ABCMdb

PMID: 25921964

Zhang R, Wang LY, Wang YF, Wu CR, Lei CL, Wang MX, Ma L
Associations of the G1961E and D2177N variants in ABCA4 and the risk of age-related macular degeneration.
Gene. 2015 Aug 1;567(1):51-7. doi: 10.1016/j.gene.2015.04.068. Epub 2015 Apr 25., [PubMed]

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No. Mutations Sentence Comment

0 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn Research paper Associations of the G1961E and D2177N variants in ABCA4 and the risk of age-related macular degeneration Rui Zhang a,1 , Li-Yuan Wang a,1 , Ya-Feng Wang a , Chang-Rui Wu b , Chun-Ling Lei c , Ming-Xu Wang a, Ìe;, Le Ma a, Ìe; a School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China b The First Affiliated Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, China c The Fourth Hospital of Xi'an, Xi'an Jiaotong University, Xi'an, China a b s t r a c t a r t i c l e i n f o Article history: Received 22 January 2015 Received in revised form 21 April 2015 Accepted 23 April 2015 Available online 25 April 2015 Keywords: Age-related macular degeneration ABCA4 Polymorphism Objective: The aim of this study was to identify the relationship between G1961E and D2177N variants in the ABCA4 gene with AMD susceptibility. Login to comment 4 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn Both G1961E (OR = 3.22, 95% CI: 1.74-5.95) and D2177N (OR = 2.36, 95% CI: 1.41-3.93) variations showed significant associations with increased risk of AMD. Login to comment 5 ABCA4 p.Asp2177Asn In addition, a more significant relationship in the D2177N mutation with increased risk for AMD was found in Americans (OR = 4.31, 95% CI: 1.90-9.73), while no association was demonstrated in Europeans. Login to comment 7 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn Conclusions: Significant evidence was found for a relationship between the G1961E and D2177N variants in ABCA4 with increased susceptibility to AMD, specifically for Americans. Login to comment 20 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn Two common sequence variants in ABCA4, G1961E (c.5882G N A) and D2177N (c.6529G N A) accounted for over half of the reported disease-associated variants; many investigators have assessed the role of ABCA4 in AMD through these two mutations (Allikmets et al., 1997; Allikmets, 2000; Souied et al., 2000). Login to comment 29 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn We performed a meta-analysis based on published data to clarify the contributions of G1961E and D2177N sequence variants towards the risk of AMD for different populations. Login to comment 38 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn First, an initial review of the identified abstracts and titles in all of the relevant articles was conducted to exclude those studies that did not address the association between G1961E or D2177N mutations and the risk of AMD. Login to comment 53 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn Statistical methods An odds ratio (OR) with a corresponding 95% confidence interval (CI) was used to assess the strength of the association between each variant and susceptibility of AMD under an allelic model (G1961E: c.5882G N A and D2177N: c.6529G N A). Login to comment 77 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu G1961E variation and AMD risk All of the included studies assessed the relationship between the G1961E variant in ABCA4 and susceptibility to AMD, whereas eight studies were ultimately excluded from the final meta-analysis due to the variation having not been detected in any of the cases or controls (Baum et al., 2003; Souied et al., 2000; Allikmets, 2000; Kuroiwa et al., 1999; De La Paz et al., 1999; Schmidt et al., 2003; Fuse et al., 2000). Login to comment 79 ABCA4 p.Gly1961Glu The frequency for A (mutation allele) was noted to be significantly higher in AMD subjects compared with normal control subjects (P b 0.001), with 37 (1.39%) and 9 (0.32%) carriers of the G1961E variant being determined in cases and controls, respectively. Login to comment 80 ABCA4 p.Gly1961Glu In the present meta-analysis, there was no significant heterogeneity across the studies (I2 = 0%; P = 0.92 for heterogeneity) and the fixed-effects pooled OR across all datasets revealed significant evidence for a relationship between G1961E and susceptibility to AMD under the allelic model (A vs. T: OR = 3.22, 95% CI: 1.745.95; Fig. 2). Login to comment 82 ABCA4 p.Gly1961Glu Compared with a wider confidence interval for the studies with hospital-based controls (OR = 1.59, 95% CI: 0.06-39.31), population-based studies tended to show a slightly stronger association of the G1961E polymorphism with AMD risk (OR = 3.31, 95% CI: 1.77-6.18, P = 0.89 for heterogeneity). Login to comment 86 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn D2177N variation and AMD risk Similar to the G1961E variant, all of the included studies reported data for the frequency of the D2177N variation in cases and controls. Login to comment 89 ABCA4 p.Asp2177Asn All of the D2177N variant occurrences were in the heterozygous state. Login to comment 91 ABCA4 p.Asp2177Asn Overall, the frequency of the risk factor A allele was higher in AMD patients than in the controls (1.66% vs. 0.58%), and the fixed effects pooled OR (A vs. T: OR = 2.36, 95% CI: 1.41-3.93; Fig. 3) estimated an elevated risk of AMD in carriers of the D2177N variant. Login to comment 93 ABCA4 p.Asp2177Asn The frequency of the A allele for D2177N in control subjects was noted to be significantly higher in Europeans compared with Americans (1.01% vs. 0.32%, P = 0.037). Login to comment 98 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn Discussion In the current study, we evaluated the effects of the G1961E and D2177N variants in ABCA4 on AMD susceptibility based on data from 24 case-control studies. Login to comment 100 ABCA4 p.Asp2177Asn Furthermore, the subgroup analyses indicated that the significant relationship between the D2177N variant and AMD was only detected in Americans, but not in Europeans. Login to comment 107 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn Two common coding polymorphisms located in ABCA4, G1961E and D2177N have been considered to be related to the risk for AMD. Login to comment 113 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn Sun et al. suggested that the G1961E protein and the D2177N protein could significantly decrease ATPase activity by retinal compared with the wild-type ABCA4 protein (Sun et al., 1999). Login to comment 117 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn First author and year Country Variation location Number Source of control Diagnostic criteria Classification criteria Genotyping methods Quality scorea Cases Controls De La Paz et al. (1999) USA G1961E, D2177N 169 56 HB Fundus photography ICGS SSCP + HA 8 Kuroiwa et al. (1999) Japan G1961E, D2177N 80 100 HB Fundus photography ICGS PCR + SSCP 8 McNeill et al. (2000) USA G1961E, D2177N 177 150 PB NR NR NR 4 Souied et al. (2000) France G1961E, D2177N 52 90 PB Fundus photography ICGS SSCP 7 Allikmets (2000) USA G1961E, D2177N 229 200 PB NR NR NR 7 USA G1961E, D2177N 101 100 PB NR NR NR 7 USA G1961E, D2177N 103 158 PB NR NR NR 6 Germany G1961E, D2177N 200 100 PB NR NR NR 7 Holland G1961E, D2177N 83 168 PB NR NR NR 6 USA G1961E, D2177N 115 100 PB NR NR NR 7 Italy G1961E, D2177N 92 171 PB NR NR NR 6 Spain G1961E, D2177N 36 34 PB NR NR NR 7 Sweden G1961E, D2177N 102 100 PB NR NR NR 6 UK G1961E, D2177N 90 20 PB NR NR NR 7 France G1961E, D2177N 67 107 PB NR NR NR 6 Rivera et al. (2000) Germany G1961E, D2177N 200 220 PB Fundus photography ICGS DGGE + DHPLC + SSCP 8 Fuse et al. (2000) Japan G1961E, D2177N 25 40 PB Fundus photography ICGS PCR 7 Webster et al. (2001) USA G1961E, D2177N 182 96 HP Fundus photography ICGS SSCP 7 Guymer et al. (2001) USA G1961E, D2177N 304 408 PB Fundus photography ICGS PCR 8 Australia G1961E, D2177N 201 187 PB Fundus photography ICGS PCR 8 Switzerland G1961E, D2177N 39 94 PB Fundus photography ICGS PCR 8 Bernstein et al. (2002) USA G1961E, D2177N 167 220 PB Fundus photography AREDS direct sequencing 7 Schmidt et al. (2003) USA G1961E, D2177N 165 59 PB Fundus photography ICGS DHPLC + PCR 8 Baum et al. (2003) China G1961E, D2177N 140 95 HP Fundus photography NR PCR 6 AREDS, Age-Related Eye Disease Study; DGGE, denaturing gradient gel electrophoresis; DHPLC, denaturing high performance liquid chromatography; HA, heteroduplex analysis; HP, hospital-based; ICGS, International Classification and Grading System; NR, not reported; PB, population-based; PCR, polymerase chain reaction; SSCP, single-strand conformation polymorphism. Login to comment 119 ABCA4 p.Gly1961Glu Fig. 2. Forest plot on the association between the G1961E variation and AMD risk under the allelic model (A vs. G). Login to comment 122 ABCA4 p.Asp2177Asn In the present study, no significant relationship between the D2177N variant and AMD risk was found in Europeans, which differed significantly from Americans. Login to comment 124 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn ABCA4 p.Asp2177Asn The results of our study showed that the frequency of the A allele for D2177N in control subjects was significantly higher in Europeans compared to Americans, which also supported the hypothesis that Americans were more likely than Europeans to Table 2 Stratified analysis of the association between the G1961E and D2177N variations and AMD. Login to comment 125 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn Subgroup G1961E D2177N N OR (95% CI) I2 (%) Pz Ph N OR (95% CI) I2 (%) Pz Ph Country of origin Europe 10 2.81 (1.14, 6.69) 0 0.82 0.60 10 1.18 (0.54, 2.57) 0 0.92 0.04 United States 10 3.89 (1.59, 9.56) 0 0.67 10 4.31 (1.90, 9.73) 0 0.78 Asia 3 NA NA NA 3 NA NA NA Australia 1 1.86 (0.17, 20.69) NA NA 1 2.33 (0.45, 12.13) NA NA Source of controls Population-based 20 3.31 (1.77, 6.18) 0 0.89 0.54 20 2.37 (1.40, 4.02) 0 0.68 0.58 Hospital-based 4 1.59 (0.06, 39.31) NA NA 4 2.12 (0.25, 18.30) 0 0.83 Age of case (years) b75 3 NA NA NA NP 3 NA NA NA NP ࣙ75 4 2.31 (0.77, 6.93) 0 0.91 4 1.46 (0.60, 3.53) 0 0.87 Classification criteria ICGS 10 2.11 (0.78, 6.28) 0 0.91 NP 10 1.54 (0.66, 3.59) 0 0.93 0.18 AREDS 1 17.11 (0.96, 305.92) NA NA 1 9.22 (1.12, 75.68) NA NA Genotyping methods PCR 5 2.39 (0.57, 10.18) 0 0.76 0.38 5 2.05 (0.61, 6.92) 0 0.82 0.33 SSCP 2 1.59 (0.06, 39.31) NA NA 2 2.64 (0.13, 55.62) NA NA Direct sequencing 1 17.11 (0.96, 305.92) NA NA 1 9.22 (1.12, 75.68) NA NA Quality scorea High 17 2.63 (1.27, 5.43) 0 0.88 0.38 17 1.96 (1.08, 3.54) 0 0.82 0.26 Moderate 6 5.47 (1.54, 19.36) 0 0.60 6 3.20 (1.05, 9.76) 0 0.42 Low 1 4.19 (0.20, 88.00) NA NA 1 9.33 (0.51, 170.05) NA NA AREDS, Age-Related Eye Disease Study; ICGS, International Classification and Grading System; OR, odds ratio; CI, confidence interval; PCR, polymerase chain reaction; Pz, P for Z test; Ph, P for between-study heterogeneity; NA, not applicable; NP, meta-regression was not possible. Login to comment 127 ABCA4 p.Asp2177Asn Fig. 3. Forest plot on the association between the D2177N variation and AMD risk under the allelic model (A vs. G). Login to comment 131 ABCA4 p.Asp2177Asn Inconsistencies in the characteristics of the populations studied might somewhat affect the findings for the D2177N variant and AMD risk. Login to comment 134 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn First, the relatively small sample sizes might reduce the statistical power to assess the association between G1961E and D2177N variations and the susceptibility to AMD. Login to comment 142 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn In conclusion, the present meta-analysis demonstrated that the variants of G1961E and D2177N in ABCA4 were significantly associated with increased risk of AMD, specifically for Americans. Login to comment