Table 1.
Well-studied candidate gene studies and findings
| Gene | Polymorphism | Relation to diabetic retinopathy and significance level | Population and size (number of participants) | Methodology (self-reported vs clinically assessed) | References |
|---|---|---|---|---|---|
| AR | C(−106)T, specifically CC genotype |
Positive assn w/DR in T2DM (P=0.03) | Iranian (206 pts) | Clinically assessed | 27 |
| C(−106)T | No sig assn w/DR in T2DM | Chinese (268 pts) | Clinically assessed | 28 | |
| C(−106)T, C allele | No sig assn w/NPDR or PDR in T2DM Positive assn w/DR in T1DM (OR =1.78, 95% CI =1.39–2.28) |
Meta-analysis of 17 studies including multiple populations (7,831 pts) | Clinically assessed in all included studies except two, which did not report how DR was determined in pts | 29 | |
| eNOS | VNTR 4b/a, a allele | Negative assn w/DR (8 studies = T2DM, 1 study = T1DM; P=0.005); no sig assn w/PDR | 9 studies for NOS3 4b/a polymorphism (3,145 pts) | Not reported | 31 |
| rs2070744 (786T/C) | No sig assn w/DR or PDR (4 studies = T2DM, 1 study = T1DM) | 5 studies for NOS3 T-786C polymorphism (2,147 pts) | |||
| rs1799983 (894G/T, also Glu298Asp) | No sig assn w/DR or PDR in T2DM | 7 studies for NOS3 G894T polymorphism (2,819 pts) Meta-analysis of 12 studies including multiple populations (8,111 pts) | |||
| VNTR 4b/a, aa genotype | Negative assn w/PDR (P=0.03) but no sig assn w/DR in T2DM | Asian Indian (1,446 pts) | Clinically assessed | 32 | |
| rs2070744 (786T/C), CC genotype rs1799983 (894G/T, also Glu298Asp), TT genotype | No sig assn w/DR or PDR in T2DM No sig assn w/DR or PDR in T2DM |
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| VNTR 4b/a, aa genotype | Negative assn w/DR in T2DM (OR =0.75, 95% CI =0.65–0.88) in Africans (2 studies) but not Caucasians (4 studies) or Asians (10 studies) |
Meta-analysis of 16 studies including multiple populations (6,664 pts) | Not reported | 33 | |
| VNTR 4b/a, a allele | Positive assn w/PDR in T2DM (P=0.01) | Slovenian (577 pts) | Clinically assessed | 34 | |
| rs1799983 (894G/T, also Glu298Asp), GG genotype | No sig assn w/PDR in T2DM | ||||
| VNTR 4b/a, aa genotype | No sig assn w/DR or PDR in T2DM | Caucasian-Brazilian (630 pts) | Clinically assessed | 35 | |
| rs2070744 (786T/C) genotype rs1799983 (894G/T, also Glu298Asp) genotype | No sig assn w/DR or PDR in T2DM No sig assn w/DR or PDR in T2DM |
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| VNTR 4b/a, aa genotype rs2070744 (786T/C) genotype rs1799983 (894G/T, also Glu298Asp) genotype |
No sig assn w/DR in T2DM No sig assn w/DR in T2DM No sig assn w/DR in T2DM | South Indian (311 pts) | Clinically assessed | 36 | |
| VNTR 4b/a genotype | No sig assn w/DR in T2DM | Meta-analysis of 15 studies including multiple populations (6,593 pts) | Not reported | 37 | |
| RAGE | −429T/C in promoter region −374T/A in promoter region |
No sig assn w/DR in T2DM No sig assn w/DR in T2DM |
Malaysian (577 pts) | Clinically assessed | 39 |
| −429T/C in promoter region −374T/A in promoter region, AA genotype Gly82Ser, 82S allelic variant |
No sig assn w/DR in T2DM Negative assn w/DR in T2DM (OR =0.64, 95% CI =0.42–0.99) No sig assn w/DR in T2DM |
Asian and Caucasian – 6 studies (2,317 pts) Asian, African, and Caucasian – 7 studies (3,339 pts) Asian – 5 studies (1,911 pts) (meta-analysis of 11 studies) |
Clinically assessed | 40 | |
| Gly82Ser, Ser82 genotype | Sig assn w/DR in T2DM (P<0.033) | North Indian (758 pts) | Clinically assessed | 41 | |
| Gly82Ser in exon 3 1704 G/T in intron 7 2184 A/G in intron 8 |
No sig assn w/DR in T2DM No sig assn w/DR in T2DM No sig assn w/DR in T2DM |
Malaysian (283 pts) | Clinically assessed | 42 | |
| Gly82Ser in exon 3 1704 G/T in intron 7 429T/C in promoter region |
No sig assn w/DR in T2DM No sig assn w/DR in T2DM No sig assn w/DR in T2DM |
Caucasian, Asian, African American (meta-analysis of 29 studies – 1000+ pts) | Not reported | 43 | |
| VEGF | rs833061 (−460 C/T) C allele rs833061 (−460 C/T) TT genotype |
Positive assn w/PDR in T2DM (P=0.0043) Negative assn w/PDR in T2DM (P=0.0126) |
Asian (Indian, Bengali Hindu – 493 pts) | Clinically assessed | 44 |
| rs699947 (−2578 A/C) rs833061 (−460T/C) C allele |
No sig assn w/DR in DM (studies include T1DM + T2DM) Positive assn w/DR (P=0.02) and PDR (P=0.02) in T2DM |
Asian and Caucasian: 6 studies (2,208 pts) Asian and Caucasian: 6 studies (1,654 pts) (meta-analysis of 11 studies; one study examined both SNPs) |
Clinically assessed | 45 | |
| rs2010963 (−634G/C) rs699947 (−2578C/A) rs3025039 (+936C/T) rs833061 (−460T/C) |
No sig assn w/DR in T2DM No sig assn w/DR in T2DM Positive assn w/DR in T2DM (P=0.01) Positive assn w/DR in T2DM (P=0.02) |
Asian and Caucasian: 7 studies (2,104 pts) Asian and Caucasian: 6 studies (1,868 pts) Asian only: 4 studies (1,147 pts) Asian only: 3 studies (746 pts) (meta-analysis of 11 studies) |
Not reported | 46 | |
| rs2010963 (−634 G/C) rs833061 (−460 C/T) C allele/CC genotype |
No sig assn w/DR/PDR in T2DM Negative assn w/NPDR (P=0.013 for genotype, P=0.002 for allele) but no sig assn w/PDR in T2DM |
Han Chinese (376 pts) | Clinically assessed | 47 | |
| rs699947 (−2578C/A) rs13207351 rs833061 (−460 C/T) rs2146323 |
Positive assn w/DR in T2DM (OR =3.54, 95% CI =1.12–11.19) Positive assn w/DR in T2DM (OR =3.76, 95% CI =1.21–11.71) No sig assn w/DR in T2DM No sig assn w/DR in T2DM |
Chinese (500 pts) | Clinically assessed | 48 | |
| rs699947 (−2578 A/C) rs2010963 (+405 G/C) |
Positive assn w/DR (type not specified) in T2DM (P=0.003) No sig assn w/DR or PDR in T2DM |
Asians and Europeans: 8 studies (2,402 pts) Asians and Europeans: 10 studies (3,448 pts) (meta-analysis of 18 studies total) | Not reported | 49 | |
| rs699947 (−2578C/A) AA genotype | Positive assn w/DR in T2DM in Asian (P=0.0002) pts but not in Caucasian pts |
Asian and Caucasian (meta-analysis of 6 studies – 1,702 pts; 1,124 of which were Asian) | Not reported | 50 | |
| rs699947 (−2578 A/C) | No sig assn w/DR unless diabetes duration of 20+ years (P<0.001) (Type of DM not specified) | Egyptian (148 pts) | Clinically assessed | 51 | |
| rs699947 (−2578 A/C) rs2010963 (+405C/G) rs3025039 (+936C/T) |
No sig assn w/DR in T2DM No sig assn w/DR in T2DM No sig assn w/DR in T2DM |
Chinese (1,040 pts) | Clinically assessed | 52 | |
| rs1570360 (−1154 G/A) | No sig assn w/NPDR or PDR in T2DM | Bengali Hindu (372 pts) | Clinically assessed | 53 | |
| rs3025039 (+936 C/T) T allele rs2010963 (+405 G/C) C allele rs2071559 (R 2/KDR-604 A/G) |
Positive assn w/PDR (P=0.0002) but not NPDR in T2DM Positive assn w/PDR (P=0.0007) but not w/NPDR in T2DM No sig assn w/NPDR or PDR in T2DM |
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| rs2010963 (−634G/C) C allele | Positive assn w/DR in T2DM (P=0.03) | Meta-analysis of 9 studies including multiple populations (2,947 pts) | Clinically assessed | 54 | |
| rs6921438 rs10738760 |
No sig assn w/DR in T2DM No sig assn w/DR in T2DM |
French (2,567 pts) | Clinically assessed | 55 |
Abbreviations: AR, aldose reductase; eNOS, endothelial nitric oxide synthase; VNTR, variable number tandem repeat; RAGE, receptor for advanced glycation end products; VEGF, vascular endothelial growth factor; PDR, proliferative diabetic retinopathy; NPDR, nonproliferative diabetic retinopathy; KDR, kinase insert domain receptor; T2DM, type 2 diabetes mellitus; T1DM, type 1 diabetes mellitus; SNP, single nucleotide polymorphism; DR, diabetic retinopathy; OR, odds ratio; CI, confidence interval; assn, association; sig, significant; pts, participants; w/, with.