2 Genetics and Diabetic Retinopathy |
39 |
|
|
more that a gene is not linked to the presence of the disease and is taken by convention as evidence that a
marker is not linked to the disease. A LOD score between –2.0 and +3.0 is taken as inconclusive.27
The LOD Score in Greater Detail
If two genetic markers are unlinked, as for example, would be the case if they were on different chromosomes, then the probability that they will appear in any given gamete from an individual is 0.5. This ceiling fraction arises from the consideration that during meiosis, the probability that the maternal and paternal chromosomes will assort together in the gamete is 1 in 2 (the two possibilities are that they assort together or they do not assort together, and each has equal probability). If the markers lie on the same chromosome, the mechanism that can lead to their separation is recombination caused by crossing over during meiosis. The probability of recombination of two genetic markers increases the farther apart on the chromosome that they are. At a maximum, if the markers are at the extreme opposite ends of the same chromosome, then crossing over could lead to these markers being separated every time meiosis occurred and their being assorted independently into gametes as though they had been on separate chromosomes. Thus the maximum recombination fraction is 0.5. The actual recombination fraction is denoted by the symbol y, and it will be less than 0.5. The likelihood of recombination fractions of y and 0.5 are calculated, and a LOD score is defined as log10 (likelihood of observed data if loci are linked at a value of y/likelihood of observed data if loci are linked at a value of 0.5).
Once linkage of a genetic marker to diabetic retinopathy has been established, candidate genes of interest may be identified using expressed sequence tags. An expressed sequence tag is a short sequence of DNA that is complementary to an expressed mRNA molecule found in the tissue of interest. The expressed mRNA molecule is used to synthesize a complementary DNA molecule of which a fragment is called an expressed sequence tag. Expressed sequence tags are useful in discovering genes and in sequencing genes.28
2.4Studies of the Genetics of Diabetic Retinopathy
2.4.1 Clinical Studies
The number of studies exploring possible genetic susceptibility to or protection from diabetic retinopathy is large, and this chapter makes no claim to providing exhaustive coverage of a topic that would require a book unto itself. Rather, our goal is to expose the clinician to an important and expanding field of inquiry in diabetic retinopathy likely to be
the source for future breakthroughs in treatment by virtue of illuminating the underlying basic defects. The interested reader is invited to consult comprehensive reviews to explore the topic in greater detail.6,9
Heritability for diabetic retinopathy has been
reported to be 27% and heritability for PDR has been reported to be 25–52%.29,30 Among South
Asian Indians, the risk of DR is higher in diabetic siblings of probands with DR than in diabetic nonsiblings.4 Some of the differences in epidemiologic aspects of diabetic retinopathy may have a genetic basis, although further study is needed to determine the answer. For example, it has been reported that Hispanic diabetics develop severe DR earlier in their course and progress more rapidly compared with blacks or whites (see Chapter 3).3 In a twin study, concordance of retinopathy was found in 35 of 37 identical twins concordant for type 2 DM but in only 21 of 31 identical twins concordant for type 1 DM, suggesting a stronger genetic effect in type 2 than in type 1 DM.5 In the Diabetes Control and Complications Study, there was an increased risk of severe retinopathy among relatives of retinopathypositive versus retinopathy-negative subjects (odds ratio 3.1, 95% CI 1.2–7.8), suggesting a possible genetic component to retinopathy severity.31
40 |
D.G. Telander et al. |
|
|
In a Mexican-American cohort, more severe diabetic retinopathy in siblings was associated with more severe retinopathy in probands (OR 1.72, 95% CI 1.03–2.88) after accounting for the effects of glycemic control and diabetic duration, but occurrence of diabetic retinopathy showed no such familial aggregation.32
2.4.2 Molecular Genetic Studies
Some of the more important candidate genes and associated polymorphisms linked to diabetic retinopathy will be reviewed below. Tables 2.1, 2.2, 2.3, 2.4, 2.5, and 2.6 list selected polymorphisms, genotypes, and haplotypes found to be risk factors, protective factors, or unassociated with different forms of DR. Inspection of the tables will show multiple inconsistencies across studies for such reasons as differences in case definitions, differences in duration of diabetes in the groups studied, in fractions of the two genders, in allele frequencies in the population samples, in methods of detecting DR grading severity of DR, in the recording and statistical handling of possibly confounding risk factors, and in the control groups used.6,9 For example, the -634C/G polymorphism in the promoter region of
the VEGF gene has been found to be associated with DR and also to be not associated with DR.33–35
Many of the listed genetic associations with forms of diabetic retinopathy have not been replicated, and much work remains to be done in diverse human population samples to identify the strong associations from the weak ones and to exclude spurious associations caused by various weaknesses in study designs.9 The tables we have included are rapidly changing and will be outdated within a short time as further genetic studies of greater statistical power and higher design quality are executed and published.
suggested a diabetic nephropathy locus on chromosome 3q.37–39 In addition, several researchers have
found a locus at chromosome 7q21 associated with an increased risk of nephropathy in diabetes.37,40–42
In this region of chromosome 7q21, Zhang and colleagues found that the T allele of an SNP rs1617640 in the promoter of the EPO gene was significantly associated with PDR and ESRD.43 Of note, EPO encodes the protein erythropoietin, which is a potent angiogenic factor expressed in the kidney and retina. This protein has been found in human vitreous in PDR.44
2.4.4 Aldose Reductase Gene
Hyperglycemia is clearly linked to the microvascular complications of diabetes, and the conversion of glucose to sorbitol by aldose reductase (ALR2) has been shown to be involved in the pathogenesis (see Chapter 1). ALR2 is found in tissues of the eye including the vascular endothelial and retinal pigment epithelial cells.45 Altered expression of the ALR2 gene may play a role in the pathogenesis of diabetic retinopathy. Genetic studies using restriction fragment length polymorphism (RFLP) analysis have inconsistently shown that aldose reductase is associated with diabetic retinopathy (Tables 2.1 and 2.6). Ko et al. have identified one allele (Z–2) of a (CA)n dinucleotide repeat polymorphic marker at the 50 end of the aldose reductase gene in Chinese type 2 diabetic patients having a strong association with early onset of diabetic retinopathy. In Asian Indians as well, the Z–2 allele was found to be associated with any DR, PDR, and DME.46 In Australian type 1 adolescent diabetics, the ALR promoter -106C allele is associated with DR, as is the Z–2 allele.47
2.4.3 EPO Promoter
PDR has been found to have 80–90% concordance rate with end-stage renal disease (ESRD).36 Several candidate gene single-nucleotide polymorphisms (SNPs) have been found and linkage analysis has
2.4.5 VEGF Gene
Vascular endothelial growth factor (VEGF) has been found to be the primary stimulus for new blood vessel growth and vascular hyperpermeability in diabetic retinopathy.48,49 Many clinical studies have demonstrated that VEGF concentrations were markedly elevated in both the vitreous and aqueous fluid of
Table 2.1 Genetic markers associated with any diabetic retinopathy (i.e., risk markers)
|
|
Type DM, |
Odds ratio (95% CI), |
|
|
|
|
Genetic marker |
Polymorphism |
ethnicity, N |
sample size |
X2 |
P |
References |
|
|
634CC* |
|
|
|
|
|
Awata et al.33 |
VEGF gene |
2, Japanese, 268 |
3.20 (1.45, 7.05) |
|
|
0.0046 |
||
Promoter region of |
Genotype for (CA) repeat:Z–2/X where |
1, British, 322 |
|
17.0 |
<0.0001 |
Demaine et al.75 |
|
|
n |
|
|
|
|
|
|
aldose reductase gene |
X is any allele other than Z+2 |
|
|
|
|
|
|
Promoter region of |
Z–2 allele for (CA)n repeat |
2, Asian Indian, 214 |
2.023 (1.06, 3.85)** |
|
|
0.029 |
Kumaramanickavel |
aldose reductase gene |
|
|
|
|
|
|
et al.46 |
Promoter region of |
Z–4 allele for (CA)n repeat |
T2, Chinese, 384 |
2.44 (1.20, 4.98)** |
|
|
<0.05 |
Lee et al.76 |
aldose reductase gene |
|
|
|
|
|
|
|
Promoter region of |
Z–2 allele |
1, Australian, 164 |
5.49 (3.39, 8.90)** |
|
|
<0.0005 |
Kao et al.47 |
aldose reductase gene |
106CC genotype |
|
|
|
|
|
|
Promoter region of |
1, Australian, 164 |
2.47 (1.30, 4.67) |
|
|
0.005 |
Kao et al.47 |
|
aldose reductase gene |
|
|
|
|
|
|
|
(CA)n IGF-1 gene |
Heterozygosity for the 192 or 194 base pair |
2, Dutch, 1,146 |
1.8 (1.0, 3.2) |
|
|
0.04 |
Rietveld et al.55 |
promoter |
alleles |
|
|
|
|
|
|
polymorphism |
|
|
|
|
|
|
|
SDH |
G-888C |
2, Polish, 154 |
1.73 (1.06, 2.83) for NPDR |
|
|
<0.05 |
Szaflik et al.77 |
Mitochondrial DNA |
Haplogroup T |
T2, Austrian,149 |
3.60 (1.02, 12.68) |
|
|
0.046# |
Kofler et al.78 |
haplogroups |
|
|
|
|
|
|
|
Endothelial nitric oxide |
Intron 4b/b genotype |
T2, West African, 384 |
2.4 (1.39, 4.09) |
|
|
0.0013 |
Chen et al.66 |
synthase gene |
|
|
|
|
|
|
|
eNOS promoter |
Haplotypes 112 (Glu298/4b/ |
2, Tunisian, 383 |
112 (1.34 [1.03, 1.73]) and 222 |
|
|
112 |
Ezzidi et al.79 |
|
-786C) and 222 (Asp298/4a/ |
|
(2.55 [1.01, 6.44]) |
|
|
(P ¼ 0.027) |
|
|
-786C) |
|
|
|
|
and 222 |
|
|
|
|
|
|
|
(P ¼ 0.048) |
|
Inducible nitric oxide |
Pentanucleotide STR |
T2, Asian Indian, 199 |
2.03 (0.96, 4.35) |
|
|
0.044 |
Kumaramanickavel |
synthase |
upstream of transcription start site (allele |
|
|
|
|
|
et al.80 |
|
210 bp) |
|
|
|
|
|
|
Receptor for AGE gene |
-429C allele |
2, Caucasian, 215 |
2.33 (1.30, 4.16)** |
|
|
0.012 |
Hudson et al.81 |
promoter region |
|
|
|
|
|
|
|
Manganese superoxide |
VV genotype of theV16A polymorphism |
2, Slovenian, 426 |
2.1 (1.2, 3.4) |
|
|
0.006 |
Petrovic et al.82 |
dismutase gene |
|
|
|
|
|
|
|
Methylene |
C677T polymorphism |
2, Japanese, 131 with |
5.33 (1.50,19.0) for NPDR |
|
|
<0.05 |
Maeda et al.74 |
tetrahydrofolate |
|
HbA1c 6.5% |
|
|
|
|
|
reductase gene |
|
|
|
|
|
|
|
*At position 634 relative to the transcription start of the VEGF gene, C is present on both alleles.
#When subjected to a Bonferroni correction, the statistical significance vanished. **Not given in paper; calculated by DJB from data in the paper.
Retinopathy Diabetic and Genetics 2
41
42 |
|
|
|
|
D.G. Telander et al. |
|
|
|
|
|
|||
Table 2.2 Genetic markers associated with diabetic macular edema (i.e., risk markers) |
|
|
|
|||
|
|
|
|
|
|
|
|
|
Type DM, |
Odds ratio (95% CI), |
|
|
|
Genetic marker |
Polymorphism |
ethnicity, N |
sample size |
X2 |
P |
References |
VEGF gene |
C-634G* |
2, Japanese, |
1.81 (1.01, 3.26) |
|
0.047 |
Awata |
|
|
378 |
|
|
|
et al.83 |
Endothelial nitric oxide |
Intron 4a allele |
2, Japanese, |
|
NG |
0.006 |
Awata |
synthase gene |
|
226 |
|
|
|
et al.84 |
Endothelial nitric oxide |
T-786C polymorphism |
2, Japanese, |
|
NG |
0.029 |
Awata |
synthase gene |
(-786C allele) |
226 |
|
|
|
et al.84 |
*At position 634 relative to the transcription start of the VEGF gene, G is present on one allele and C is present on the other. NG=not given.
Table 2.3 Genetic markers associated with severe nonproliferative or proliferative diabetic retinopathy (i.e., risk markers)
|
|
|
Odds ratio (95% |
|
|
|
|
Polymorphism/genotype/ |
Type DM, |
CI) or Chi- |
|
|
|
Genetic marker |
haplotype |
ethnicity, N |
square statistics |
P |
References |
|
|
|
|
|
|
|
|
VEGF gene |
c.-160CC* genotype |
1 and 2, |
10.5 |
(2.3, 47.7) |
0.0003 |
Churchill et al.85 |
|
|
British, 106 |
|
|
|
|
VEGF gene |
c.-152AA genotype |
1 and 2, |
3.5 (1.5, 7.7) |
0.0022 |
Churchill et al.85 |
|
|
|
British, 106 |
|
|
|
|
VEGF gene |
c.-116AA genotype |
1 and 2, |
7.9 (3.1, 19.9) |
<0.0001 |
Churchill et al.85 |
|
|
|
British, 106 |
|
|
|
|
VEGF gene |
c.-406C allele |
1 and 2, |
2.5 (1.20, 5.23) |
0.027 |
Ray et al.51 |
|
|
|
British,267 |
|
|
|
|
VEGF gene |
-160C/-152A/-116A |
1 and 2, |
3.34 |
(1.89, 5.91) |
0.0001695 |
Churchill et al.85 |
|
haplotype |
British, 106 |
|
|
1.62 10 5 |
|
VEGF gene |
-460C/-417T/-172C/- |
1 and 2, |
29.9 |
(3.91, 229) |
Churchill et al.85 |
|
|
165C/-160C/-152A/- |
British, 106 |
|
|
|
|
|
141A/-116A/+405C |
|
|
|
|
|
|
haplotype |
|
|
|
|
|
VEGF gene |
c.-634CC |
2, Caucasian, |
1.85 |
(1.2, 2.8) |
0.04 |
Errera et al.34** |
|
|
501 |
|
|
|
|
VEGF gene |
Homozygosity for rs833070 |
1, Japanese, |
1.67 |
(1.01, 2.54) |
0.047 |
Nakanishi and |
|
|
175 |
|
|
|
Watanabe86 |
VEGF gene |
Homozygosity for |
1, Japanese, |
1.67 |
(1.01, 2.74) |
0.047 |
Nakanishi and |
|
rs2146323 |
175 |
|
|
|
Watanabe86 |
Promoter region of |
-2578 A/A genotype |
2, Japanese, |
7.7 (1.8, 30.9) |
0.002 |
Nakamura et al.52 |
|
VEGF gene |
|
469 |
|
|
|
|
Promoter region of the |
Homozygous for T allele of |
1 and 2, US |
2.01 |
(1.23,3.29) |
0.036 |
Tong et al.43 |
erythropoietin gene |
an SNP rs1617640 |
Caucasian, |
|
|
|
|
|
|
613 |
|
|
|
|
TNF beta gene |
Allele 8 (111 base pair) |
2, Asian |
NG |
|
0.003 |
Kumaramanickavel |
|
|
Indian,207 |
|
|
|
et al.93 |
PPARG gene |
-2819G allele |
2, Italian, 112 |
2.30 |
(1.09–4.83) |
0.02 |
Costa et al.87 |
|
|
females |
|
|
|
|
ICAM-1 gene |
EE genotype of K469E |
2, Slovenian, |
2.0; 95% |
0.013 |
Petrovic et al.82 |
|
426confidence interval [CI]
¼1.1–3.5
Basic fibroblast growth |
-553T/A |
2, Slovenian, |
2.0, 95% |
0.03 |
Petrovicˇet al.88 |
factor (bFGF) gene |
|
206 |
confidence |
|
|
|
|
|
interval |
|
|
Solute carrier family 2, |
rs841846 |
1, African |
¼ 1.0–3.9 |
0.000160 |
10 |
LR |
Roy et al. |
||||
member 1 |
|
American, |
|
|
|
|
|
437 |
|
|
|
|
|
|
|
|
|
2 Genetics and Diabetic Retinopathy |
|
|
|
43 |
|
|
|
|
|
|
|
Table 2.3 (continued) |
|
|
|
|
|
|
|
|
Odds ratio (95% |
|
|
|
Polymorphism/genotype/ |
Type DM, |
CI) or Chi- |
|
|
Genetic marker |
haplotype |
ethnicity, N |
square statistics |
P |
References |
|
|
|
|
|
|
Major histo |
rs2523608 |
1, African |
LR |
0.00599 |
Roy et al.10 |
compatibility complex, |
|
American, |
|
|
|
class 1, B |
|
437 |
|
|
|
Major histo |
*0201/0302 genotype |
1, Swedish, 56 |
X2=15 |
0.01 |
Agardh et al.56 |
compatibility |
|
|
|
|
|
complex, DQA1 locus |
|
|
|
|
|
FMS-like tyrosine |
rs622227 |
1, African |
LR |
0.00735 |
Roy et al.10 |
kinase 1 |
|
American, |
|
|
|
|
|
437 |
|
|
|
Angiotensin convertin |
DD genotype |
2, Tunisian, |
3.516 |
0.001 |
Feghhi et al.70 |
enzyme insertion/ |
|
230 |
|
|
|
deletion |
|
|
|
|
|
polymorphism |
|
|
|
|
|
|
|
|
|
|
|
*At position 160 relative to the transcription start of the VEGF gene, C is present on both alleles. **Other studies in other populations have not confirmed this association.33,89
LR ¼ logistic regression was used rather than odds ratios. NG ¼ not given in the paper.
Table 2.4 Genetic markers associated with sight-threatening retinopathy (diabetic macular edema or proliferative diabetic retinopathy)
|
|
|
Odds ratio (95% CI), |
|
|
Genetic marker |
Polymorphism |
Type DM, ethnicity, N |
sample size |
P |
References |
|
|
|
|
|
|
AGER gene |
c.-374A |
1, Scandinavian, 742; 2, |
1.65 (1.11–2.45); 2957 |
0.01 |
Lindholm et al.90 |
polymorphism |
|
Scandinavian, 2957 |
DR, |
|
|
|
|
|
206 NDC |
|
|
Polymorphism for |
Z–2 allele |
2, Asian Indian, 214 |
NG |
0.004 |
Kumaramanickavel |
(CA)n repeat in |
|
|
|
|
et al.46 |
promoter region of |
|
|
|
|
|
aldose reductase gene |
|
|
|
|
|
|
|
|
|
|
|
C=Caucasian; NDC=non-diabetic controls; NG=not given in the paper.
Table 2.5 Genetic markers associated with diabetes without retinopathy (i.e., protective markers)
|
|
|
Odds ratio |
|
|
|
|
|
Type DM, |
(95% CI), |
|
|
|
Genetic marker |
Polymorphism |
ethnicity, N |
sample size |
X2 |
P |
References |
VEGF genotype |
c.-160CT* |
1 and 2, |
8.63 (1.96, |
|
0.0008 |
Churchill et al.85 |
|
|
British, 106 |
37.95) |
|
|
|
|
c.-152AG |
1 and 2, |
1.87 (1.04, |
|
0.0353 |
Churchill et al.85 |
|
|
British, 106 |
3.35) |
|
|
|
|
c.-116AG |
1 and 2, |
4.8 (2.6, 8.8) |
|
<0.0001 |
Churchill et al.85 |
|
|
British, 106 |
|
|
|
|
VEGF gene haplotype |
-160T/-152G/-116G |
1 and 2, |
12.5 (1.61, |
|
0.006181 |
Churchill et al.85 |
associations |
|
British, 106 |
100) |
|
|
|
|
-460C/-417T/-172C/- |
1 and 2, |
20 (2.86, 100) |
|
0.000373 |
Churchill et al.85 |
|
165C/-160C/-152A/- |
British, 106 |
|
|
|
|
|
141A/-116G/+405G |
|
|
|
|
|
Genotype for (CA)n |
Z+2/Y where Y is any |
1, Caucasian, |
|
30.1 |
<0.00001 |
Demaine et al.75 (see |
repeat in promoter |
allele other than Z–2 |
229 |
|
|
|
also91,92 |
region of aldose reductase gene
44 |
|
|
|
|
|
|
D.G. Telander et al. |
|
|
|
|
|
|
|
|
Table 2.5 (continued) |
|
|
|
|
|
|
|
|
|
|
|
Odds ratio |
|
|
|
|
|
Type DM, |
(95% CI), |
|
|
|
|
Genetic marker |
Polymorphism |
ethnicity, N |
sample size |
X2 |
P |
References |
|
EDN1 Lys198Asn |
EDN1 Asn/Asn |
2, Chinese, |
0.19 (0.07, |
|
0.002 |
Li et al.21 |
|
polymorphism |
|
343 |
|
0.53), 216 |
|
|
|
|
|
|
|
DR, 127 |
|
|
|
|
|
|
|
DM |
|
|
|
|
|
|
|
controls |
|
P ¼ 0.015 |
|
Endothelial nitric |
(haplotype 122 (Glu298/ |
2, Tunisian, |
0.51 (0.30, |
|
Ezzidi et al.79 |
||
oxide (eNOS) gene |
4a/-786C)] |
383 |
|
0.88) |
|
|
|
promoter |
|
|
|
|
|
|
|
TNF-b gene |
STR upstream of |
2, Asian |
|
0.236 (0.087, |
|
0.002 |
Kumaramanickavel |
|
promoter region: allele |
Indians, |
0.638)** |
|
|
et al.93 |
|
|
4 (103 base pair) with |
207 |
|
|
|
|
|
|
(GT)9 repeat |
|
|
|
|
|
|
SUMO4 gene |
M55V |
1, Caucasian, |
0.37, (0.32, |
|
0.004 |
Rudofsky et al. 94 |
|
|
|
223 |
|
0.43) |
|
|
|
Plasminogen activator |
5G/5G genotype |
2, Pima |
|
|
8.22 |
0.016 |
Nagi et al.95 |
inhibitor 1 gene |
|
Indians, |
|
|
|
|
|
|
|
171 |
|
|
|
|
|
Receptor for AGE |
GS genotype for the |
2, Asian |
|
0.34 (0.136, |
|
0.03 |
Kumaramanickavel |
gene |
Gly82Ser |
Indians, |
0.863)** |
|
|
et al.64 |
|
|
polymorphism in exon |
200 |
|
|
|
|
|
|
3 (Ser 82 allele) |
|
|
|
|
|
|
|
|||||||
*At position 160 relative to the transcription start of the VEGF gene, C is present on one allele and T on the other allele. |
|||||||
**Not given in paper; calculated by DJB from data in the paper. |
|
|
|
|
|
||
Table 2.6 Negative studies looking for associations with various forms of diabetic retinopathy |
|
||||||
|
|
|
|
|
|
|
|
|
Specific polymorphisms (P) and |
|
|
Type |
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Genetic marker |
haplotypes (H) |
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Type DM, ethnicity, N |
retinopathy |
References |
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MMP-2 gene |
-168G/T, -735 C/T, -790T/G, - |
2, Czech, 490 |
PDR |
|
Beranek et al.96 |
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1306C/T, and -1575G/A |
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MMP-9 gene |
-1562C/T, R279Q |
|
2, Czech, 490 |
PDR |
|
Beranek et al.96 |
|
IL-6 gene promoter |
-174G>C variant |
|
1 and 2, German, 733 |
Any DR |
Rudofsky et al. 97 |
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Promoter region of VEGF |
-634C/G polymorphism |
|
2, Japanese, 469 |
PDR |
|
Nakamura et al.52 |
|
gene |
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Promoter region of VEGF |
-634C/G polymorphism |
|
2, Asian Indian, 208 |
Any DR |
Uthra et al.35 |
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gene |
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Promoter region of VEGF |
-634C/G polymorphism |
|
2, Slovenian, 555 |
PDR |
|
Petrovic et al.98 |
|
gene |
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Tumor necrosis factor |
rs1800629, rs1041981, and |
2, Chinese, 194 |
Any DR |
Wang et al.99 |
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gene |
rs2857713 polymorphisms |
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Endothelial nitric oxide |
G894T polymorphism |
|
2, West African, 384 |
Any DR |
Chen et al.66 |
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synthase gene |
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Endothelial nitric oxide |
Intron 4a/b polymorphism |
2, Japanese, 215 |
Any DR |
Neugebauer |
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synthase gene |
|
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|
|
|
et al.100 |
Receptor for AGE gene |
Gly82Ser polymorphism in |
2, Chinese, 156 |
Any DR |
Liu and Xiang63 |
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exon 3 (Ser 82 allele) |
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Receptor for AGE gene |
-429T/C polymorphism |
|
2, Caucasian, 215 |
Any DR |
Hudson et al.101 |
||
promoter region |
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Angiotensin II type 1 |
A1166C polymorphism |
|
2, Chinese, 827 |
Any DR |
Thomas et al.102 |
||
receptor gene |
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Angiotensin I-converting |
287 base pair Alu-repetitive |
1 and 2, diverse, 2010 |
Any DR |
Fujisawa et al.68 |
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enzyme gene |
sequence in intron 16 |
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insertion/deletion |
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polymorphism |
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Hereditary |
C282Y polymorphism |
|
2, Australian,1245 |
Any DR |
Davis et al.103 |
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hemochromatosis gene |
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