Polymorphisms in <i>TIE2</i> and <i>ANGPT-1</i> genes are associated with protection against diabetic retinopathy in a Brazilian population

Dieter, Cristine; Lemos, Natália Emerim; de Faria Corrêa, Nathalia Rodrigues; Assmann, Taís Silveira; Pellenz, Felipe Mateus; Canani, Luís Henrique; Brondani, Letícia de Almeida; Bauer, Andrea Carla; Crispim, Daisy

doi:10.20945/2359-3997000000624

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Original Article • Arch. Endocrinol. Metab. 67 (5) • 2023 • https://doi.org/10.20945/2359-3997000000624 copy

Polymorphisms in TIE2 and ANGPT-1 genes are associated with protection against diabetic retinopathy in a Brazilian population

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Objective:

The objective of this study was to investigate the association between SNPs in the TIE2 and ANGPT-1 genes and diabetic retinopathy (DR).

Subjects and methods:

This study comprised 603 patients with type 2 diabetes mellitus (T2DM) and DR (cases) and 388 patients with T2DM for more than 10 years and without DR (controls). The TIE2 rs639225 (A/G) and rs638203 (A/G) SNPs and the ANGPT-1 rs4324901 (G/T) and rs2507800 (T/A) SNPs were genotyped by real-time PCR using TaqMan MGB probes.

Results:

The G/G genotype of the rs639225/TIE2, the G/G genotype of the rs638203/TIE2 and the T allele of the rs4324901/ANGPT-1 SNPs were associated with protection against DR after adjustment for age, glycated hemoglobin, gender, and presence of hypertension (P = 0.042, P = 0.003, and P = 0.028, respectively). No association was found between the rs2507800/ANGPT-1 SNP and DR.

Conclusion:

We demonstrated, for the first time, the association of TIE2 rs638203 and rsrs939225 SNPs and ANGPT-1 rs4324901 SNP with protection against DR in a Brazilian population.

Keywords
ANGPT-1 gene; TIE2 gene; polymorphism; type 2 diabetes mellitus; diabetic retinopathy

Characteristics	Patients with T2DM		P ^* * P value was computed using Student's t-tests or x2 tests, as appropriate. T2DM: type 2 diabetes mellitus; BMI: body mass index; DR: diabetic retinopathy; HDL: high-density lipoprotein; LDL: low-density lipoprotein; eGFR: estimated glomerular filtration rate; HbA1c: glycated hemoglobin; T2DM: type 2 diabetes mellitus; UAE: urinary albumin excretion.
Characteristics	Without DR n = 388	With DR n = 603
Age (years)	69.4 ± 10.5	65.8 ± 10.5	0.0001
Gender (% male)	37.4	51.6	0.0001
BMI (kg/m²)	29.0 ± 5.1	28.2 ± 5.2	0.017
Ethnicity (% non-white)	18.4	25.2	0.017
HbA1c (%)	7.4 ± 1.8	7.8 ± 2.1	0.005
Hypertension (%)	82.3	91.2	0.0001
Duration of diabetes (years)	20.6 ± 8.8	20.6 ± 9.6	0.935
Cholesterol total (mg/dL)	194.9 ± 49.6	198.3 ± 51.3	0.340
Triglycerides (mg/dL)	148.0 (103.5-209.0)	149.0 (102.0-215.0)	0.818
HDL cholesterol (mg/dL)	46.5 ± 12.6	45.3 ± 14.0	0.163
LDL cholesterol (mg/dL)	112.7 ± 43.5	119.2 ± 46.4	0.045
eGFR (mL/min per 1.73 m²)	74.0 (51.0-90.0)	53.0 (16.0-76.0)	0.0001
UAE (mg/g)	8.3 (3.1-36.6)	53.1 (8.6-369.6)	0.0001
Diabetic kidney disease (%)	48.4	75.7	0.0001

	Patients with DM (controls)	Patients with DR (cases)	Unadjusted P^* * P-values were calculated using x2 tests.	Adjusted OR (95% CI) /^† † P-values and OR (95% CI) obtained using logistic regression analyses adjusting for age, gender, HbA1c, and presence of hypertension. DM: diabetes mellitus; DR: diabetic retinopathy; OR: odds ratio; CI: confidence interval. P
*rs639225 – TIE2*	368	547
Genotype
A/A	119 (32.3)	193 (35.3)		1
A/G	157 (42.7)	244 (44.6)		0.886 (0.622-1.264)/0.505
G/G	92 (25.0)	110 (20.1)	0.211	0.642 (0.419-0.984)/0.042
Allele
A	0.54	0.58
G	0.46	0.42	0.107
Recessive model
A/A + A/G	276 (75.0)	437 (79.9)		1
G/G	92 (25.0)	110 (20.1)	0.095	0.687 (0.471-1.001)/0.051
Additive model
A/A	119 (56.4)	193 (63.7)		1
G/G	92 (43.6)	110 (36.3)	0.115	0.643 (0.419-0.986)/0.043
Dominant model
A/A	119 (32.3)	193 (35.3)		1
A/G + G/G	249 (67.7)	354 (64.7)	0.395	0.798 (0.575-1.108)/0.178
rs638203 – TIE2	368	562
Genotype
A/A	118 (32.1)	197 (35.1)		1
A/G	156 (42.4)	260 (46.3)		0.921 (0.645-1.313)/0.648
G/G	94 (25.5)	105 (18.7)	0.046	0.523 (0.340-0.804)/0.003
Allele
A	0.53	0.58
G	0.47	0.42	0.040
Recessive model
A/A + A/G	274 (74.5)	457 (81.3)		1
G/G	94 (25.5)	105 (18.7)	0.016	0.548 (0.376-0.800)/0.002
Additive model
A/A	118 (55.7)	197 (65.2)		1
G/G	94 (44.3)	105 (34.8)	0.036	0.527 (0.343-0.812)/0.004
Dominant model
A/A	118 (32.1)	197 (35.1)		1
A/G + G/G	250 (67.9)	365 (64.9)	0.384	0.770 (0.554-1.070)/0.119
rs4324901 – ANGPT-1	354	532
Genotype
G/G	152 (42.9)	271 (50.9)		1
G/T	149 (42.1)	194 (36.5)		0.724 (0.514-1.019)/0.064
T/T	53 (15.0)	67 (12.6)	0.064	0.640 (0396-1.034)/0.068
Allele
G	0.64	0.69
T	0.36	0.31	0.026
Recessive model
G/G + G/T	301 (85.0)	465 (87.4)		1
T/T	53(15.0)	67(12.6)	0.361	0.742 (0.473-1.166)/0.196
Additive model
G/G	152 (74.1)	271 (80.2)		1
T/T	53 (25.9)	67 (19.8)	0.125	0.651 (0.402-1.053)/0.080
Dominant model
G/G	152 (42.9)	271 (50.9)		1
G/T + T/T	202 (57.1)	261 (49.1)	0.023	0.701 (0.510-0.963)/0.028
rs2507800 – ANGPT-1	356	547
Genotype
T/T	154 (43.3)	246 (45.0)		1
T/A	142 (39.9)	221 (40.4)		0.1030 (0.733-1.448)/0.865
A/A	60 (16.9)	80 (14.6)	0.656	0.832 (0.523-1.323)/0.437
Allele
T	0.63	0.65
A	0.37	0.35	0.421
Recessive model
T/T + T/A	296 (83.1)	467 (85.4)		1
A/A	60 (16.9)	80 (14.6)	0.418	0.820 (0.531-1.267)/0.371
Additive model
T/T	154 (72.0)	246 (75.5)		1
A/A	60 (28.0)	80 (24.5)	0.420	0.835 (0.523-1.333)/0.449
Dominant model
T/T	154 (43.3)	246 (45.0)		1
T/A + A/A	202 (56.7)	301 (55.0)	0.661	0.972 (0.709-1.333)/0.861
Haplotype ANGPT-1	331	494
0-2 mutated alleles	262 (79.2)	418 (84.6)		1
3-4 mutated alleles	69 (20.8)	76 (15.4)	0.054	0.602 (0.392-0.925)/0.021

	T2DM patients without DKD	DKD patients	Unadjusted P^* * P-values were calculated using x2 tests.	Adjusted OR (95% IC) /^† † P-values and OR (95% CI) obtained using logistic regression analyses adjusting for age, gender, HbA1c, presence of hypertension and diabetic retinopathy. P
rs639225 – TIE2	337	742
Genotype
A/A	114 (33.9)	263 (35.4)	0.224	1
A/G	140 (41.5)	331 (44.7)		1.081 (0.756-1.546)/0.669
G/G	83 (24.6)	148 (19.9)		0.976 (0.633-1.504)/0.912
Allele
A	0.55	0.58	0.186	-
G	0.45	0.42
Recessive model
A/A + A/G	254 (75.4)	594 (80.1)	0.097	1
G/G	83 (24.6)	148 (19.9)		0.935 (0.63-1.373)/0.730
Additive model
A/A	114 (57.9)	263 (64.0)	0.172	1
G/G	83 (42.1)	148 (36.0)		0.939 (0.609-1.446)/0.774
Dominant model
A/A	114 (33.8)	263 (35.4)	0.655	1
A/G + G/G	223 (66.2)	479 (64.6)		1.046 (0.752-1.454)/0.791
rs638203 – TIE2	349	761
Genotype
A/A	119 (34.1)	264 (34.7)	0.088	1
A/G	143 (41.0)	350 (46.0)		1.159 (0.814-1.650)/0.412
G/G	87 (24.9)	147 (19.3)		0.912 (0.595-1.398)/0.672
Allele
A	0.55	0.58	0.185	-
G	0.45	0.42
Recessive model
A/A + A/G	262 (75.1)	614 (80.7)	0.040	1
G/G	87 (24.9)	147 (19.3)		0.839 (0.574-1.226)/0.365
Additive model
A/A	119 (57.8)	264 (64.2)	0.141	1
G/G	87 (42.2)	147 (35.8)		0.868 (0.566-1.332)/0.518
Dominant model
A/A	119 (34.1)	264 (34.7)	0.900	1
A/G + G/G	230 (65.9)	497 (65.3)		1.073 (0.775-1.487)/0.671
rs4324901 – ANGPT-1	331	726
Genotype
G/G	151 (45.6)	353 (48.6)	0.645	1
G/T	133 (40.2)	279 (38.5)		0.897 (0.634-1.268)/0.539
T/T	47 (14.2)	94 (12.9)		1.289 (0.790-2.103)/0.309
Allele
G	0.66	0.68	0.115	-
T	0.34	0.32
Recessive model
G/G + G/T	284 (85.8)	632 (87.1)	0.647	1
T/T	47 (14.2)	94 (12.9)		1.355 (0.853-2.152)/0.198
Additive model
G/G	151 (76.3)	353 (79.0)	0.506	1
T/T	47 (23.7)	94 (21.0)		1.328 (0.807-2.184)/0.264
Dominant model
G/G	151 (45.6)	353 (48.6)	0.401	1
G/T + T/T	180 (54.4)	373 (51.4)		0.990 (0.718-1.364)/0.951
rs2507800 – ANGPT-1	335	739
Genotype
T/T	150 (44.8)	313 (42.4)	0.270	1
T/A	129 (38.5)	321 (43.4)		1.256 (0.888-1.776)/0.197
A/A	56 (16.7)	105 (14.2)		1.231 (0.765-1.981)/0.391
Allele
T	0.64	0.64	0.976	-
A	0.36	0.36
Recessive model
T/T + T/A	279 (83.3)	634 (85.8)	0.330	1
A/A	56 (16.7)	105 (14.2)		1.103 (0.706-1.723)/0.666
Additive model
T/T	150 (72.8)	313 (74.9)	0.648	1
A/A	56 (27.2)	105 (25.1)		1.269 (0.780-2.063)/0.337
Dominant model
T/T	150 (44.8)	313 (42.4)	0.499	1
T/A + A/A	185 (55.2)	426 (57.6)		1.249 (0.907-1.722)/0.174

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[1] Correspondence to: Daisy Crispim, Rua Ramiro Barcelos, 2.350, prédio 12, 4° andar 90035-003 – Porto Alegre, RS, Brasil. dcmoreira@hcpa.edu.br