The Role of Genetic Polymorphisms in Diabetic Retinopathy: Narrative Review
Abstract
:1. Introduction
2. Materials and Methods
Literature Search Strategy
3. Results and Discussion
3.1. Chromosome 1
Gene | Polymorphism or rs ID Number | No. of Participants | Results | References |
---|---|---|---|---|
SELP | rs6128 | DM n = 2691 DNR n = 1032, DR n = 222 (EA) DNR n = 552, DR n = 271 (AfA) DNR n = 54, DR n = 25 (AsA) DNR n = 151, DR n = 80 (HA) | The SNPs in SELP gene were associated with DR only in the European American population. The strongest association was found to rs6128 (OR = 0.43, p = 0.0001), whereas to rs6133, and rs3917779 the odds ratios were: OR = 0.38, p = 0.0004 and OR = 0.39, p = 0.0006, respectively. Association was also not significant in independent Asian and Caucasian (Europe) cohorts. | [25] |
rs6133 | ||||
rs3917779 | ||||
SELP | rs6128 | DM2 n = 629 IFG n = 266 (AfA) | The rs6128 genotypes distribution in three subgroups (healthy, IFG, DM2) had no significant differences, but participants without retinopathy were more likely to be minor allele homozygotes (TT; 5.7%) than those with retinopathy (p = 0.03). The rs6128 minor allele homozygotes had lower mean P-selectin plasma levels than major allele carriers (25.8 ng/mL vs. 34.5 ng/mL; p = 0.046). There were no significant associations with either retinopathy or P-selectin levels for rs6133 and rs3917779. | [26] |
rs6133 | ||||
rs3917779 | ||||
SELP | rs6128 | DM2 n = 110 DNR n = 55 PDR n = 55 (Yazd, Iran) | rs6128 and rs6133 variations were not associated with PDR; significant different distributions of rs3917779 alleles and genotypes were found: allele C frequency was higher in PDR group (OR = 42.9, p < 0.001); CC genotype had a frequency of 0.96 and was strongly associated with PDR (p < 0.0001); in the DNR group, frequency of TT genotype was 0.62 (p < 0.0001); no heterozygotes were identified in either group. | [24] |
rs6133 | ||||
rs3917779 | ||||
MTHFR | rs1801133 (C677T) | DR n = 1747 (n = 1141 As, n = 606 NAs) CTR (DNR and H) n = 3146 (n = 1589 As, n = 1557 NAs) | Analysis in the overall group in the genetic model CT vs. CC revealed OR = 1.46, p < 0.01, and in the model TT vs. CC revealed OR = 2.45, p < 0.01 (Rmo OR = 1.67, p < 0.01, and Dmo OR = 1.71, p < 0.01). From stratification analysis by ethnicity: in Asian populations CT vs. CC revealed OR = 1.71, p < 0.01, and TT vs. CC revealed OR = 2.97, p = 0.02 (Rmo OR = 2.16, p = 0.11, and Dmo OR = 1.98, p < 0.01); in non-Asian populations CT vs. CC revealed OR = 1.15, p = 0.38, and TT vs. CC revealed OR = 1.33, p = 0.04 (Rmo OR = 1.24, p = 0.05, and Dmo OR = 1.18, p = 0.21). Subgroup analysis by DM type: in DM2 group CT vs. CC revealed OR = 1.50, p < 0.01, and TT vs. CC revealed OR = 2.68, p < 0.01 (Rmo OR = 2.05, p = 0.01, and Dmo OR = 1.72, p < 0.01); in the non-DM2 group CT vs. CC revealed OR = 1.30, p = 0.12, and TT vs. CC revealed OR = 1.75, p = 0.05 (Rmo OR = 1.38, p = 0.14, and Dmo OR = 1.46, p = 0.04). The authors concluded that the rs1801133 polymorphism was significantly associated with DR risk in the DM2 and Asian groups, especially in the Asian group (both DM types). Genetic factors seem to have more impact on Asian population. | [30] |
MTHFR | rs1801131 (A1298C) | DM2 n = 607 DR n = 159 DNR n = 448 (AR) | A1298C MTHFR polymorphism increases the risk of DR developing in Arabian countries, but only in the dominant genetic model (OR = 2.96, p < 0.01). However, as results demonstrate a non-additive effect, an over-dominant pattern was suggested. Broader studies covering the aspect of A1298C polymorphism in DR were recommended. | [35] |
MTHFR | rs1801133 (C677T) | DM2 n = 375 (DNR n = 196; NPDR n = 95; PDR n = 84) n = 205 CTR (H) (Pakistan) | The minor allele of rs1801133 (T) had a protective effect (OR = 0.59, p = 0.00228) in DM2, whereas in the case of the minor allele of rs1801131 (C) the association with DM2 was not found (OR = 1.18, p = 0.35). None of these SNPs showed an association with increased risk of NPDR (rs1801133 OR = 0.88, p = 0.59, rs1801131 OR = 1.57, p = 0.06) or PDR (rs1801133 OR = 0.81, p = 0.50, rs1801131 OR = 1.71, p = 0.08). | [36] |
rs1801131 (A1298C) | ||||
NVL | rs142293996 | Discovery stage: DM2 n = 5857; n = 3246 (Eur) DNR n = 1970, DR n = 1276 (NPDR n = 878, PDR n = 398) n = 2611 (AfA) DNR n = 941, DR n = 1670 (NPDR n = 573, PDR n = 1097) Replication stage: n = 37,708 (DM1 and DM2) n = 18,545 (Eur) DNR n = 7713, DR n = 10,832 n = 16,453 (As) DNR n = 7751, DR n = 8702 n = 2710 (His) DNR n = 1240, DR n = 1470 | Seven SNPs met GWAS significance (all from PDR or extreme cases of DR; two separate loci in AfA and 5 loci in Eur). The most strongly associated variants were rs142293996 (chromosome 1) in Europeans (OR = 2.38, p = 2.1 × 10−9) and rs115523882 (chromosome 3) in African Americans (OR = 3.10, p = 5.4 × 10−9), but only rs142293996 passed meta-analysis with replication samples, after adjusting for covariates based on a Fisher exact test (extreme cases of PDR in Europeans). | [37] |
CRP | rs2808629 | DM2 n = 1018 DNR n = 400 DR n = 618 (China) | Four tagging SNPs (rs2808629, rs3093077, rs1130864 and rs2808634) within CRP region were genotyped for all the participants. The rs2808629 (G allele) was significantly associated with increased susceptibility to DR (OR = 1.296, p = 0.006). This association remained significant after adjustment for confounding factors, including HbA1c levels, duration of diabetes, systolic and diastolic blood pressure, BMI and sex (OR = 1.261, p = 0.030). No significant association with DR severity was observed (p = 0.387 for trend analysis) | [39] |
3.2. Chromosome 2
3.3. Chromosome 3
3.4. Chromosome 4
3.5. Chromosome 5
3.6. Chromosome 6
3.7. Chromosome 7
3.8. Chromosome 8
3.9. Chromosome 9
3.10. Chromosome 10
3.11. Chromosome 11
3.12. Chromosome 12
3.13. Chromosome 13
3.14. Chromosome 14
3.15. Chromosome 15
3.16. Chromosome 16
3.17. Chromosome 17
3.18. Chromosome 18
3.19. Chromosome 19
3.20. Chromosome 20
3.21. Chromosome 21
3.22. Chromosome 22
3.23. Chromosome X/Chromosome Y
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Gene | Polymorphism or rs ID Number | No. of Participants | Results | References |
---|---|---|---|---|
EHD3 | rs3754840 | DM2 n = 14,080 in total; Discovery stage: DR set-1 n = 5415, set-2 n = 790, DNR set-1 n = 4676, set-2 n = 1779 Validation stage: DR n = 2260, DNR n = 723 Replication stage: DR n = 750, DNR n = 839 (Japan) | Results revealed EHD3 as a novel susceptibility gene to DR (allele T) (association p = 2.17 × 10−6 < 2.71 × 10−6 = 0.05/18480). | [44] |
CAPN10 | SNP43 | DNR n = 238 DR n = 121 | Distribution of genotypes: DR (46.3% GG; 41.3% GA; 12.4% AA); DNR (45.8% GG; 45.0% GA; 9.2% AA); p = 0.60 | [48] |
Gene | Polymorphism or rs Number | No. of Participants | Results | References |
---|---|---|---|---|
PPAR γ | rs1801282 (Pro12Ala) | DR n = 4369 CTR n = 5658 (DNR + H) | The two common SNPs were analyzed: rs1801282 C/G, and rs3856806 C/T. The pooled results did not reveal an association between PPAR-γ rs1801282 C/G and DR susceptibility in the overall population. Not significant was also race-based stratification (Caucasian and Asian), the HWE status, control design, or DR subtype stratification. Same as above, the pooled results indicated no association between the rs3856806 C/T polymorphism and DR susceptibility in the overall population in any of the five genetic models (OR = 0.74, and p = 0.19). | [54] |
rs3856806 | DR n = 902 CTR n = 845 (DNR + H) | |||
PPAR γ | rs1801282 (Pro12Ala) | DNR n = 238 DR n = 121 | Distribution of genotypes: DR (71.1% Pro/Pro; 25.6% Pro/Ala; 3.3% Ala/Ala); DNR (66.4% Pro/Pro; 30.7% Pro/Ala; 2.9% Ala/Ala). Pro12Ala might be associated with decreased risk of DR. Effect may be indirect. | [48] |
SST3B | rs12630354 | DM2 in total n = 14,080; Discovery stage: DR set-1 n = 5415, set-2 n = 790, DNR set-1 n = 4676, set-2 n = 1779 Validation stage: DR n = 2260, DNR n = 723 Replication stage: DR n = 750, DNR n = 839 (Japan) | The authors identified new SNP loci 73 kbp upstream of STT3B predisposing to DR (OR = 1.17, p = 1.62 × 10−9). Risk allele T might be involved in transcriptional regulation and may contribute to DR susceptibility through a consequent upregulation of STT3B expression. | [44] |
GOLIM4 (nearest gene) | rs115523882 | Discovery stage: DM2 n = 5857; n = 3246 (Eur) DNR n = 1970, DR n = 1276 (NPDR n = 878, PDR n = 398) n = 2611 (AfA) DNR n = 941, DR n = 1670 (NPDR n = 573, PDR n = 1097) Replication stage: n = 37,708 (DM1 and DM2) n = 18,545 (Eur) DNR n = 7713, DR n = 10,832 n = 16,453 (As) DNR n = 7751, DR n = 8702 n = 2710 (His) DNR n = 1240, DR n = 1470 | The rs115523882 was the most strongly associated variants in African American PDR patients (OR = 3.10, p = 5.4 × 10−9), but with no genome-wide significance in replication (possibly insufficient power to replicate caused by a low frequency in other ethnic groups). | [37] |
Gene | Polymorphism or rs Number | No. of Participants | Results | References |
---|---|---|---|---|
CEP135 | rs4865047 | DM1 n = 469 PDR n = 208 NPDR n = 261 (EA) | No associations were significant at a genome-wide level, but the top association was at rs4865047 (OR = 0.65, p = 0.11, PCA = 2.06 × 10−5). | [7] |
CEP135 | rs4865047 | DM1 n = 132 PDR n = 48 NPDR (CTR) n = 84 H n = 90 | The distribution of rs4865047 (CEP135) genotypes was significantly different between PDR and NPDR when compared with the reference group (p < 0.001), with no detection of minor allele homozygotes (TT) in either group. MAF in PDR and NPDR were much higher than in the reference group (OR = 4.325, p = 0.001 and OR = 6.089, p < 0.0001 respectively). The risk prediction in the codominant model showed that CT carriers of minor alleles had a seven-fold higher odds ratio of PDR when compared with wild-type homozygous carriers CC and when compared to the reference group (OR = 7.2, p = 0.001). | [57] |
NPY2R | rs1902491 | DM1 n = 469 PDR n = 208 NPDR n = 261 (EA) | The analysis showed that the top association was at rs1902491 (OR = 0.81, p = 0.13, PCA = 2.81 × 10−5), a new locus associated with PDR. | [7] |
NPY2R | rs1902491 | DM1 n = 132 PDR n = 48 NPDR (CTR) n = 84 H n = 90 | There were no significant differences in the distribution of rs1902491 genotype frequencies (PDR and NPDR versus the reference group, p > 0.05). MAF of rs1902491 did not differ significantly between the groups (p > 0.05). The risk prediction in additive, recessive and codominant models showed the possible protective effect against PDR, but without significance. | [57] |
Gene | Polymorphism or rs Number | No. of Participants | Results | References |
---|---|---|---|---|
VEGF | +405 | DM2 n = 426 (DR n = 195) CTR n = 493 | +405 genotype was not associated with diabetic complications in type 2 diabetes patients. | [66] |
rs2010963 −634 G/C | DNR n = 215 (PDR n = 82; NPDR n = 72) CTR n = 61 | The G/C polymorphism genotype distribution and the frequency of the C allele were significantly higher in the NPDR group than in control patients (OR = 1.69, 95% CI = 1.03–2.79). Analysis of the distribution of combined genotypes of the VEGF gene revealed the prevalence of the C/C-C/C genotype in NPDR patients (OR = 8.26, 95% CI = 1.79–37.99) and C/G-CC in PDR patients (OR = 3.36, 95% CI = 1.39–8.12). | [65] | |
−460 C/T rs833061 | No association between the C/T polymorphism and diabetic retinopathy. | |||
rs2010963 | DNR (CTR) n = 118 DR n = 150 | Among seven common polymorphisms in the promoter region, 5-untranslated region (UTR) and 3UTR of the VEGF gene, genotype distribution of the C(634)G polymorphism differed significantly (p = 0.011) between DR and CTR, and the C allele was significantly increased in patients with retinopathy compared with those without retinopathy (p = 0.0037). The odds ratio (OR) for the CC genotype of C(634)G to the GG genotype was 3.20 (95% CI 1.45–7.05, p = 0.0046). | [61] | |
rs201963 | n = 213 (DNR n = 87; DR n = 44 and n = 82 with no DR evidence) | No significant association was observed between genotypes, alleles and haplotypes of −634C/G polymorphisms and DR or its severity. | [62] | |
rs2010963 | DM2 total n = 268 (DNR n = 139; DR n = 129) | No significant association was observed between analyzed group (p = 0.67) | [63] | |
rs3025039 | n = 213 (DNR n = 87; DR n = 44 and n = 82 with no DR evidence) | No significant association was observed between genotypes, alleles and haplotypes of 936C/T polymorphisms and DR or its severity. | [62] | |
rs3025039 | DR n = 41 DNR n = 118 | A higher frequency of the TT genotype was observed in patients with proliferative diabetic retinopathy (p = 0.02). VEGF 936 C/T polymorphism was associated with plasma levels of VEGF, and DM2 patients with DR are characterized by a particular VEGF genotype and have higher VEGF levels than DNR and the general healthy subjects. | [64] | |
rs3025039 | DM2 total n = 268 (DNR n = 139; DR n = 129) | No significant association was observed between analyzed group (p = 0.93) | [63] | |
rs833069 | No significant association was observed between analyzed group (p = 0.74) | |||
rs699949 | It was found to have a significant association with DR (OR = 3.54 CI = 1.12–11.19) | |||
rs833061 | It was found to have a significant association with DR (OR = 3.72 CI = 1.17–11.85) | |||
rs13207351 | It was found to have a significant association with DR (OR = 3.76 CI = 1.21–11.71) | |||
rs2146323 | It was found to have a significant association with DR (OR = 2.25 CI = 0.81–6.29) | |||
rs3025021 | It was found to have no association with DR (OR = 1.08 CI = 0.26–4.44) |
Gene | Polymorphism or rs Number | No. of Participants | Results | References |
---|---|---|---|---|
IL-6 | rs1800795 | DR (DM2) n = 215 DNR n = 207 | DR patients with PDR had a significantly higher frequency of IL-6 –174 GC (OR 0.58; 95% CI 0.34–0.99; p = 0.011) than DNR. | [67] |
rs1800796 | DR patients with PDR had a significantly higher frequency of IL-6 –572 GG (OR 0.53; 95% CI 0.24–1.14; p = 0.016) than DNR. | |||
eNOS | rs2070745 | DR (DM1) n = 249 CTR n = 100 | The significant difference was observed between diabetic patients and healthy controls [CC + CT vs. TT p = 0.05, OR = 1.5, 95% CI 0.9–2.5]. The genotype frequencies for eNOS gene polymorphism were also significantly different between diabetic retinopaths and healthy controls [CC + CT vs. TT p = 0.0000 OR = 3.4, 95% CI 1.9–6.1]. | [70] |
G894T | DR n = 94 CTR n = 94 | There was no difference between prevalence of TT, GT or GG genotype based on age and sex. There was no correlation between DR or proteinuria and genotypes of eNOs. | [71] | |
AR | rs759853 (C106T) | DNR n = 120 DR n = 160 | There was no correlation between rs759853 polymorphism and DR in Egyptian population. | [75] |
PAI-1 | rs1799768 | DR n = 196 DNR n = 200 CTR n = 196 | Genetic analysis for PAI-1 gene polymorphism indicates that the frequency of PAI-1 rs1799768 genotypes in DR and DNR compared to controls is not significant. | [78] |
Gene | Polymorphism or rs Number | No. of Participants | Results | References |
---|---|---|---|---|
PALM2 | rs14050842 | DM2 in total n = 14,080; Discovery stage: DR set-1 n = 5415, set-2 n = 790, DNR set-1 n = 4676, set-2 n = 1779 Validation stage: DR n = 2260, DNR n = 723 Replication stage: DR n = 750, DNR n = 839 | New SNP on PALM gene was identified as predisposing to DR (p = 4.19 × 10−8, OR = 1.61, 95% CI 1.36–1.) | [36] |
Gene | Polymorphism rs Number | No. of Participants | Results | References |
---|---|---|---|---|
RNLS | rs2296545 | DM2 n = 860 DNR n = 405; DR n = 328 CTR n = 400 | Retinopathy subgroup showed a significantly higher frequency of G allele (OR 1.4, 95% CI 1.16–1.72, p = 0.0005) and GG genotype (OR 1.86, 95% CI 1.26–2.75, p = 0.001). SNP might be considered a risk factor for diabetic retinopathy in DM2 patients | [81] |
PLXDC2 | rs1571942 (C/T) | DM2 n = 749, DR n = 174, DNR n = 575, CTR n = 100 | Risk allele C. A 1.67-fold greater risk of developing of DR (OR, 1.67; 95% CI, 1.06–2.65) | [79] |
ARHGAP22 | rs4838605 (C/T) | Risk allele C. A 1.58-fold risk greater risk of developing of DR (95% CI, 1.00–2.52) | ||
ARHGAP22 | rs11101355 (T/C) | Risk allele T. A 1.65-fold greater risk of developing of DR (95% CI, 1.05–2.60). | ||
ARHGAP22 | rs11101357 (A/G) | Risk allele A. A 1.65-fold greater risk of developing of DR (95% CI, 1.05–2.60). | ||
Unknown nearest gene | rs12219125 SNP (T/G) | Risk allele T. A 1.62-fold increase in DR risk (95% CI, 1.02–2.58). | ||
Unknown nearest gene | rs4462262 SNP (C/T) | Risk allele C. A 1.54-fold increase in DR risk (95% CI, 0.79–2.99). |
Gene | Polymorphism rs Number | No. of Participants | Results | References |
---|---|---|---|---|
HS6ST3 (and MYSM1, PLXDC2, ARHGAP22) | rs2038823 | DM2 n = 749, DR n = 174, DNR n = 575, CTR n = 100 | Significant associations were identified in chromosome regions 1, 5, 10 and 13 after adjusting for diabetes duration and HbA1C levels. The results suggest that HS6ST3, and also MYSM1, PLXDC2, ARHGAP22, and an unknown gene on chromosome 5q are involved in the pathogenesis of diabetic retinopathy. | [79] |
PLXDC2 | rs1571942 (C/T) | Risk allele C. A 1.67-fold greater risk of developing of DR (OR, 1.67; 95% CI, 1.06–2.65) | ||
ARHGAP22 | rs4838605 (C/T) | Risk allele C. A 1.58-fold risk greater risk of developing of DR (95% CI, 1.00–2.52) | ||
ARHGAP22 | rs11101355 (T/C) | Risk allele T. A 1.65-fold greater risk of developing of DR (95% CI, 1.05–2.60). | ||
ARHGAP22 | rs11101357 (A/G) | Risk allele A. A 1.65-fold greater risk of developing of DR (95% CI, 1.05–2.60). | ||
Unknown nearest gene | rs12219125 SNP (T/G) | Risk allele T. A 1.62-fold increase in DR risk (95% CI, 1.02–2.58). | ||
Unknown nearest gene | rs4462262 SNP (C/T) | Risk allele C. A 1.54-fold increase in DR risk (95% CI, 0.79–2.99). |
Gene | Polymorphism or rs Number | No. of Participants | Results | References |
---|---|---|---|---|
MYO5C | rs3751624 | NPDR n = 102 PDR n = 72 DNR (DM2) n = 573 | Allele A of rs3751624 SNP is associated with higher susceptibilities to DR | [83] |
Gene | Polymorphism or rs Number | No. of Participants | Results | References |
---|---|---|---|---|
A2BP1 | rs7355553 (A/G) | DR (DM1) n = 973 CTR n = 1856 | Meta OR = 0.68, p-value 6.4 × 10−7 | [7] |
CCDC101 | rs151320 (A/G) | Meta OR = 0.575, p-value 3.1 × 10−6 | ||
NUPR1 | rs151227 (C/T) | Meta OR = 0.575, p-value 3.2 × 10−6 | ||
CCDC101 | rs151229 (C/T) | Meta OR = 0.575, p-value 3.2 × 10−6 | ||
CCDC101 | rs151230 (C/T) | Meta OR = 0.575, p-value 3.2 × 10−6 | ||
CCDC101 | rs11641853 (C/T) | Meta OR = 0.576, p-value 3.4 × 10−6 | ||
CCDC101 | rs10521145 (C/T) | Meta OR = 0.575, p-value 3.4 × 10−6 | ||
ZNRF1 | rs17684886 (A/T) | Meta OR = 0.559, p-value 6.8 × 10−6 | ||
SULT1A1 | rs11074904 (C/T) | Meta OR = 0.557, p-value 7.8 × 10−6 | ||
SULT1A2 | rs11647881 (G/T) | Meta OR = 0.585, p-value 8.6 × 10−6 |
Gene | Polymorphism or rs Number | No. of Participants | Results | References |
---|---|---|---|---|
FAM18B (gene ID 51030); (TVP23B) | rs11871508 (G>A) | PDR n = 8 DNR n = 9 | Factors such as hyperglycemia, VEGF (vascular endothelial growth factor) and AGE (advanced glycation end products) downregulated FAM18B expression in primary human retinal microvascular endothelial cells. CD34+ /VEGFR2+ mononuclear cells from patients with PDR showed significantly reduced FAM18B mRNA expression compared to DNR group. | [11] |
ACE | Insertion/deletion (I/D) polymorphism in the ACE gene | DR n = 1039 CTR n = 1185 | There was a statistically significant association between tested polymorphism and DR (DD vs. II: OR = 1.73, 95% CI 1.19–2.51; DD + ID vs. II: OR = 1.41, 95% CI 1.16–1.72; DD vs. ID + II: OR = 1.55, 95% CI 1.13–2.12) | [87] |
ACE | Insertion/deletion (I/D) polymorphism in the ACE gene | DR (DM2) n = 178 DNR n = 206 | The D allele of the ACE gene is independently associated with DR in Iranian type 2 diabetic patients (OR = 1.831, 95% CI = 1.074–3.124; p = 0.026) | [90] |
ACE | Insertion/deletion (I/D) polymorphism in the ACE gene | NPDR n = 136 PDR n = 94 | The DD genotype was more common in the PDR group (p < 0.001). Results suggest that the DD genotype increases ACE activity, which in turn increases the risk of proliferation in diabetic retinopathy. | [91] |
ACE | rs4646994 | DR n = 196 DNR n = 200 CTR n = 196 | There is no statistically significant difference between DR males and females compared to the corresponding controls. The results were significantly high between DR and DNR genotype frequencies in males. The recessive pattern was found to be significantly associated with DR males (OR = 0.45 [95% CI = 0.20–0.99], p < 0.05), while in females they are not significant compared to appropriate controls. | [65] |
ACE | 2350 G/A AA genotype (rs4343) | DNR (DM2) n = 145 DR (DM2) n = 82 CTR n = 90 | ACE 2350 G/A distribution genotypes (GG, GA and AA) were as follows: 35.56, 45.55 and 18.89% in the CTR group, 28.57, 46.03 and 25.40% in the group DNR group and 15.85, 46.34 and 37.81% in DR group. No significant differences were confirmed in genotype frequency distribution (p = 0.5266) or allele frequency distribution (p = 0.2425) between CTR and DNR groups. Distribution of genotype frequencies (p = 0.0026) and allele frequencies (p = 0.0003) in the DR group showed a significant difference compared to the CTR group. | [77] |
GRB2 | rs9896052 | DNR n = 508 DR n = 336 | Association with sight-threatening diabetic retinopathy in both the type 2 (OR = 1.50 (CI 95% 1.03–2.18; p = 0.035)) and the type 1 (OR = 1.56 (CI 95% 1.02–2.38, p = 0.041)). | [93] |
Gene | Polymorphism or rs Number | No. of Participants | Results | References |
---|---|---|---|---|
APOE | e2/e3/e4 polymorphisms | DR (DM1) n = 76; DNR (DM1) n = 96 | Neither APOE alleles frequencies or APOE genotypes frequencies differed between patients with and without diabetic retinopathy | [98] |
e2/e3/e4 polymorphisms | CTR [H] n = 107 DM1 + DM2 n = 141: DM1 n = 46 DM2 n = 95 (who also had DR n = 81) | No evidence of an association between APOE alleles and proliferative DR (epsilon2, epsilon3 and epsilon4 in cases: 9, 76, and 15%, and in controls: 5, 88, and 12%, respectively), but the carriers of epsilon2 allele were more frequent among patients with type 2 DM and DR than in controls [cases: 15/95 (15.8%); controls: 7/107 (6.5%); p < 0.05]. | [97] | |
e2/e3/e4 polymorphisms | DNR n = 1144 DR n = 254 | APOE gene polymorphisms were not associated with diabetic retinopathy in either Caucasians or African Americans. In African Americans, the E2/E4 genotype (n = 6) was associated with increased prevalence of hard exudates (odds ratio [OR] 4.10, 95% confidence interval [CI] 1.30 to 12.90), as was the E2/E3 genotype (n = 9, OR 2.64, 95% CI 1.01 to 6.95). No association between APOE genotypes and hard exudates was found in Caucasians. | [12] | |
APOE2 rs7412; Arg158Cys); APOE4 (rs429358; Cys112Arg) | CTR [H] n = 2055 DM2 n = 1274 | APOE4 allele revealed an association with retinopathy. Carriers of at least one APOE4 allele (rs429358) are protected against DM2 related retinopathy (OR [95% CI] = 0.65 [0.42–0.99]. Protection against retinopathy is driven mostly by females (OR [95% CI] = 0.50 [0.25–0.99]); and remains significant (p = 0.044) after adjustment for diabetes duration and BMI. | [96] | |
ICAM-1 | ICAM-1 469 (K/K, K/E, E/E) | DNR (DM2) [Ret −] n = 50 DR (DM2) [Ret +] n = 81 | Allele frequency Ret −: 0.50 for K allele; Ret +: 0.64 for K allele; OR = 1.92 (1.16–3.17). The frequency of ICAM-1 469KK genotype and K allele were significantly higher in the patients with DR than in DNR (genotype 42% vs. 20%, χ2 = 6.70, p = 0.035; allele 66% vs. 50%, χ2 = 6.49, p = 0.011). These data suggest that the ICAM-1 469KK genotype could be a genetic risk factor for retinopathy in Type 2 diabetes mellitus. | [101] |
Gene | Polymorphism or rs Number | No. of Participants | Results | References |
---|---|---|---|---|
PTPN1 | rs3787345 | DNR n = 238 DR n = 121 | Distribution of genotypes: DR (20.7% CC; 51.2% CT; 28.1% TT); DNR (18.9% CC; 52.1% CT; 29.0% TT); 0 = 0.92 | [48] |
rs754118 | Distribution of genotypes: DR (34.7% CC; 48.8% CT; 16.5% TT); DNR (34.9% CC; 52.1% CT; 13.0% TT); 0 = 0.64 | |||
JPH2 | rs761207 | DNR n = 575 DR n = 174 | 1.43-fold (95% CI 1.04–1.98) | [102] |
rs6031415 | 1.42-fold (95% CI = 1.02–1.97) |
Gene | Polymorphism or rs Number | No. of Participants | Results | References |
---|---|---|---|---|
TIMP-3 | −899 (T/A) in the promoter region of the gene | PDR n = 113 DM2 n = 158 CTR n = 100 | Genotype frequencies of TT/TA/AA were 98.2%/1.8%/0.0% (99.1% A, 0.9% G) for PDR, 96.2%/3.8%/0.0% (98.1% A, 1.9% G) for DM2, and 90.0%/10%/0.0% (95.0% A, 5.0% G) for CTR. | [105] |
−915 (A/G) in the promoter region of the gene | Genotype frequencies of AA/AG/GG genotypes were 47.8%/45.1%/7.1% (70.4% T, 29.6%G) for PDR, 45.0%/43.0%/12.0% (66.5% T, 33.5% G) for DM2, and 40.0%/42.0%/18.0% (61.0% T, 39.0% G) for CTR. | |||
−1296 (T/C) in the promoter region of the gene | Genotype frequencies of TT/TC/CC were 47.8%/45.1%/7.1% (70.4% T, 29.6% C) for PDR, 45.0%/43.0%/12.0% (66.5% T, 33.5% C) for DM2, and 40.0%/42.0%/18.0% (61.0% T, 39.0% C) for CTR. |
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Sienkiewicz-Szłapka, E.; Fiedorowicz, E.; Król-Grzymała, A.; Kordulewska, N.; Rozmus, D.; Cieślińska, A.; Grzybowski, A. The Role of Genetic Polymorphisms in Diabetic Retinopathy: Narrative Review. Int. J. Mol. Sci. 2023, 24, 15865. https://doi.org/10.3390/ijms242115865
Sienkiewicz-Szłapka E, Fiedorowicz E, Król-Grzymała A, Kordulewska N, Rozmus D, Cieślińska A, Grzybowski A. The Role of Genetic Polymorphisms in Diabetic Retinopathy: Narrative Review. International Journal of Molecular Sciences. 2023; 24(21):15865. https://doi.org/10.3390/ijms242115865
Chicago/Turabian StyleSienkiewicz-Szłapka, Edyta, Ewa Fiedorowicz, Angelika Król-Grzymała, Natalia Kordulewska, Dominika Rozmus, Anna Cieślińska, and Andrzej Grzybowski. 2023. "The Role of Genetic Polymorphisms in Diabetic Retinopathy: Narrative Review" International Journal of Molecular Sciences 24, no. 21: 15865. https://doi.org/10.3390/ijms242115865