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Our meta-analysis initially collected 791 published articles, including 782 papers collected by our search strategy and 9 papers through the references. After scanning the abstracts and full texts according to the inclusion and exclusion criteria, we included 59 eligible articles with 6,872 cases and 8,250 controls in this paper. The protocol of the process for literature identification and selection is listed in Figure 1, and the baseline characteristics of the included studies are summarized in Table 1, all the results of meta-analysis is shown in Table 2.
Study Year Region Ethnicity Genotyping method Sample
size (case/
control)Quality
scoreHWE Y/N(P) ε2/ε2(n)+
ε2/ε3(n)ε2/ε4(n)+
ε3/ε3(n)ε3/ε4(n)+
ε4/ε4(n)case control case control case control Singh[36] 2006 India Asian PCR-RELP 90/97 9 Y(0.184) 1+4 1+7 2+78 0+74 5+0 13+2 Al-Majed[16] 2011 Kuwait Other PCR-RELP 105/62 6 N(0.006) 7+2 2+3 2+73 2+46 6+15 9+1 Chaudhary[9] 2012 Bangkok Other PCR-RELP 155/149 8 Y(0.121) 1+2 2+12 1+117 0+113 30+4 21+1 Errera[37] 2006 Brazil Other PCR-RELP 95/107 7 Y(0.584) 0+13 0+7 2+68 0+77 12+0 23+0 Alharbi[17] 2014 Riyadh Other TaqMan 438/460 7 N(< 0.001) 35+26 27+18 13+290 11+334 35+39 60+10 Inamdar[38] 2000 India Asian Flat gel isoelectric focusing 60/40 8 Y(0.054) 2+8 1+9 3+17 2+10 16+14 8+10 Kwon[39] 2007 Korea Asian PCR-RELP 94/88 7 Y(0.924) 0+13 0+5 3+63 0+70 14+1 12+1 Atta[18] 2016 Egypt Other PCR-RELP 45/45 5 Y(0.098) 0+12 0+3 12+12 3+30 9+0 9+0 Vauhkonen[40] 1997 Finland Caucasian PCR-RELP 86/125 8 Y(0.963) 0+7 0+9 3+48 2+76 20+8 33+5 Erdogan[19] 2009 Turkey Caucasian PCR-RELP 56/35 7 N(< 0.001) 0+4 0+0 0+40 0+28 12+0 7+0 Eto[41] 1986 Japan Asian Flat gel isoelectric focusing 105/111 8 Y(0.339) 0+9 1+10 0+73 1+80 21+2 16+3 Guan[42] 2009 China Asian PCR-LDR 213/111 7 Y(0.499) 8+32 1+32 7+141 1+88 24+1 9+1 Leiva[43] 2005 Chile Other PCR-RELP 193/139 7 Y(0.293) 0+12 0+10 4+133 3+87 43+1 39+0 Liu[44] 2003 China Asian PCR-RELP 80/81 7 Y(0.217) 0+11 0+4 1+56 2+64 12+0 11+0 Mehmet[20] 2015 Turkey Caucasian PCR-RELP 100/50 8 N(0.039) 0+6 0+22 0+81 0+19 13+0 9+0 Xie[45] 2011 China Asian PCR-RELP 60/20 7 Y(0.936) 0+13 1+3 4+8 2+8 19+16 5+1 Mustapic[21] 2012 Croatia Caucasian TaqMan 196/456 6 Y(0.331) 0+35 1+48 2+127 2+328 30+2 76+1 Santos[46] 2002 Mexico Other PCR-RELP 36/22 8 Y(0.423) 0+0 1+2 0+32 1+10 3+1 8+0 Kamboh[47] 1995 USA Caucasian IEF-immunoblottin and PCR 116/659 6 Y(0.992) 0+23 6+88 5+62 19+382 26+0 150+14 Ng[48] 2016 China Asian Other 386/200 6 Y(0.168) 4+53 1+32 5+282 6+142 39+3 19+0 Eto[49] 1995 Japan Asian Flat gel isoelectric focusing 281/576 8 Y(0.609) 1+25 2+35 1+192 4+414 55+7 111+10 Morbois Trabut[50] 2006 France Caucasian PCR-RELP 210/481 7 Y(0.773) 2+31 5+71 1+143 14+294 33+0 87+10 Powell[51] 2003 UK Caucasian PCR-RELP 187/102 7 Y(0.094) 3+22 2+7 3+89 1+57 27+3 21+0 Guangda[52] 1999 China Asian PCR-RELP 89/72 7 Y(0.122) 1+13 1+7 1+66 2+53 7+1 7+2 Zhang[53] 2000 China Asian PCR-RELP 63/71 8 N(0.009) 0+7 0+5 0+50 3+56 6+0 6+0 Zhang[54] 2003 China Asian PCR-RELP 74/191 8 Y(0.878) 0+5 1+23 1+55 1+134 12+1 31+1 Sun[55] 2013 China Asian PCR-RELP 243/78 7 Y(0.414) 6+36 2+12 0+180 1+55 21+0 6+1 Hua[56] 2006 China Asian PCR-RELP 50/60 8 Y(0.190) 2+4 0+7 4+68 2+75 20+2 13+3 Guo[57] 2003 China Asian PCR-RELP 40/52 7 Y(0.739) 0+4 0+5 2+23 1+39 9+2 6+1 Liang[23] 2017 China Asian PCR-RELP 44/374 6 Y(0.816) 1+3 5+57 1+31 6+267 7+1 38+1 Shen[58] 2002 China Asian PCR-RELP 106/110 7 Y(0.577) 1+7 1+12 2+84 4+74 11+1 18+1 Zheng[59] 1998 China Asian PCR-RELP 112/60 8 Y(0.801) 2+16 1+8 1+81 0+45 11+1 6+0 Hua[60] 2004 China Asian PCR-RELP 38/60 7 Y(0.434) 1+7 0+4 2+24 1+45 4+0 8+2 Liu[24] 2014 China Asian PCR-RELP 215/298 7 N(< 0.001)) 10+0 2+0 0+174 0+272 31+0 23+1 Xiang[61] 1995 China Asian PCR-RELP 125/50 7 Y(0.715) 2+16 0+4 0+78 1+38 26+3 6+1 Chen[25] 2006 China Asian PCR-RELP 97/105 7 Y(0.906) 2+15 1+18 1+70 2+72 8+1 10+1 Xiang[62] 1999 China Asian PCR-ASO 130/50 8 Y(0.715) 3+14 0+4 1+85 1+38 24+3 6+1 Shen[63] 2002 China Asian PCR-RELP 35/50 6 Y(0.112) 3+11 0+6 2+4 4+31 14+0 9+0 Xiong[26] 2013 China Asian PCR-RELP 121/112 8 Y(0.991) 0+15 1+13 1+72 2+72 31+2 22+2 Zhou[64] 2005 China Asian PCR-RELP 67/68 7 Y(0.263) 0+13 2+9 1+47 0+46 6+0 11+0 Xiang[65] 2005 China Asian PCR-ASO 101/95 7 Y(0.438) 1+10 1+10 1+65 1+65 20+4 15+3 Long[66] 1999 China Asian PCR-RELP 67/135 7 Y(0.124) 0+15 0+18 3+36 4+101 12+1 12+0 Liang[67] 2005 China Asian PCR-RELP 145/90 8 Y(0.592) 0+17 0+12 6+102 2+68 18+2 8+0 Gu[68] 2004 China Asian PCR-RELP 63/90 8 Y(0.592) 0+9 0+12 3+43 2+68 7+1 8+0 Yang[69] 1995 China Asian PCR-RELP 125/50 7 N(0.028) 2+16 1+3 0+78 1+38 26+3 5+2 Rong[32] 2013 China Asian PCR-RELP 18/29 7 Y(0.953) 0+4 0+8 0+18 0+29 2+0 1+0 Liu[27] 2016 China Asian PCR-RELP 300/300 8 N(< 0.001) 14+0 2+0 0+243 0+274 43+0 23+1 Tang[28] 2007 China Asian PCR-RELP 41/60 6 Y(0.80) 0+1 0+3 2+28 1+43 10+0 13+0 Qiu[70] 2008 China Asian PCR-RELP 129/110 8 Y(0.481) 0+14 1+18 3+95 2+76 14+3 11+2 Guo[71] 2007 China Asian ARMS-PCR 40/40 6 Y(0.618) 0+1 1+4 3+29 1+27 7+1 7+0 Xiong[72] 2008 China Asian MultiARMS PCR 316/512 6 Y(0.744) 2+18 3+48 6+230 9+359 47+13 87+6 Ge[29] 2013 China Asian PCR-RELP 200/210 7 Y(0.544) 3+35 8+40 2+86 8+103 73+1 47+4 Xiang[73] 2010 China Asian PCR-RELP 41/102 7 Y(0.473) 0+5 0+13 1+28 0+70 7+0 19+0 Luo[30] 2016 China Asian PCR-RELP 35/50 6 N(0.005) 0+3 0+2 1+28 3+38 2+1 7+0 Zhang[74] 2007 China Asian PCR-RELP 38/49 6 N(0.015) 0+2 0+1 0+32 2+39 3+1 7+0 Wang[31] 2014 China Asian PCR-RELP 57/55 8 N(0.027) 0+4 2+7 2+33 4+28 13+5 8+6 Zhang[75] 1999 China Asian PCR-RELP 56/76 5 Y(0.631) 0+3 1+7 1+40 2+55 11+1 11+1 Xiong[76] 2005 China Asian PCR-RELP 32/30 7 Y(0.608) 1+5 0+4 1+22 1+23 2+1 2+0 Dai[77] 2000 China Asian PCR-RELP 32/90 8 Y(0.253) 0+5 0+14 0+23 1+64 3+1 9+2 Note. HWE, Hardy-Weinberg equilibrium. Table 1. Main characteristics of the included studies
Variable OR (95% CI) I2 (%) P ApoE alleles ε2 1.16 (0.98, 1.37) 62 0.079 ε4 1.18 (1.09, 1.28) 36 < 0.001 ApoE genotypes ε2/ε2 1.46 (1.11, 1.93) 0 0.007 ε2/ε3 1.09 (0.90, 1.32) 55 0.397 ε2/ε4 1.15 (0.90, 1.46) 0 0.276 ε3/ε4 1.11 (1.01, 1.22) 39 0.039 ε4/ε4 1.71 (1.33, 2.19) 0 < 0.001 Note. ApoE alleles (ε2 and ε4) and genotypes (ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε4, and ε4/ε4) were compared with ε3 and ε3/ε3. Table 2. Meta-analysis results of association between ApoE polymorphism and type 2 diabetes
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We found a significant heterogeneity when we comparing ApoE ε2 with ε3 allele (I2 = 62%), and had the pooled OR of 1.16 (95% CI: 0.98-1.37; P = 0.079) calculated by the random-effects model (Figure 2); however, there was not heterogeneity in the comparison of ApoE ε4 with ε3 allele (I2 = 36%), and the pooled OR was 1.18 (95% CI: 1.09-1.28; P < 0.001) when the fixed-effects model was applied to compare ApoE ε4 with ε3 (Figure 3), indicating that ApoE ε4 allele may be a risk factor for type 2 diabetes.
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There were five genotypes (ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε4
, and ε4/ε4) were compared with ε3/ε3 genotype. No significant heterogeneity was found when the comparison was performed between the ε2/ε2 and ε3/ε3 genotypes (I2 = 0%), and the yielded OR of ε2/ε2 genotype versus ε3/ε3 genotype using a fixed-effects model was 1.46 (95% CI: 1.11-1.93; P = 0.007) (Figure 4), indicating that the ε2/ε2 genotype might produce a harmful effect on type 2 diabetes. However, when ε2/ε3 genotype was compared with ε3/ε3 genotype, there was significant heterogeneity (I2 = 55%), and the yielded OR of ε2/ε3 genotype versus ε3/ε3 genotype using a random-effects model was 1.09 (95% CI: 0.90-1.32; P = 0.397) (Figure 5). Compared with ε3/ε3 genotype, there were no significant heterogeneity between ε2/ε4, ε3/ε4, and ε4/ε4 genotype, respectively (I2 = 0%, I2 = 39%, and I2 = 0%). The yielded OR of ε2/ε4 genotype versus ε3/ε3 genotype using a fixed-effects model was 1.15 (95% CI: 0.90-1.46; P = 0.276) (Figure 6). The yielded OR of ε3/ε4 genotype versus ε3/ε3 genotype using a fixed-effects model was 1.11 (95% CI: 1.01-1.22; P = 0.039) (Figure 7). For the comparison of ε4/ε4 genotype with ε3/ε3 genotype, the yielded OR showed a 1.71-fold risk of type 2 diabetes (OR = 1.71; 95% CI: 1.33-2.19; P < 0.001) using the fixed-effects model (Figure 8). Figure 4. Forest plot for the result of association between type 2 diabetes and ApoE ε2/ε2 genotype vs. ε3/ε3 genotype based on a fixed-effects model
Figure 5. Forest plot for the result of association between type 2 diabetes and ApoE ε2/ε3 genotype vs. ε3/ε3 genotype based on a random-effects model
Figure 6. Forest plot for the result of association between type 2 diabetes and ApoE ε2/ε4 genotype vs. ε3/ε3 genotype based on a fixed-effects model
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We conducted subgroup analysis stratified by ethnicity, quality score and Hardy–Weinberg equilibrium in order to identify main sources of heterogeneity. There were significant heterogeneity in the comparison of ApoE ε2 with ε3 allele (I2 = 62%) and the comparison of ε2/ε3 genotype with ε3/ε3 genotype (I2 = 55%) in our paper; however, we could not identify the sources of heterogeneity and there was no significant association between ApoE polymorphisms and type 2 diabetes in different subgroups (Supplementary Figures S1-S3, available in www.besjournal.com).
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Funnel plots was used to assess and Begg’s and Egger’s tests to quantify the publication bias. All the funnel plots for ApoE allele and ApoE genotypes seemed symmetrical (Supplementary Figures S4-S5, available in www.besjournal.com), and the results of Begg’s and Egger’s tests revealed that no publication bias was present for the association between ApoE allele and type 2 diabetes and between the ApoE genotypes and type 2 diabetes (all P > 0.05).
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According to our results of sensitivity analysis, no individual study produced influence on the corresponding pooled ORs and 95% CIs in the comparison of ApoE allele with ε3 allele or in the comparison of ApoE genotypes with genotype ε3/ε3 genotype, which indicated these results were relatively stable and credible.
Association between ApoE Polymorphism and Type 2 Diabetes: A Meta-Analysis of 59 Studies
doi: 10.3967/bes2019.104
- Received Date: 2019-05-31
- Accepted Date: 2019-09-17
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Key words:
- Apolipoprotein E /
- Polymorphism /
- Type 2 diabetes /
- Meta-analysis
Abstract:
Citation: | CHEN Da Wei, SHI Ji Kang, LI Yun, YANG Yu, REN Shu Ping. Association between ApoE Polymorphism and Type 2 Diabetes: A Meta-Analysis of 59 Studies[J]. Biomedical and Environmental Sciences, 2019, 32(11): 823-838. doi: 10.3967/bes2019.104 |