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A total of 342 Chinese Han discordant IS sib pairs consisting of 342 confirmed IS patients and 342 IS-free siblings were enrolled in the present study. The mean age at enrollment for IS patients was 61.09 ± 9.22. The mean age at enrollment for IS-free siblings was 57.52 ± 9.05. The mean age at onset for IS patients was 55.4 ± 9.09. Compared with IS-free siblings, IS patients were older, had a higher proportion of male, and had higher rates of diabetes mellitus and hypertension. IS patients also had higher smoking rate, as well as higher FBG levels, higher TG levels and lower HDL-C levels. The total adiponectin levels of IS patients were lower than IS-free siblings.
There were no significant differences with respect to alcohol consumption, BMI, TC, LDL-C, and HMW adiponectin levels between IS patients and IS-free siblings (Table 1).
Items IS IS-free Siblings P N 342 342 - Age 61.09 ± 9.22 57.52 ± 9.05 < 0.001^ Male 223 (65.20) 170 (49.71) < 0.001^ Diabetes mellitus 143 (41.81) 84 (24.56) < 0.001^ Hypertension 297 (86.84) 213 (62.28) < 0.001^ Smoker 203 (59.36) 150 (43.86) < 0.001^ Drinker 127 (37.13) 105 (30.70) 0.063 BMI 26.37 ± 3.57 26.18 ± 3.55 0.456 FBG 6.51 ± 2.78 5.98 ± 2.48 0.005^ TC 4.25 ± 1.23 4.27 ± 1.17 0.810 ln TG 0.49 ± 0.58 0.36 ± 0.62 0.002^ HDL-C 1.27 ± 0.44 1.40 ± 0.53 < 0.001^ LDL-C 2.87 ± 0.86 2.87 ± 0.81 0.969 ln total adiponectin 8.75 ± 0.89 8.92 ± 0.86 0.035^ ln HMW adiponectin 7.46 ± 0.74 7.54 ± 0.70 0.180 Note. Continuous variables were described as mean ± standard deviation. Categorical variables were described as frequency (proportion). IS: ischemic stroke; BMI: body mass index, kg/m2; FBG: fast blood glucose, mmol/L; TC: total cholesterol, mmol/L; ln TG: natural logarithmically transformed total triglycerides, mmol/L; HDL-C: high-density lipoprotein cholesterol, mmol/L; LDL-C: low-density lipoprotein cholesterol, mmol/L; ln total adiponectin: natural logarithmically transformed total adiponectin, ng/mL; ln HMW adiponectin: natural logarithmically transformed high-molecular weight adiponectin, ng/mL. ^P < 0.05. Table 1. Anthropometric, Lifestyle Characteristics and Biochemical Indices of Ischemic Stroke Sib-pairs
Associations between CDH13 SNPs and Adiponectin Levels In IS-free individuals, rs4783244 T allele was associated with total adiponectin levels (per T allele: Coef = -0.257: P = 0.001) but not HMW adiponectin levels (per T allele: Coef = -0.079 P = 0.204). Compared with rs4783244 GG genotype, GT/TT genotypes were associated with lower total adiponectin levels (GT/TT vs. GG: Coef = -0.265: P = 0.008).
In IS-free siblings, rs7193788 A allele was associated with total adiponectin levels (per A allele: Coef = -0.221: P = 0.001) and HMW adiponectin levels (per A allele: Coef = -0.163: P = 0.003). Compared with rs7193788 GG genotype, GA/AA genotypes were associated with lower total adiponectin levels (GA/AA vs. GG: Coef = -0.303: P = 0.006) and lower HMW adiponectin levels (GA/AA vs. GG: Coef = -0.222: P = 0.013). However, these associations were not found in IS patients (Table 2).
SNP Genotype IS Patients IS-free Siblings Mean ± SD Coef P* Mean ± SD Coef P* Total adiponectin rs4783244 per T - -0.062 0.473 - -0.257 0.001^ GG 8.83 ± 0.97 Ref - 9.05 ± 0.91 Ref - GT/TT 8.69 ± 0.83 -0.137 0.241 8.83 ±0.82 -0.265 0.008^ rs7193788 per A - -0.086 0.302 - -0.221 0.001^ GG 8.98 ± 0.76 Ref - 9.00 ± 0.86 Ref - GA/AA 8.70 ± 0.93 -0.274 0.051 8.71 ± 0.85 -0.303 0.006^ HMW adiponectin rs4783244 per T - -0.034 0.649 - -0.079 0.204 GG 7.49 ± 0.74 Ref - 7.56 ± 0.76 Ref - GT/TT 7.43 ± 0.74 -0.063 0.529 7.53 ± 0.64 -0.073 0.366 rs7193788 per A - -0.017 0.816 - -0.163 0.003^ GG 7.46 ± 0.73 Ref - 7.61 ± 0.70 Ref - GA/AA 7.43 ± 0.81 -0.037 0.759 7.36 ± 0.66 -0.222 0.013^ Note. *Adjusting for age, sex, diabetes mellitus, hypertension, smoking status, drinking status, BMI, ln TG, HDL-C. HMW adiponectin: high-molecular weight adiponectin. ^P < 0.05. Table 2. Associations between CDH13 SNPs and Adiponectin Levels in IS patients and IS-free Siblings
Associations between CDH13 SNPs and Ischemic Stroke CDH13 rs7193788 was significantly associated with IS after Bonferroni correction (α = 0.025). Compared with individuals of rs7193788 GG genotype, those of GA/AA genotypes had higher risks of IS (GA/AA vs. GG: unadjusted: OR = 1.48: 95% CI: 1.05-2.09: P = 0.025, adjusted: OR = 1.55: 95% CI: 1.07-2.24: P = 0.020). No association was found between rs4783244 and IS (Table 3).
SNP Location MAF HWE P-Value Genotype Unadjusted Adjusted* OR 95% CI P OR 95% CI P rs4783244 16:82628663 T (0.348) 0.818 GG Ref - - Ref - - GT/TT 1.05 0.79: 1.40 0.736 1.09 0.80: 1.49 0.582 rs7193788 16:82622555 G (0.478) 0.666 GG Ref - - Ref - - GA/AA 1.48 1.05: 2.09 0.025^ 1.55 1.07: 2.24 0.020^ Note. *Adjusting for age, sex, diabetes mellitus, hypertension, smoking status, drinking status, BMI, lnTG, HDL-C. MAF: minor allele frequency. ^P < 0.05. Table 3. Associations between CDH13 SNPs and Ischemic Stroke
Interactions between CDH13 SNPs and Other Risk Factors for IS We investigated interactions between 2 CDH13 SNPs and smoking, drinking, BMI, history of hypertension, history of diabetes for IS. We observed a statistically significant interaction between CDH13 rs7193788 and diabetes (P = 0.036). Compared to diabetes-free individuals with rs7193788 GG genotype, diabetes patients with rs7193788 GA/AA genotypes had higher risks for IS (unadjusted: OR = 3.17: 95% CI: 1.96-5.12: P < 0.001, adjusted: OR = 2.64: 95% CI: 1.58-4.40: P < 0.001)
No interaction was found between CDH13 rs4783244 and diabetes for IS (P = 0.268). However, compared to diabetes-free individuals with rs4783244 GG genotype, diabetes patients with rs4783244 GT/TT genotypes had higher risks for IS (Unadjusted: OR = 2.50: 95% CI: 1.62-3.86: P < 0.001, adjusted: OR = 2.03: 95% CI: 1.27-3.24: P = 0.003) (Table 4).
Diabetes Genotype Unadjusted Adjusted P for Interaction OR 95% CI P* OR 95% CI P* rs4783244 No GG Ref - - Ref - - 0.268 GT/TT 0.96 0.67: 1.37 0.825 0.99 0.67: 1.45 0.941 Yes GG 1.78 1.12: 2.83 0.015^ 1.53 0.93: 2.52 0.092 GT/TT 2.50 1.62: 3.86 < 0.001^ 2.03 1.27: 3.24 0.003^ rs7193788 No GG Ref - - Ref - - 0.036^ GA/AA 1.19 0.78: 1.83 0.421 1.20 0.76: 1.89 0.425 Yes GG 1.30 0.68: 2.46 0.424 1.12 0.57: 2.21 0.735 GA/AA 3.17 1.96: 5.12 < 0.001^ 2.64 1.58: 4.40 < 0.001^ Adjusting for age, sex, hypertension, smoking status, drinking status, BMI, lnTG, HDL-C. ^P < 0.05. Table 4. Interactions between CDH13 SNPs and Diabetes for Ischemic Stroke