Abstract
In the past decade, a number of case–control studies have been carried out to investigate the relationship between the ApoE polymorphism and diabetic nephropathy. However, the results have been inconclusive. To investigate this inconsistency, we performed a meta-analysis of all available studies dealing with the relationship between the ApoE polymorphism and DN. The 23 studies in the meta- analysis included 6,012 diabetic patients with (n = 2,979) and without (n = 3,033) DN. The ApoE ε2 allele was significantly associated with DN (OR = 1.64, 95% CI: 1.26–2.13; P(Z) = 0.00027), whereas the ε4 allele was non-significantly associated with DN (OR = 0.93, 95% CI: 0.78–1.11; P(Z) = 0.418). However, significant heterogeneity was detected. In further subgroup analyses, genotyping methods, outcome of cases and duration of diabetes in controls were found to explain some of the heterogeneity. Genotypic analysis also found a strong association between the ε2 carriers and DN (OR = 1.61, 95% CI: 1.22–2.13; P(Z) = 0.001) and indicated that ε4 tended to have a marginally significant protective effect for DN (OR = 0.82, 95% CI: 0.65–1.03; P(Z) = 0.085). The results of our meta-analysis support a genetic association between the ApoE polymorphism and DN. ε2 increases the risk of DN in diabetes patients, while ε4 trends to be protective. These findings may have implications for therapeutic intervention in diabetic nephropathy.



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Abbreviations
- DN:
-
Diabetic Nephropathy
- ApoE:
-
Apolipoprotein E
- HWE:
-
Hardy-Weinberg equilibrium
- OR:
-
Odds Ratio
- CI:
-
Confidence Interval
References
Gross JL et al (2005) Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care 28(1):164–176
Rippin JD, Patel A, Bain SC (2001) Genetics of diabetic nephropathy. Best Pract Res Clin Endocrinol Metab 15(3):345–358
Kimura H et al (1998) Apolipoprotein E4 reduces risk of diabetic nephropathy in patients with NIDDM. Am J Kidney Dis 31(4):666–673
Chowdhury TA et al (1999) Genetic determinants of diabetic nephropathy. Clin Sci (Lond) 96(3):221–230
Joss N et al (2005) Influence of apolipoprotein E genotype on progression of diabetic nephropathy. Nephron Exp Nephrol 101(4):e127–e133
Quinn M et al (1996) Familial factors determine the development of diabetic nephropathy in patients with IDDM. Diabetologia 39(8):940–945
Ravid M et al (1998) Main risk factors for nephropathy in type 2 diabetes mellitus are plasma cholesterol levels, mean blood pressure, and hyperglycemia. Arch Intern Med 158(9):998–1004
Ha SK et al (1999) Association between apolipoprotein E polymorphism and macroalbuminuria in patients with non-insulin dependent diabetes mellitus. Nephrol Dial Transplant 14(9):2144–2149
Jandeleit-Dahm K et al (1999) Role of hyperlipidemia in progressive renal disease: focus on diabetic nephropathy. Kidney Int Suppl 71:S31–S36
Lam KS et al (1995) Cholesterol-lowering therapy may retard the progression of diabetic nephropathy. Diabetologia 38(5):604–609
Eto M et al (2002) Apolipoprotein E genetic polymorphism, remnant lipoproteins, and nephropathy in type 2 diabetic patients. Am J Kidney Dis 40(2):243–251
Park JS et al (2004) Apolipoprotein E genetic polymorphism and diabetic microangiopathy in type 2 diabetic patients. J Korean Diab Assoc 28:511–520
Krieger M, Herz J (1994) Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu Rev Biochem 63:601–637
Mahley RW (1988) Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240(4852):622–630
Ha TS et al (2004) Regulation of glomerular endothelial cell proteoglycans by glucose. J Korean Med Sci 19(2):245–252
Moorhead JF et al (1982) Lipid nephrotoxicity in chronic progressive glomerular and tubulo-interstitial disease. Lancet 2(8311):1309–1311
Diamond JR (1991) Analogous pathobiologic mechanisms in glomerulosclerosis and atherosclerosis. Kidney Int Suppl 31:S29–S34
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188
Zintzaras E, Hadjigeorgiou GM (2004) Association of paraoxonase 1 gene polymorphisms with risk of Parkinson’s disease: a meta-analysis. J Hum Genet 49(9):474–481
Woolf B (1955) On estimating the relation between blood group and disease. Ann Hum Genet 19(4):251–253
Egger M et al (1997) Bias in meta-analysis detected by a simple, graphical test. Bmj 315(7109):629–634
Horita K, Eto M, Makino I (1994) Apolipoprotein E2, renal failure and lipid abnormalities in non-insulin-dependent diabetes mellitus. Atherosclerosis 107(2):203–211
Onuma T et al (1996) Apolipoprotein E genotypes and risk of diabetic nephropathy. J Am Soc Nephrol 7(7):1075–1078
Chowdhury TA et al (1998) Association of apolipoprotein epsilon2 allele with diabetic nephropathy in Caucasian subjects with IDDM. Diabetes 47(2):278–280
Tarnow L et al (2000) Plasminogen activator inhibitor-1 and apolipoprotein E gene polymorphisms and diabetic angiopathy. Nephrol Dial Transplant 15(5):625–630
Hadjadj S et al (2000) Lack of relationship in long-term type 1 diabetic patients between diabetic nephropathy and polymorphisms in apolipoprotein epsilon, lipoprotein lipase and cholesteryl ester transfer protein. Genetique de la Nephropathie Diabetique Study Group. Donnees Epidemiologiques sur le Syndrome d’Insulino-Resistance Study Group. Nephrol Dial Transplant 15(12):1971–1976
Araki S et al (2000) APOE polymorphisms and the development of diabetic nephropathy in type 1 diabetes: results of case-control and family-based studies. Diabetes 49(12):2190–2195
Shcherbak NS (2001) Apolipoprotein E gene polymorphism is not a strong risk factor for diabetic nephropathy and retinopathy in Type I diabetes: case-control study. BMC Med Genet 2:8
Akarsu E, Purum Ü (2001) A relation between the apolipoprotein E genotypes and microalbuminuria in type 2 diabetes mellitus. Turk J Med Sci 31:59–64
Orchard TJ et al (2002) Nephropathy in type 1 diabetes: a manifestation of insulin resistance and multiple genetic susceptibilities? Further evidence from the Pittsburgh Epidemiology of Diabetes Complication Study. Kidney Int 62(3):963–970
Hsieh MC et al (2002) Higher frequency of apolipoprotein E2 allele in type 2 diabetic patients with nephropathy in Taiwan. J Nephrol 15(4):368–373
Araki S et al (2003) APOE polymorphism and the progression of diabetic nephropathy in Japanese subjects with type 2 diabetes: results of a prospective observational follow-up study. Diabetes Care 26(8):2416–2420
Liu L et al (2003) Co-inheritance of specific genotypes of HSPG and ApoE gene increases risk of type 2 diabetic nephropathy. Mol Cell Biochem 254(1–2):353–358
Ng MC et al (2006) Association of lipoprotein lipase S447X, apolipoprotein E exon 4, and apoC3–455T>C polymorphisms on the susceptibility to diabetic nephropathy. Clin Genet 70(1):20–28
Leiva E et al (2007) Relationship between Apolipoprotein E polymorphism and nephropathy in type-2 diabetic patients. Diabetes Res Clin Pract 78(2):196–201
Kwon MK et al (2007) Association between apolipoprotein E genetic polymorphism and the development of diabetic nephropathy in type 2 diabetic patients. Diabetes Res Clin Pract 77(Suppl 1):S228–S232
Ilhan N et al (2007) Apo E gene polymorphism on development of diabetic nephropathy. Cell Biochem Funct 25(5):527–532
Ma SW, Benzie IF, Yeung VT (2008) Type 2 diabetes mellitus and its renal complications in relation to apolipoprotein E gene polymorphism. Transl Res 152(3):134–142
Guan J et al (2009) Apolipoprotein E polymorphism and expression in type 2 diabetic patients with nephropathy: clinicopathological correlation. Nephrol Dial Transplant 24(6):1889–1895
Erdogan M et al (2009) The relationship of the apolipoprotein E gene polymorphismin Turkish Type 2 diabetic patients with and without nephropathy. J Endocrinol Invest 32(3):219–222
Eto M et al (1995) Increased frequency of apolipoprotein epsilon 2 allele in non-insulin dependent diabetic (NIDDM) patients with nephropathy. Clin Genet 48(6):288–292
Xu MQ, St Clair D, He L (2006) Meta-analysis of association between ApoE epsilon4 allele and schizophrenia. Schizophr Res 84(2–3):228–235
Liberopoulos E, Siamopoulos K, Elisaf M (2004) Apolipoprotein E and renal disease. Am J Kidney Dis 43(2):223–233
Sato H et al (1991) Immunohistological localization of apolipoproteins in the glomeruli in renal disease: specifically apoB and apoE. Clin Nephrol 36(3):127–133
Bruneval P et al (2002) Mesangial expansion associated with glomerular endothelial cell activation and macrophage recruitment is developing in hyperlipidaemic apoE null mice. Nephrol Dial Transplant 17(12):2099–2107
Chen G et al (2001) A protective role for kidney apolipoprotein E. Regulation of mesangial cell proliferation and matrix expansion. J Biol Chem 276(52):49142–49147
Acknowledgments
This work was supported by grants (2006CB910600, 2007CB947300, 07DZ22917, and 09DJ1400601), by the Shanghai Leading Academic Discipline Project (B205), the Shanghai Municipality Science & Technology Commission (2008ZD001, 05JC14090,07DJ14005). the Chinese Academy of Sciences(KSCX2-YW-R-01) and the National Natural Science Foundation of China (30700203).
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Li, Y., Tang, K., Zhang, Z. et al. Genetic diversity of the apolipoprotein E gene and diabetic nephropathy: a meta-analysis. Mol Biol Rep 38, 3243–3252 (2011). https://doi.org/10.1007/s11033-010-9999-z
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DOI: https://doi.org/10.1007/s11033-010-9999-z