Polymorphisms in glucose homeostasis genes are associated with cardiovascular and renal parameters in patients with diabetic nephropathy

Figures & data

Table 1. Demographic and clinical characteristics of the population of study.

	Controls	DN
N	506	318
Age (yrs)	57 (17)	63 (18)***
Men	274 (54.2)	208 (65.4)**
BMI (kg)	27.8 (5.33)	29.12 (7.95)**
Albumin/Creatinine (mg/g)	7.2 (45.12)	186.41 (841.56)***
eGFR (ml/min/1.73m2)	89.19 (21.8)	29.43 (21.2)***
Stage of CKD
3		120 (37.7)
4-5		125 (39.3)
Dialysis		73 (23.0)
Smoking
Non-smoker	195 (38.5)	123 (38.7)
Current-smoker	106 (20.9)	66 (20.8)
′Former-smoker	205 (40.5)	129 (40.6)
Hypertension
No	325 (64.2)	4 (1.3)
Yes	181 (35.8)	314 (98.7)***
Hyperlipidaemia
No	327 (64.6)	58 (18.2)
Yes	179 (35.4)	260 (81.8)***
Pulse pressure (mmHg)	51 (16)	70 (27)***
Systolic blood pressure (mmHg)	132 (24)	150 (33)***
Dyastolic blood pressure (mmHg)	80 (14)	79.5 (16)
Triglycerides (mg/dL)	100 (68)	130 (89)***
Total cholesterol (mg/dL)	203.2 ± 34.74	170.38 ± 38.26*
LDL-Cholesterol (mg/dL)	126.68 ± 32.03	94.86 ± 34.17
HDL-Cholesterol (mg/dL)	51.1 (20)	44 (18)***
Calcium (mg/dL)	9.4 (0.55)	9.3 (0.74)***
Phosphorus (mg/dL)	3.49 (0.79)	4 (1.33)***
Calcium-phosphorus product	29.07 (47.44)	37.2 (11.15)***
Glycated haemoglobin (%)	5.6 (0.9)	7.1 (1.8)***
Fasting sugar (mg/dL)	97 (19)	139.5 (80)***
TyG	8.48 (0.80)	9.07 (0.96)***
Insulin	6 (1.2)	244 (76.7)***
ACEi	43 (8.5)	101 (31.8)***
ARBs	100 (19.8)	200 (62.9)***
Oral hypoglycaemic agents	45 (8.9)	102 (32.1)***
CCIMT (mm)	0.71 (0.21)	0.76 (0.23)***
CV Event
No	497 (98.2)	253 (79.6)
Yes	9 (1.8)	65 (20.4)***
Presence of plaque
No	229 (45.3)	57 (17.9)
Yes	277 (54.7)	261 (82.1)***

Data are shown as median (interquartile range), mean ± standard deviation or count and percentages in parenthesis.

BMI: body mass index; CCIMT: common carotid intimate media thickness; DN: diabetic nephropathy; eGFR: estimated glomerular filtration rate; TyG: Triglycerides and glucose index. ACEi: angiotensin converting enzyme inhibitors; ARBs: angiotensin II receptor blockers. *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 1. Estimated glomerular filtration rate (eGFR) values according to the presence of rs710218 (A), rs841848 (B) and rs3813008 (C) variants, and albumin-to-creatinine ratios (ACR) distributed by rs3758947 genotypes (D) in patients with diabetic nephropathy. Manhattan plots show the p-value for the association of all the SNPs studied regarding eGFR (E) and ACR (F). *p < 0.05.

Figure 2. Distribution of common carotid intima media thickness (CCIMT) values according to different genotypes of ABCC8 in patients with diabetic nephropathy. The Manhattan plot shows the p-value for the association of all the SNPs studied. *p < 0.05.

Table 2. Variables of interest in patients of diabetic nephropathy experiencing or not cardiovascular events.

	No CVE	CVE	p Value
N	253	65
Age (yrs)	63 (19)	64 (15)	0.293
Sex
Women	93 (36.8)	17 (26.2)	0.071
Men	160 (63.2)	48 (73.8)
BMI (kg)	28.67 (8.54)	29.28 (5.48)	0.908
ACR (mg/g)	170.2 (818)	259.11 (2179)	0.526
eGFR (ml/min)	29.52 (21.25)	27.78 (20.17)	0.514
Stage of CKD
3	98 (38.7)	22 (33.8)	0.244
4-5	102 (40.3)	23 (35.4)
Dialysis	53 (20.9)	20 (30.8)
Smoking
Non-smoker	100 (39.5)	23 (35.4)	0.718
Current-smoker	53 (20.9)	13 (20)
Former-smoker	100 (39.5)	29 (44.6)
Hypertension
No	2 (0.8)	2 (3.1)	0.187
Yes	251 (99.2)	63 (96.9)
Hyperlipidaemia
No	46 (18.2)	12 (18.5)	0.542
Yes	207 (81.8)	53 (81.5)
Pulse pressure (mmHg)	71.1 ± 20	73.23 ± 20.52	0.723
Systolic lood pressure (mmHg)	150.04 ± 23.54	153.54 ± 25.63	0.635
Dyastolic blood pressure (mmHg)	78.94 ± 11.50	80.31 ± 12.87	0.471
Total cholesterol (mg/dL)	168 (49)	164 (60)	0.803
Triglycerides and glucose index	9.11 ± 0.78	9.13 ± 0.71	0.458
CCIMT	0.76 (0.21)	0.83 (0.30)	p < 0.05
Presence of plaque
No	53 (20.9)	4 (6.2)	p < 0.01
Yes	200 (79.1)	61 (93.8)
Glucose (mg/dL)	139 (81)	149 (77)	0.706
Calcium (mg/dL)	9.3 (0.71)	9.1 (0.8)	0.453
Sodium (mEq/L)	140 (3)	140 (4)	0.662
Potassium (mEq/L)	4.92 ± 0.6	5.11 ± 0.63	0.496

ACR: albumin-to-creatinin ratio; CCIMT: common carotid intimate media thickness.

Figure 3. Kaplan–Meier curves depicting cardiovascular event-free survival in patients with diabetic nephropathy carrying the SLC2A2 rs8192675 (A) or SLC5A2 rs9924771 (B) polymorphisms.

Table 3. Cox regression analysis showing the effect of rs8192675 and rs9924771 on cardiovascular event-free survival in diabetic nephropathy patients.

	B	SE	Wald	OR	CI	p Value
rs8192675	−0.69	0.26	7.27	0.50	0.30-0.83	0.007
rs9924771	0.631	0.26	5.76	1.90	1.14-3.19	0.015
Age	0.012	0.01	1.09	1.01	0.99-1.3	0.297
Sex	0.461	0.30	2.43	1.59	0.89-2.83	0.119
BMI	−0.033	0.03	1.85	0.97	0.92-1.02	0.173
Hyperlipidaemia	0.156	0.33	0.23	1.17	0.62-2.22	0.634
CKD stage	0.533	0.18	8.93	1.71	1.20-2.42	0.003
Hypertension	−0.952	0.77	1.52	0.39	0.09-1.76	0.218

BMI: body mass index; CKD: chronic kidney disease.

Figure 4. Effect of interactions between SNPs in glucose homeostasis genes on several clinical phenotypes in CKD patients. Significant hits discussed in the text are highlighted in red. The diagonal line contains the P values from likelihood ratio test for the crude effect of each SNP, which are sorted by their genomic position. The upper triangle in the matrix contains the P values for the interaction (epistasis) log-likelihood ratio test. Finally, the lower triangle contains the P values from likelihood ratio test comparing the two-SNP additive likelihood to the best of the single-SNP models. eGFR: estimated glomerular filtration rate (ml/min/1.73 m²); ACR: albumin-to-creatinine ratio (mg/g); CV: cardiovascular; CCIMT: common carotid intima media thickness.

Data availability statement

The datasets underlying this article can be found at Figshare with DOI 10.6084/m9.figshare.20936788