Baseline characteristics of subject
A total of 500 T2DM cases (59.87 ± 12.87 years, 358 males and 142 females) and 501 controls (59.85 ± 9.34 years, 358 males and 143 females) were recruited. The distribution in age and sex between the T2D patients and controls was similar (p = 0.973 and p = 0.508, respectively). There were statistical differences between the two groups with respect to biochemical indexes including fasting blood glucose, total cholesterol, LDL-C, HDL-C, urea, serum uric acid (all p < 0.05, Table 1).
Table 1
Characteristics of patients with T2DM and controls
Variable | Cases (n = 500) | Controls ( n = 501) | p |
Age (year, mean ± SD) | 59.87 ± 12.87 | 59.85 ± 9.34 | 0.973 |
> 60 / ≤ 60 | 240/260 | 268/233 | |
Gender Male/Female | 358/142 | 358/143 | 0.508 |
BMI (kg/m2) < 24 / ≥ 24 | 203/239 | 130/188 | |
Unavailable | 58 | 183 | |
Smoking Yes / No | 219/280 | 98/164 | |
Unavailable | 1 | 239 | |
Drinking Yes / No | 109/385 | 103/140 | |
Unavailable | 6 | 258 | |
T2DM duration (years) >10 / ≤10 | 193/307 | | |
Fasting blood glucose (mmol/L) | 8.14 ± 3.35 | 5.65 ± 0.51 | < 0.001 |
Total cholesterol (mmol/L) | 4.18 ± 2.01 | 4.93 ± 4.00 | < 0.001 |
Triglyceride (mmol/L) | 1.91 ± 1.90 | 1.74 ± 0.97 | 0.088 |
LDL-C (mmol/L) | 2.46 ± 0.90 | 2.61 ± 0.76 | 0.012 |
HDL-C (mmol/L) | 1.05 ± 0.72 | 1.16 ± 0.55 | 0.024 |
Urea (mmol/L) | 6.52 ± 3.26 | 5.42 ± 2.78 | < 0.001 |
Creatinine (µmol/L) | 71.20 ± 52.66 | 68.74 ± 12.87 | 0.322 |
GFR (mL/min) | 96.62 ± 22.22 | 96.07 ± 19.78 | 0.710 |
Serum uric acid (µmol/L) | 333.17 ± 99.15 | 318.33 ± 76.64 | 0.013 |
Diabetic complications | | | |
Diabetic nephropathy | 146 | | |
Diabetic retinopathy | 69 | | |
T2DM with coronary heart disease | 126 | | |
T2DM with hypertension | 269 | | |
T2DM, type 2 diabetes mellitus; BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; UCRP, ubiquitin cross-reactive protein. |
p values were calculated by χ2 test for continuous variables and student’s t test for categorical variables. |
Bold indicate that p < 0.05 indicates statistical difference. |
Analysis for association between SOCS2 variants and T2DM susceptibility
As shown in Table 2, three SNPs in SOCS2 (rs3825199, rs11107116 and rs10492321) were associated with the increased risk of T2DM occurrence. The risk genotype of rs3825199-AG, rs11107116-GT and rs10492321-TA were more prevalent in patients than controls exhibiting a higher susceptibility to T2DM: for rs3825199, AG vs AA, OR = 1.44, 95% CI: 1.11–1.88, p = 0.007; for rs11107116, GT vs GG, OR = 1.39, 95% CI: 1.07–1.81, p = 0.014; for rs10492321, TA vs TT, OR = 1.48, 95% CI: 1.13–1.93, p = 0.004, respectively. In addition, the elevated risk association with T2DM was also observed in the dominant model (rs3825199, OR = 1.35, 95% CI: 1.05–1.73, p = 0.020; rs11107116, OR = 1.30, 95% CI: 1.01–1.67, p = 0.038; and rs10492321, OR = 1.40, 95% CI: 1.09–1.81, p = 0.009).
Table 2
Correlation between SOCS2 variants and T2DM risk
SNPs ID | Models | Genotype | Case | Control | Adjusted by age and gender |
OR (95%CI) | p |
rs3825199 | Allele | A | 646 | 676 | 1 | |
G | 354 | 326 | 1.14 (0.94–1.37) | 0.176 |
Genotype | AA | 200 | 237 | 1 | |
AG | 246 | 202 | 1.44 (1.11–1.88) | 0.007 |
GG | 54 | 62 | 1.03 (0.68–1.56) | 0.881 |
Dominant | AG-GG vs AA | | | 1.35 (1.05–1.73) | 0.020 |
Recessive | GG vs AA-AG | | | 0.86 (0.58–1.26) | 0.437 |
Log-additive | AA + AG + GG | | | 1.14 (0.94–1.37) | 0.177 |
rs11107116 | Allele | G | 653 | 679 | 1 | |
T | 347 | 323 | 1.12 (0.93–1.35) | 0.243 |
Genotype | GG | 205 | 238 | 1 | |
GT | 243 | 203 | 1.39 (1.07–1.81) | 0.014 |
TT | 52 | 60 | 1.01 (0.66–1.52) | 0.978 |
Dominant | GT-TT vs GG | | | 1.30 (1.01–1.67) | 0.038 |
Recessive | TT vs GG-GT | | | 0.85 (0.58–1.27) | 0.430 |
Log-additive | GG + GT + TT | | | 1.12 (0.93–1.35) | 0.243 |
rs10492321 | Allele | T | 617 | 656 | 1 | |
A | 383 | 346 | 1.18 (0.98–1.41) | 0.080 |
Genotype | TT | 183 | 224 | 1 | |
TA | 251 | 208 | 1.48 (1.13–1.93) | 0.004 |
AA | 66 | 69 | 1.17 (0.79–1.73) | 0.428 |
Dominant | TA-AA vs TT | | | 1.40 (1.09–1.81) | 0.009 |
Recessive | AA vs TT-TA | | | 0.95 (0.66–1.37) | 0.791 |
Log-additive | TT + TA + AA | | | 1.18 (0.98–1.41) | 0.081 |
SNP, single nucleotide polymorphism; T2DM, type 2 diabetes mellitus; OR, odds ratio; 95% CI, 95% confidence interval. |
p values were calculated by logistic regression analysis with adjustments for age and gender. |
Bold indicate that p < 0.05 means the data is statistically significant. |
Stratified analysis for the relationship of SOCS2 variants to T2DM risk
Stratified analyses were performed to explore the relationship between SOCS2 SNPs and T2DM risk factors, including age, gender, smoking, drinking and BMI. Stratified by gender, rs3825199, rs11107116 and rs10492321 conferred to the increased T2DM risk among males not females under the allele, genotype, dominant and additive models (Suppl_Table 3). Based on age, the study population was stratified into two groups: those older than 60 years and those younger than or equal to 60 years. No significant relation of SOCS2 variants to T2DM risk in those older than 60 years was observed. While, high risk association was found for rs3825199, rs11107116 and rs10492321 in subjects aged ≤ 60 years (Suppl_Table 3).
In smoker, increased risk of T2DM developing was found for rs10492321 polymorphism (Suppl_Table 4). Among non-smoker, the risk effect of rs3825199, rs11107116 and rs10492321 on T2DM occurrence was observed under the genotype and dominant models. In drinker, rs10859525 was a protective factor for T2DM developing, while rs3825199 increased T2DM susceptibility. In non-drinker, a trend of higher risk of developing T2DM was also found for subjects with the AG/AG-GG genotypes of rs3825199, GT genotype of rs11107116 and TA/TA-AA genotypes of rs10492321 (Suppl_Table 4). Among subjects with BMI > 24 kg/m2, rs10859563 was associated with the reduced T2DM predisposition. In subjects with BMI ≤ 24 kg/m2, rs3825199-AG genotype and rs11107116-GT genotype had 1.66- and 1.64- fold increased risk of developing T2DM than their reference genotype (Suppl_Table 5).
Analysis for association between SOCS2 variants and diabetic nephropathy or diabetic retinopathy in T2DM patients
We next investigated the association between SOCS2 variants and diabetic nephropathy or diabetic retinopathy in T2DM patients (Table 3). We found that rs10859525 (G vs A, OR = 0.68, p = 0.017; AA + AG + GG, OR = 0.71, p = 0.040) and rs10859563 (C vs G, OR = 0.72, p = 0.022; CC vs GG, OR = 0.51, p = 0.024; GC-CC vs GG, OR = 0.61, p = 0.016; GG + GC + CC, OR = 0.70, p = 0.013) had the reduced risk of diabetic nephropathy in T2DM patients. Moreover, the protective effect of rs10859525 on the risk of diabetic retinopathy in T2DM patients was observed under the allele (OR = 0.63, p = 0.042), genotype (OR = 0.53, p = 0.034), dominant (OR = 0.53, p = 0.025) and additive (OR = 0.63, p = 0.042) models.
Table 3
Association of SOCS2 variants with diabetic nephropathy and diabetic retinopathy in T2DM patients
SNP ID | Model | DN vs No DN | DR vs No DR |
OR (95%CI) | p | OR (95%CI) | p |
rs10859525 | G vs A | 0.68 (0.50–0.94) | 0.017 | 0.63 (0.41–0.99) | 0.042 |
AG vs AA | 0.74 (0.49–1.12) | 0.152 | 0.53 (0.29–0.95) | 0.034 |
GG vs AA | 0.47 (0.20–1.12) | 0.087 | 0.53 (0.19–1.50) | 0.232 |
AG-GG vs AA | 0.69 (0.46–1.03) | 0.069 | 0.53 (0.31–0.92) | 0.025 |
GG vs AA-AG | 0.53 (0.23–1.25) | 0.147 | 0.70 (0.25–1.91) | 0.480 |
AA + AG + GG | 0.71 (0.51–0.99) | 0.040 | 0.63 (0.40–0.98) | 0.042 |
rs10859563 | C vs G | 0.72 (0.55–0.96) | 0.022 | 1.01 (0.69–1.48) | 0.965 |
GC vs GG | 0.65 (0.42–1.00) | 0.051 | 1.04 (0.56–1.92) | 0.899 |
CC vs GG | 0.51 (0.28–0.91) | 0.024 | 1.01 (0.44–2.32) | 0.980 |
GC-CC vs GG | 0.61 (0.40–0.91) | 0.016 | 1.03 (0.58–1.86) | 0.912 |
CC vs GG-GC | 0.65 (0.38–1.11) | 0.113 | 0.99 (0.47–2.06) | 0.969 |
GG + GC + CC | 0.70 (0.53–0.93) | 0.013 | 1.01 (0.68–1.51) | 0.956 |
T2DM, type 2 diabetes mellitus; SNP, single nucleotide polymorphism; DN, diabetic nephropathy; DR, diabetic retinopathy; OR, odds ratio; 95% CI, 95% confidence interval. |
p values were calculated by logistic regression analysis with adjustments for age and gender. |
Bold indicate that p < 0.05 indicates statistical significance. |
Association of SOCS2 variants in T2DM patients with coronary heart disease or hypertension versus controls
Additionally, the association of SOCS2 variants with the combined effect of T2DM and coronary heart disease/hypertension was examined (Table 4). We found that rs3825199 (GG vs AA, OR = 0.35, p = 0.035; and GG vs AA-AG, OR = 0.31, p = 0.014), rs11107116 (TT vs GG, OR = 0.28, p = 0.020; and TT vs GG-GT, OR = 0.25, p = 0.009) and rs10859563 (C vs G, OR = 0.70, p = 0.015; CC vs GG, OR = 0.48, p = 0.020; and GG + GC + CC, OR = 0.70, p = 0.018) had the reduced risk for T2DM patients with coronary heart disease compared with healthy controls. However, there was no significant association for T2DM patients with hypertension.
Table 4
Association of SOCS2 variants in T2DM patients with coronary heart disease or hypertension versus controls
SNP ID | Model | T2DM patients with CHD | T2DM patients with hypertension |
OR (95%CI) | p | OR (95%CI) | p |
rs3825199 | G vs A | 0.90 (0.66–1.21) | 0.470 | 1.12 (0.90–1.4) | 0.303 |
AG vs AA | 1.33 (0.88–2.01) | 0.182 | 1.38 (1.00–1.91) | 0.050 |
GG vs AA | 0.35 (0.13–0.93) | 0.035 | 1.02 (0.61–1.70) | 0.951 |
AG-GG vs AA | 1.11 (0.74–1.66) | 0.617 | 1.30 (0.96–1.77) | 0.095 |
GG vs AA-AG | 0.31 (0.12–0.79) | 0.014 | 0.86 (0.53–1.40) | 0.548 |
AA + AG + GG | 0.88 (0.65–1.20) | 0.419 | 1.12 (0.89–1.40) | 0.344 |
rs11107116 | T vs G | 0.87 (0.65–1.18) | 0.381 | 1.11 (0.89–1.39) | 0.353 |
GT vs GG | 1.29 (0.85–1.95) | 0.225 | 1.33 (0.96–1.84) | 0.083 |
TT vs GG | 0.28 (0.10–0.82) | 0.020 | 1.00 (0.60–1.68) | 0.999 |
GT-TT vs GG | 1.07 (0.72–1.61) | 0.738 | 1.26 (0.93–1.71) | 0.144 |
TT vs GG-GT | 0.25 (0.09–0.71) | 0.009 | 0.87 (0.53–1.42) | 0.566 |
GG + GT + TT | 0.85 (0.62–1.16) | 0.309 | 1.10 (0.88–1.38) | 0.414 |
rs10859563 | C vs G | 0.70 (0.53–0.93) | 0.015 | 0.93 (0.75–1.15) | 0.489 |
GC vs GG | 0.75 (0.48–1.16) | 0.190 | 0.82 (0.58–1.16) | 0.258 |
CC vs GG | 0.48 (0.25–0.89) | 0.020 | 0.87 (0.57–1.34) | 0.533 |
GC-CC vs GG | 0.66 (0.44–1.00) | 0.052 | 0.84 (0.61–1.15) | 0.272 |
CC vs GG-GC | 0.56 (0.31–1.00) | 0.050 | 0.98 (0.67–1.43) | 0.913 |
GG + GC + CC | 0.70 (0.52–0.94) | 0.018 | 0.92 (0.74–1.14) | 0.435 |
T2DM, type 2 diabetes mellitus; SNP, single nucleotide polymorphism; CHD, coronary heart disease; OR, odds ratio; 95% CI, 95% confidence interval. |
p values were calculated by logistic regression analysis with adjustments for age and gender. |
Bold indicate that p < 0.05 indicates statistical significance. |