The contribution of genetic variants of SLC2A1 gene in T2DM and T2DM-nephropathy: association study and meta-analysis

Figures & data

Table 1. Clinical profiles of the study-cohort.

Parameters	Case-control study population groups (n = 498)
	HC	DM	p Value*		DM-DN	DM + DN	p Value*
N	246	352	n.a.		155	197	n.a.
Sex [m; n (%)]	136 (55.3)	181 (51.4)	.361		74 (47.7)	107 (54.3)	.238
Age (years)	71 ± 9.2	68 ± 8.9	<.001		68 ± 9.1	69 ± 8.8	.427
DM duration (years)	n.a.	16.3 ± 8.0	n.a.		15.7 ± 8.3	16.8 ± 7.8	.508
HbA1c (%)	n.d.	7.35 ± 1.31	n.a.		7.20 ± 1.34	7.47 ± 1.29	.019
Insulin treatment (%)	n.a.	105 (29.8)	n.a.		50 (32.3)	55 (27.9)	.412
Hypertension (%)	0	224 (63.6)	<.001		98 (63.2)	126 (63.9)	.911
Cardiovascular disease (%)	0	110 (31.3)	<.001		41 (26.5)	69 (35.0)	.105
Creatinine (mg/dl)	0.77 ± 0.15	1.46 ± 1.37	<.001		0.90 ± 0.18	1.84 ± 1.67	<.001
Urea (mg/dl)	30 ± 7.9	59 ± 34	<.001		42 ± 13.6	71 ± 38.3	<.001
Albuminuria (mg/d)	n.d.	470 ± 856	n.a.		43.9 ± 53.3	782 ± 1019	<.001
Proteinuria (mg/d)	n.d.	788 ± 1468	n.a.		105 ± 80.0	788 ± 1468	<.001

Clinical profiles of the study-cohort, consisting of 195 cases (i.e., T2DM-nephropathy; DM + DN), 157 diseased controls (i.e., T2DM without nephropathy; DM-DN) and 246 healthy controls (HC). Continuous data are given as mean and standard deviation [x ± SD] and categorical data as count and percentage [n (%)].

* p Values were calculated by the Mann–Whitney U test for continuous variables or the χ² test for categorical variables as appropriate.

Table 2. Distribution of genotypes of SLC2A1 variants.

Variant	Genotype	DM + DN N (%)	DM-DN N (%)	HC N (%)	*p Value	**ORG (95% CI)
rs12407920	C C	154 (79.4)	124 (80.5)	212 (88.0)	.044	1.55 (1.09–2.19)
	C T	38 (19.6)	30 (19.5)	26 (10.8)
	T T	2 (1.0)	0 (0)	3 (1.2)
rs2297976	G G	122 (63.9)	96 (64.0)	153 (63.2)	.973	0.99 (0.76–1.29)
	G T	62 (32.5)	48 (32.0)	82 (33.9)
	T T	7 (3.7)	6 (4.0)	7 (2.9)
rs710221	G G	66 (34.6)	49 (33.3)	77 (32.9)	.930	0.98 (0.77–1.24)
	G A	89 (46.6)	74 (50.3)	118 (50.4)
	A A	36 (18.8)	24 (16.3)	39 (16.7)
rs2086856	A A	86 (44.8)	73 (48.7)	111 (46.6)	.369	1.11 (0.87–1.41)
	A G	80 (41.7)	64 (42.7)	108 (45.4)
	G G	26 (13.5)	13 (8.7)	19 (8.0)
rs12130264	C C	176 (90.3)	136 (89.5)	209 (87.1)	.492	0.80 (0.52–1.23)
	C T	17 (8.7)	16 (10.5)	30 (12.5)
	C C	2 (1.0)	0 (0.0)	1 (0.4)
rs841847	C C	86 (44.8)	71 (46.7)	147 (60.2)	.015	1.49 (1.16–1.89)
	C T	87 (45.3)	67 (44.1)	79 (32.4)
	T T	19 (9.9)	14 (9.2)	18 (7.4)
rs841853	C C	70 (36.3)	61 (41.2)	126 (52.3)	.018	1.46 (1.15–1.86)
	C A	99 (51.3)	69 (46.6)	91 (37.8)
	A A	24 (12.4)	18 (12.2)	24 (10.0)
rs3729548	C C	71 (36.8)	48 (32.9)	72 (30.0)	.240	0.78 (0.62–0.98)
	C T	94 (48.7)	69 (47.3)	113 (47.1)
	T T	28 (14.5)	29 (19.9)	55 (22.9)
rs841855	G G	129 (68.3)	113 (75.8)	169 (70.4)	.509	1.05 (0.79–1.41)
	G A	55 (29.1)	31 (20.8)	65 (27.1)
	A A	5 (2.6)	5 (3.4)	6 (2.5)
rs3768029	C C	54 (28.6)	32 (21.3)	65 (26.6)	.213	0.86 (0.68–1.08)
	C T	100 (52.9)	82 (54.7)	115 (47.1)
	T T	35 (18.5)	36 (24.0)	64 (26.2)
rs12071418	C C	189 (97.9)	147 (96.1)	231 (96.7)	.583	0.76 (0.36–1.58)
	C G	4 (2.1)	6 (3.9)	8 (3.3)
	G G	0 (0.0)	0 (0.0)	0 (0.0)
rs3820549	C C	102 (53.1)	86 (56.2)	124 (50.8)	.842	0.94 (0.74–1.20)
	C G	72 (37.5)	56 (36.6)	98 (40.2)
	G G	18 (9.4)	11 (7.2)	22 (9.0)
rs3820546	G G	49 (25.8)	42 (27.6)	70 (29.0)	.362	0.96 (0.77–1.20)
	G A	107 (56.3)	75 (49.3)	113 (46.9)
	A A	34 (17.9)	35 (23.0)	58 (24.1)
rs11537641	G G	131 (67.9)	107 (70.9)	159 (66.0)	.484	0.91 (0.69–1.20)
	G A	58 (30.1)	39 (25.8)	70 (29.0)
	A A	4 (2.1)	5 (3.3)	12 (5.0)

Distribution of genotypes of SLC2A1 variants among cases with T2DM-nephropathy (T2DM-nephropathy; DM + DN), diseased (T2DM without nephropathy; DM-DN) and healthy (HC) control subjects. *χ² p Values and **the generalized odds ratio (OR_G) with respective 95% confidence intervals (95% CI) calculated for testing the association between genotype distribution of each variant and disease progression. OR_G and p values are in bold in case of statistical significance.

Table 3. Association between SLC2A1 gene variants and T2DM- nephropathy for the additive and co-dominant models.

Variant	Genetic model	OR (95% CI)	*p-Value	ORadj. (95% CI)	#p-Value
rs12407920 C/T	Additive	0.92 (0.15–5.56)	0.926	0.69 (0.09-5.02)	.715
	Co-dominant	2.01 (1.17–3.45)	0.010	1.98 (1.14–3.43)	.015
rs2297976 G/T	Additive	1.25 (0.43–3.67)	0.679	1.17 (0.39–3.47)	.778
	Co-dominant	0.94 (0.63–1.40)	0.755	0.92 (0.61–1.38)	.677
rs710221 G/A	Additive	1.08 (0.61–1,88)	0.795	1.01 (0.56–1.81)	.987
	Co-dominant	0.86 (0.58–1.26)	0.432	0.85 (0.58–1.26)	.425
rs2086856 A/G	Additive	1.77 (0.92–3.40)	0.089	1.85 (0.94–3.65)	.075
	Co-dominant	0.86 (0.59–1.26)	0.441	0.85 (0.58–1.26)	.452
rs12130264 C/T	Additive	2.37 (0.21–26,41)	0.482	2.81 (0.25–31,79)	.403
	Co-dominant	0.67 (0.36 1.25)	0.209	0.72 (0.38–1.38)	.327
rs841847 C/T	Additive	1.80 (0.90–3.62)	0.097	1.77 (0.84–3.70)	.131
	Co-dominant	1.73 (1.17–2.56)	0.006	1.73 (1.16–2.58)	.007
rs841853 C/A	Additive	1.80 (0.95–3.40)	0.070	1.85 (0.94–3.61)	.073
	Co-dominant	1.74 (1.18–2.55)	0.005	1.75 (1.18–2.58)	.005
rs3729548 C/T	Additive	0.52 (0.29–0.90)	0.021	0.50 (0.28–0.92)	.025
	Co-dominant	1.07 (0.73–1.56)	0.737	1.06 (0.72–1.56)	.778
rs841855 G/A	Additive	1.09 (0.33–3,66)	0.887	1.04 (0.31–3.55)	.948
	Co-dominant	1.10 (0.72–1.69)	0.644	1.12 (0.73–1.73)	.608
rs3768029 C/T	Additive	0.66 (0.38–1.14)	0.135	0.65 (0.37–1,16)	.146
	Co-dominant	1.26 (0.86–1.84)	0.233	1.29 (0.87–1,90)	.202
rs12071418 C/G	Additive	**n.a.	**n.a.	**n.a.	**n.a.
	Co-dominant	0.61 (0.18–2.06)	0.427	0.59 (0.17–2.01)	.396
rs3820549 C/G	Additive	0.99 (0.51–1.95)	0.988	0.99 (0.50–1.99)	.987
	Co-dominant	0.89 (0.61–1,32)	0.571	0.88 (0.59–1.30)	.517
rs3820546 G/A	Additive	0.84 (0.48–1.46)	0.534	0.85 (0.48–1,50)	.577
	Co-dominant	1.46 (0.99–2.14)	0.052	1.35 (0.92–2.00)	.126
rs11537641 G/A	Additive	0.40 (0.13–1.28)	0.125	0.36 (0.11–1,17)	.089
	Co-dominant	1.05 (0.69–1.59)	0.819	1.03 (0.68–1.58)	.874

Odds Ratio (OR) and the corresponding 95% Confidence Intervals (CI) for testing the association between the SLC2A1 gene variants and T2DM-nephropathy for the additive and co-dominant models. The ORs adjusted for age and sex calculated by univariate logistic regression are also shown. In all variants, the ORs are calculated considering the heterozygote as the risk genotype for the co-dominant model and the minor allele as the risk allele for the additive model.

* χ² p Values.

# Multivariate logistic regression p values.

** Not applicable, because there are no G allele homozygotes. OR and p values are in bold in case of statistical significance.

Table 4. The degree of dominance index (h-index).

Variant	h-Index	Mode of inheritance
rs12407920 C/T	8.37	Dominance of allele T
rs841847 C/T	0.93	Dominance of allele T
rs841853 C/A	0.94	Dominance of allele A
rs3729548 C/T	0.10	None-dominance (additiveness)

The degree of dominance index (h-index) as an estimate for the mode of inheritance, calculated on the basis of unadjusted odds ratio (OR) values and the respective mode of inheritance for all SLC2A1 variants with a significant association to type 2 diabetes leading to nephropathy, found for the additive and co-dominant inheritance models.

Table 5. Estimates (D′, r² and p values) of linkage disequilibrium (LD) between pairs of SLC2A1 variants.

Variant	LD	rs2297976	rs710221	rs2086856	rs12130264	rs841847	rs841853	rs3729548	rs841855	rs3768029	rs12071418	rs3820549	rs3820546	rs11537641
rs12407920	D′	0.99 (0.99)	1.00 (0.99)	1.00 (1.00)	0.04 (0.59)	0.31 (0.49)	0.89 (0.83)	0.85 (0.89)	0.99 (0.99)	0.04 (0.22)	0.04 (1.00)	0.19 (0.65)	0.41 (0.57)	0.69 (0.99)
	r^2	0.03 (0.02)	0.09 (0.05)	0.21 (0.15)	0.00 (0.00)	0.02 (0.06)	0.16 (0.12)	0.05 (0.05)	0.03 (0.01)	0.00 (0.00)	0.00 (0.00)	0.00 (0.01)	0.02 (0.02)	0.01 (0.02)
	p	.03 (.09)	<.01	<.01	.18 (.29)	.1 (<.01)	<.01	.12 (<.01)	.45 (.15)	.26 (.29)	1.00 (.18)	.40 (.14)	.20 (.01)	.28 (.06)
rs2297976	D′	–	1.00 (1.00)	0.99 (0.99)	1.00 (0.99)	0.76 (0.63)	0.77 (0.64)	0.87 (0.97)	0.99 (0.53)	0.90 (0.84)	0.58 (0.80)	0.65 (0.10)	0.04 (0.24)	0.17 (0.04)
	r^2	–	0.35 (0.33)	0.13 (0.11)	0.01 (0.02)	0.30 (0.32)	0.24 (0.25)	0.12 (0.19)	0.05 (0.01)	0.17 (0.18)	0.01 (0.04)	0.04 (0.01)	0.00 (0.01)	0.00 (0.00)
	p	–	<.01	<.01	<.01 (.09)	<.01	<.01	<.01	.26 (.80	<.01	.38 (.02)	.19 (.61)	.45 (.30)	.97 (.21)
rs710221	D′	–	–	0.38 (0.51)	1.00 (0.99)	0.18 (0.26)	0.09 (0.21)	0.88 (0.88)	0.85 (0.93)	0.76 (0.66)	0.26 (0.99)	0.31 (0.59)	0.42 (0.43)	0.89 (0.87)
	r^2	–	–	0.10 (0.16)	0.04 (0.05)	0.02 (0.03)	0.00 (0.02)	0.37 (0.49)	0.21 (0.21)	0.35 (0.32)	0.00 (0.02)	0.05 (0.19)	0.11 (0.12)	0.21 (0.25)
	p	–	–	<.01	<.01	.38 (.04)	.68 (.13)	<.01	<.01	<.01	.73 (.09)	.02 (<.01)	<.01	<.01
rs2086856	D′	–	–	–	0.99 (0.99)	0.47 (0.29)	0.13 (0.05)	0.81 (0.79)	0.85 (0.85)	0.43 (0.46)	0.04 (0.63)	0.40 (0.37)	0.58 (0.65)	0.70 (0.54)
	r^2	–	–	–	0.03 (0.03)	0.05 (0.01)	0.00 (0.00)	0.21 (0.24)	0.30 (0.31)	0.08 (0.10)	0.00 (0.00)	0.12 (0.12)	0.15 (0.18)	0.19 (0.16)
	p	–	–	–	.04 (.28)	.02 (.03)	.48 (.47)	<.01	<.01	.01 (<.01)	.57 (.89)	<.01	<.01	<.01
rs12130264	D′	–	–	–	–	0.16 (0.99)	0.32 (0.81)	0.72 (0.91)	0.97 (0.99)	0.47 (0.45)	1.00 (0.99)	0.99 (0.84)	0.26 (0.72)	0.96 (0.99)
	r^2	–	–	–	–	0.00 (0.02)	0.00 (0.02)	0.04 (0.07)	0.01 (0.01)	0.01 (0.01)	0.00 (0.00)	0.02 (0.02)	0.01 (0.04)	0.01 (0.02)
	p	–	–	–	–	.10 (.13)	.06 (.07)	<.01	.28 (.65)	.12 (.09)	.17 (.86)	.10 (.03)	.01 (.02)	.22 (.23)
rs841847	D′	–	–	–	–	–	1.00 (1.00)	1.00 (1.00)	0.99 (0.99)	0.93 (0.95)	1.00 (0.96)	0.33 (0.35)	0.24 (0.40)	0.81 (0.81)
	r^2	–	–	–	–	–	0.78 (0.74)	0.30 (0.26)	0.10 (0.06)	0.34 (0.28)	0.01 (0.01)	0.02 (0.02)	0.02 (0.04)	0.06 (0.05)
	p	–	–	–	–	–	<.01	<.01	<.01 (.01)	<.01	.25 (.37)	.23 (.18)	.21 (.00)	.02 (.00)
rs841853	D′	–	–	–	–	–	–	1.00 (1.00)	0.99 (0.99)	0.69 (0.63)	0.99 (0.99)	0.19 (0.13)	0.29 (0.39)	0.85 (0.80)
	r^2	–	–	–	–	–	–	0.39 (0.35)	0.13 ((0.08)	0.24 (0.16)	0.01 (0.01)	0.01 (0.00)	0.04 (0.05)	0.09 (0.06)
	p	–	–	–	–	–	–	<.01	<.01	<.01	.36 (.38)	.29 (.46)	.06 (<.01)	<.01
rs3729548	D′	–	–	–	–	–	–	–	1.00 (1.00)	0.94 (0.84)	0.04 (0.99)	0.71 (0.75)	0.63 (0.56)	0.79 (0.89)
	r^2	–	–	–	–	–	–	–	0.13 (0.16)	0.66 (0.61)	0.00 (0.01)	0.12 (0.19)	0.29 (0.29	0.08 (0.17
	p	–	–	–	–	–	–	–	<.01	<.01	.65 (.29)	<.01	<.01	<.01
rs841855	D′	–	–	–	–	–	–	–	–	1.00 (1.00)	0.59 (0.08)	0.78 (0.94)	0.72 (0.91)	0.80 (0.85)
	r^2	–	–	–	–	–	–	–	–	0.17 (0.19)	0.00 (0.00)	0.34 (0.42)	0.09 (0.14)	0.60 (0.59)
	p	–	–	–	–	–	–	–	–	<.01	1.00 (.84)	<.01	<.01	<.01
rs3768029	D′	–	–	–	–	–	–	–	–	–	0.91 (0.99)	0.52 (0.57)	0.57 (0.59)	0.84 (0.88)
	r^2	–	–	–	–	–	–	–	–	–	0.01 (0.02)	0.09 (0.13)	0.30 (0.32)	0.12 (0.18)
	p	–	–	–	–	–	–	–	–	–	.84 (.13)	<.01	<.01	<.01
rs12071418	D′	–	–	–	–	–	–	–	–	–	–	0.99 (1.00)	0.96 (0.99)	0.23 (0.81)
	r^2	–	–	–	–	–	–	–	–	–	–	0.02 (0.04)	0.01 (0.02)	<0.01 (0.05)
	p	–	–	–	–	–	–	–	–	–	–	.13 (.01)	.17 (.19)	.59 (.01)
rs3820549	D′	–	–	–	–	–	–	–	–	–	–	–	1.00 (1.00)	0.93 (0.95)
	r^2	–	–	–	–	–	–	–	–	–	–	–	0.33 (0.37)	0.45 (0.54)
	p	–	–	–	–	–	–	–	–	–	–	–	<.01	<.01
rs3820546	D′	–	–	–	–	–	–	–	–	–	–	–	–	1.00 (1.00)
	r^2	–	–	–	–	–	–	–	–	–	–	–	–	0.17 (0.22)
	p	–	–	–	–	–	–	–	–	–	–	–	–	<.01

Estimates (D$\prime$, r² and p values) of linkage disequilibrium (LD) between pairs of SLC2A1 variants (SNPs) in patients with type 2 diabetes leading to nephropathy (cases, DN) and in healthy controls (HC). LD estimates of HC are shown in brackets.

Table 6. Estimated haplotype frequencies for the 14 SLC2A1 variants.

	Estimated frequencies			χ^2	Global
Haplotypes of SNPs 1–14*	DM + DN	HC	Odds ratio (95%CI)	p-Value	p-Value
C G A G C C C C A C C G G A	0.127	0.121	1.009 (0.638–0.597)	.969	.132
C T A A C T A C G C C C A G	0.074	0.067	1.063 (0.594–0.902)	.838
C G G A C C C T G T C C A G	0.285	0.290	0.908 (0.637–0.292)	.591
C G G A T C C T G T C C A G	0.010	0.038	0.248 (0.075–0.817)	.014
C T A A C T A C G C C C G G	0.097	0.060	1.633 (0.927–0.875)	.087
C G G A C T A C G C C C G G	0.031	0.015	2.067 (0.726–0.888)	.165
T G G G C T A C G C C C G G	0.032	0.041	0.732 (0.330–0.627)	.443
C G G A C C C T G T C C G G	0.039	0.048	0.773 (0.371–0.610)	.491
C G G A C T A C G C C G G G	0.044	0.029	1.481 (0.667–0.288)	.332

Estimated haplotype frequencies for the 14 SLC2A1 variants (SNPs 1–14: rs12407920 C/T, rs2297976 G/T, rs710221 G/A, rs2086856 A/G, rs12130264 C/T, rs841847 C/T, rs841853 C/A, rs3729548 C/T, rs841855 G/A, rs3768029 C/T, rs12071418 C/G, rs3820549 C/G, rs3820546 G/A, rs11537641 G/A) in cases (T2DM-nephropathy; DM + DN) and in healthy controls (HC). The p values for comparison between cases and HC of the frequencies of each haplotype and the global p values for testing the overall difference in haplotype frequencies are shown.

* Only haplotypes with a frequency of >0.03 in either cases (DM + DN) or controls (HC) are shown. OR and p values are in bold in case of statistical significance.

Figure 1. Flowchart showing how studies were selected for meta-analysis.

Figure 2. Forest plot presenting results of individual studies and pooled estimates from both main and subgroup meta-analyses between diseased controls versus cases.

Figure 3. Forest plot presenting results of individual studies and pooled estimates from both main and subgroup meta-analyses between healthy controls versus diseased controls versus cases.

Figure 4. Forest plot presenting results of individual studies and pooled estimates from both main and subgroup meta-analyses between healthy controls versus cases.

Table 7. Characteristics of studies included in meta-analysis.

Variant	References	Ethnicity	PMID	DM	Trait	N	Selection criteria	N	Selection criteria	N	Selection criteria	HWE HT	HWE DC	Analyses
SLC2A1 rs841853	[10]	Caucasians	19822956	T2DM	DN	92	Pers. albuminuria	56	DM >15 y, pers. norm/ria matched for age, BMI	92	Non-diabetics matched for age, BMI		No	DC-C, HT-DC-C, HT-C
	[36]	Africans (Tunisia)	18821326	T2DM	DN	126	Pers. albuminuria, retinopathy	273	DM >10 y, norm/ria				No	DC-C
	[37]	Caucasians	12086959	T1DM	DN	262	Pers. macr/ria or d. ESRD	230	Pers. norm/ria , DM ≥15 y					DC-C
	[38]	Caucasians	11231353	T1DM	DN	70	Pers. proteinuria, retinopathy, DM ≥10 y	44	DM≥ 20 y, pers. norm/ria	104	Non-diabetics			DC-C, HT-DC-C, HT-C
	[39]	Caucasians	11477169	T1DM	DN	199	Pers. macr/ria , retinopathy	192	Pers. norm/ria matched for gender, age, DM duration					DC-C
	[40]	E. Asians	10231446	T2DM	DN	64	Pers. albuminuria or proteinuria with or without impaired renal function	45	Only diabetics	124	Non-diabetics			DC-C, HT-DC-C, HT-C
	[41]	Caucasians	11168944	T2DM	DN	282	Pers. micr/ria/proteinuria/CRF	162	Pers. norm/ria, DM ≥10 y	194	Non-diabetics		No	DC-C, HT-DC-C, HT-C
	[42]	Caucasians	9789717	T2DM	DN	60	Pers. micro/macroalbuminuria	100	Pers. norm/ria matched for gender, age, BMI, DM duration and HbA1c and lipidic profile	90	Non-diabetics			DC-C, HT-DC-C, HT-C
SLC2A1 rs1385129	[43]	Caucasians-Brazilians	25701507	T1DM	DN	203	Pers. micro/macroalbuminuria	249	Pers. norm/ria and serum Cr.<1.7 mg/dl					DC-C
	[44]	Asians	26337659	T2DM	DN	126	Pers. micr/ria	150	Pers. norm/ria				No	DC-C
	[36]	Africans (Tunisia)	18821326	T2DM	DN	126	Pers. albuminuria, retinopathy	273	DM >10 y, norm/ria					DC-C
	[37]	Caucasians	12086959	T1DM	DN	262	Pers. macr/ria or d. ESRD	230	Pers. norm/ria , DM duration ≥15 y					DC-C
SLC2A1 rs841847	[36]	Africans (Tunisia)	18821326	T2DM	DN	126	Pers. albuminuria, retinopathy	273	DM >10 y, norm/ria					DC-C
	[43]	Caucasians-Brazilians	25701507	T1DM	DN	203	Pers. micro/macroalbuminuria	249	Pers. norm/ria and serum Cr.<1.7 mg/dl					DC-C
	[37]	Caucasians	12086959	T1DM	DN	262	Pers. macr/ria or d. ESRD	230	Pers. norm/ria, DM ≥15 y					DC-C
SLC2A1 rs841848	[36]	Africans (Tunisia)	18821326	T2DM	DN	126	Pers. albuminuria, retinopathy	273	DM >10 y, norm/ria					DC-C
	[43]	Caucasians-Brazilians	25701507	T1DM	DN	203	Pers. micro/macroalbuminuria	249	Pers. norm/ria and s. Cr.<1.7 mg/dl					DC-C
	[37]	Caucasians	12086959	T1DM	DN	262	Pers. macr/ria or d. ESRD	230	Pers. norm/ria , DM ≥15 y					DC-C
SLC2A1 rs710218	[36]	Africans (Tunisia)	18821326	T2DM	DN	126	Pers. albuminuria, retinopathy	273	DM >10 y, norm/ria				No	DC-C
	[38]	Caucasians	15745834	T1DM	DN	131	DM ≥10 y, pers. proteinuria, diabetic retinopathy	72	Uncomplicated, DM ≥20 y without retinopathy and proteinuria	99	Non-diabetics			DC-C
								35	DM <10 y without retinopathy, proteinuria or overt neuropathy

Table 8. Results from meta-analyses based on genotype counts.

Diseased controls versus cases
Gene	Variant	RS	Studies (n)	Cases/Controls (n)	RE ORG	95% LL	95% UL	I^2(%)	PQ	PE
SLC2A1	XbaI(+)>XbaI(−)	rs841853	9	1311/1226	1.26	0.98	1.61	62.31	0.01	0.04
SLC2A1	All in HWE		6	811/735	1.43	1.09	1.88	50.90	0.07	0.08
Subgroup analyses
T1DM	XbaI(+)>XbaI(−)	rs841853	3	494/443	1.49	1.00	2.23	62.13	0.07	0.16
T2DM	XbaI(+)>XbaI(−)	rs841853	6	817/783	1.14	0.84	1.57	60.86	0.03	0.05
Caucasians	XbaI(+)>XbaI(−)	rs841853	7	1121/908	1.19	0.91	1.56	62.17	0.01	0.12
Non-Caucasians	XbaI(+)>XbaI(−)	rs841853	2	190/318	1.71	0.69	4.27	76.70	0.04	na
Sensitivity analysis
Excluding current case-control	XbaI(+)>XbaI(−)	rs841853	8	1118/1078	1.29	0.97	1.72	67.020	0	0.05
	All in HWE		5	618/587	1.54	1.09	2.16	57.70	0.05	0.13
SLC2A1	HaeIII SNP	rs1385129	4	716/899	0.74	0.350	1.57	92.05	0	0.18
	All in HWE		3	590/749	1.14	0.73	1.76	74.96	0.02	0.11
SLC2A1	Enh2 SNP1 G>A	rs841847	4	783/904	1.48	0.85	2.60	89.27	0	0.13
SLC2A1	All in HWE		4
Subgroup analyses
T1DM	Enh2 SNP1 G>A	rs841847	2	465/479	1.10	0.87	1.40	0	0.92	na
T2DM	Enh2 SNP1 G>A	rs841847	2	318/425	2.02	0.58	7.00	94.83	0	na
Caucasians	Enh2 SNP1 G>A	rs841847	2	454/382	1.08	0.85	1.39	0	0.96	na
Non-Caucasians	Enh2 SNP1 G>A	rs841847	2	329/522	2.06	0.62	6.86	94.81	0	na
Sensitivity analysis
Excluding current case-control	Enh2 SNP1 G>A	rs841847	3	591/752	1.65	0.78	3.51	92.21	0	0.16
	All in HWE		3
SLC2A1	Enh2 SNP2 C>T	rs841848	3	588/750	1.18	0.95	1.45	0	0.62	0.35
	All in HWE		3
Subgroup analyses
T1DM	Enh2 SNP2 C>T	rs841848	2	462/477	1.14	0.88	1.48	0	0.37	na
T2DM	Enh2 SNP2 C>T	rs841848	1	na	na	na	na	na	na	na
Caucasians	Enh2 SNP2 C>T	rs841848	2	462/477	1.14	0.88	1.48	0	0.37	na
Non-Caucasians	Enh2 SNP2 C>T	rs841848	1	na	na	na	na	na	na	na
Sensitivity analysis
Excluding current case-control	Enh2 SNP2 C>T	rs841848	na	na	na	na	na	na	na	na
SLC2A1	HpyCH4V	rs710218	2	257/380	3.87	0.61	24.38	96.94	0.00	na
	All in HWE		2
Healthy controls versus diseased controls versus cases
SLC2A1	XbaI(+)>XbaI(−)	rs841853	6	761/554/845	1.36	0.98	1.89	84.03	0	0.10
SLC2A1	All in HWE		6
Subgroup analyses
T1DM	XbaI(+)>XbaI(−)	rs841853	1	na	na	na	na	na	na	na
T2DM	XbaI(+)>XbaI(−)	rs841853	5	691/510/741	1.36	0.92	2.00	87.14	0	0.17
Caucasians	XbaI(+)>XbaI(−)	rs841853	5	697/509/721	1.17	0.91	1.51	69.98	0.01	0.21
Non-Caucasians	XbaI(+)>XbaI(−)	rs841853	1	na	na	na	na	na	na	na
Sensitivity analysis
Excluding current case-control	XbaI(+)>XbaI(−)	rs841853	5	568/406/604	1.34	0.88	2.04	86.30	0	0.07
	All in HWE		5
Healthy controls versus cases
SLC2A1	XbaI(+)>XbaI(−)	rs841853	6	761/845	1.58	1.01	2.48	83.03	0	0.23
	All in HWE		6
Subgroup analyses
T1DM	XbaI(+)>XbaI(−)	rs841853	1	na	na	na	na	na	na	na
T2DM	XbaI(+)>XbaI(−)	rs841853	5	691/741	1.56	0.92	2.65	86.15	0	0.28
Caucasians	XbaI(+)>XbaI(−)	rs841853	5	697/721	1.29	0.92	1.81	66.67	0.02	0.42
Non-Caucasians	XbaI(+)>XbaI(−)	rs841853	1	na	na	na	na	na	na	na
Sensitivity Analysis	XbaI(+)>XbaI(−)	rs841853	5	568/604	1.568	0.875	2.81	85.765	0	0.15
Excluding current case-control	All in HWE		5

na: non-applicable.

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