,
3.249
1.723,
2.222
1.938,
2.907
95% CI
No. of
studies
Comparison
Total sample
size (n)
3.276
2.769
2.692
2.715
2.742
2.725
2.396
1.953
2.706
2.556,
2.906
2.569,
2.928
2.547,
2.896
2.086,
3.315
2.580,
2.972
2.912,
3.686
2.231,
3.281
1.711,
2.230
2.004,
2.866
Fixed effects
TABLE 5. CONTINUED.
3.211
2.794
2.692
2.719
2.761
2.734
2.471
1.953
2.708
Odds ratio
2.366,
3.158
2.376,
3.209
2.351,
3.145
2.086,
3.315
2.333,
3.346
2.711,
3.802
2.219,
3.305
1.711,
2.230
1.946,
3.138
95% CI
Random effects
11.596
73.265
0.481
81.68
79.116
80.195
9.387
1.024
7.311
0.072
0.786
0.153
0.994
0.397
P value
Heterogeneity
48.3
83.6
79.2
79.8
78.8
36.2
4.3
I2 (%)
0.426
0.423
0.422
3998/4805
1471/1225
5027/5878
3998/4805
1471/1225
18
3
13
7
11
7
18
17
18
3
13
7
11
7
East Asian
Caucasian
Wet AMD
HWE
1971
Adjusted HWE
East Asian
Caucasian
Wet AMD
Total
HWE
Adjusted HWE
1029/1073
4425/4355
289/325
5027/5878
4893/5744
1029/1073
4425/4355
289/325
5027/5878
2.507
2.285
2.519
2.424
2.334
2.38
2.353
9.767
7.021
8.567
7.57
7.51
7.826
Adjusted HWE
4893/5744
17
7.512
Odds ratio
0.387,
0.467
0.384,
0.463
0.383,
0.462
2.062,
2.865
1.983,
3.147
1.921,
2.694
1.999,
3.088
2.072,
2.665
2.093,
2.702
2.058,
2.643
/
5.326,
10.850
5.509,
12.600
4.678,
9.950
6.169,
14.480
5.703,
9.659
5.886,
10.140
5.692,
9.672
/
95% CI
HWE
5027/5878
Total sample
size (n)
18
No. of
studies
TT versus GG
Total
Comparison
2.564
2.293
2.531
2.422
1.843
2.316
2.343
2.336
9.134
6.846
7.828
7.261
6.934
7.1
7.394
7.096
2.134,
2.558
2.138,
2.569
2.115,
2.535
1.203,
2.823
2.198,
2.669
2.053,
3.122
2.074,
2.536
2.137,
3.076
6.069,
8.296
6.294,
8.683
6.071,
8.303
4.206,
11.431
6.076,
8.677
5.786,
10.582
5.703,
8.218
6.951,
12.002
Fixed effects
TABLE 5. CONTINUED.
2.567
2.253
2.519
2.445
2.119
2.29
2.336
2.324
9.521
6.708
8.273
7.41
6.934
7.209
7.533
7.216
Odds ratio
1.993,
2.709
1.990,
2.741
1.956,
2.681
0.893,
5.029
2.082,
2.871
1.813,
3.501
1.886,
2.691
2.065,
3.191
5.492,
9.480
5.707,
9.943
5.483,
9.480
4.206,
11.431
5.176,
10.607
5.191,
13.185
4.734,
9.505
5.922,
15.307
95% CI
Random effects
7.834
29.067
13.05
29.79
7.783
45.09
42.638
42.812
17.209
33.919
13.738
45.035
1.232
48.331
43.926
48.208
0.251
0.001
0.042
0.003
0.02
0.001
0.009
0.033
0.54
P value
Heterogeneity
23.4
65.6
54
59.7
74.5
62.3
62.5
60.3
65.6
71.1
56.9
73.8
65.4
64.2
65.3
I2 (%)
1972
0.406
0.428
/
0.395,
0.483
0.354,
0.513
0.382,
0.475
0.341,
0.472
95% CI
Fixed effects
Odds ratio
95% CI
Random effects
Summary odds ratios of HTRA1 rs11200638 polymorphism and LOC387715/ARMS2 rs10490924 polymorphism.
0.433
Odds ratio
Wet AMD
Total sample
size (n)
/
0.438
No. of
studies
East Asian
Caucasian
Comparison
TABLE 5. CONTINUED.
P value
Heterogeneity
I2 (%)
1973
1974
1975
2.
3.
4.
5.
6.
7.
8.
9.
1976
1977
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
1978
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
1979
19
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