Role of Apolipoprotein E gene polymorphism in the risk of familial hypercholesterolemia: a case-control study

  • Turky H Almigbal Department of Family and Community Medicine, King Saud University, Riyadh, Saudi Arabia.
  • Mohammed Ali Batais Department of Family and Community Medicine, King Saud University, Riyadh, Saudi Arabia.
  • Rana M Hasanato Department of Pathology College of Medicine and University Hospitals, King Saud University, Riyadh, Kingdom of Saudi Arabia.
  • Fawaziah Khalaf Alharbi Department of Biology Science, College of Science and Arts, Al-Qassim University, Al-Qassim, Saudi Arabia.
  • Imran Ali Khan Dr. Imran Ali Khan Mohammed Research Scientist Clinical Laboratory Sciences Department College of Applied Medical Sciences King Saud University Riyadh-11433 Kingdom of Saudi Arabia
  • Khalid Khalaf Alharbi Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, PO Box-10219, Riyadh-11433, Kingdom of Saudi Arabia.


Familial Hypercholesterolemia (FH) is characterized by elevated cholesterol; this is based on biochemical, clinical, and genetic studies and FH disease, which was documented even with limited mutations. Earlier studies were associated with Apolipoprotein E (ApoE) in variable diseases. The current study aims to investigate the genetic association between FH disease and ApoE gene (rs429358 and rs7412) in the Saudi population. This study has been carried out as a case-control and is a hospital-based study in Saudi Arabia. Two hundred and four subjects were recruited as FH participants (n=104) and the others as controls (n=100). Common polymorphisms (rs429358 and rs7412) were selected from the ApoE gene and we then performed the genotyping as the TaqMan assay. Moreover, the ApoE risk allele E4 is significantly associated in FH cases and controls (OR-2.24 (95%CI: 1.06-4.70); p=0.02). Lipid profile parameters were significantly associated (p<0.05); however, a combination of ApoE alleles and lipid profiles could not find a correlation (p>0.05). The FH case-control study was associated with the E4 allele in the Saudi population. The risk of allele E4 which is a reliable marker for lipid profiles, but did not correlate with ApoE alleles. 

Author Biographies

Turky H Almigbal, Department of Family and Community Medicine, King Saud University, Riyadh, Saudi Arabia.
Assistant Professor
Mohammed Ali Batais, Department of Family and Community Medicine, King Saud University, Riyadh, Saudi Arabia.
Assistant Professor
Rana M Hasanato, Department of Pathology College of Medicine and University Hospitals, King Saud University, Riyadh, Kingdom of Saudi Arabia.
Associate Professor
Fawaziah Khalaf Alharbi, Department of Biology Science, College of Science and Arts, Al-Qassim University, Al-Qassim, Saudi Arabia.
Assistant Professor
Imran Ali Khan, Dr. Imran Ali Khan Mohammed Research Scientist Clinical Laboratory Sciences Department College of Applied Medical Sciences King Saud University Riyadh-11433 Kingdom of Saudi Arabia
Assistant Professor
Khalid Khalaf Alharbi, Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, PO Box-10219, Riyadh-11433, Kingdom of Saudi Arabia.



Afroze, D., Yousuf, A., Tramboo, N. A., Shah, Z. A., & Ahmad, A. (2016). ApoE gene polymorphism and its relationship with coronary artery disease in ethnic Kashmiri population. Clin Exp Med, 16(4), 551-556. doi:10.1007/s10238-015-0389-7

Agarwal, R., & Tripathi, C. B. (2014). Association of apolipoprotein E genetic variation in Alzheimer's disease in Indian population: a meta-analysis. Am J Alzheimers Dis Other Demen, 29(7), 575-582. doi:10.1177/1533317514531443

Al-Allaf, F. A., Alashwal, A., Abduljaleel, Z., Taher, M. M., Bouazzaoui, A., Abalkhail, H., . . . Athar, M. (2017). Compound heterozygous LDLR variant in severely affected familial hypercholesterolemia patient. Acta Biochim Pol, 64(1), 75-79. doi:10.18388/abp.2016_1283

Al-Allaf, F. A., Alashwal, A., Abduljaleel, Z., Taher, M. M., Siddiqui, S. S., Bouazzaoui, A., . . . Athar, M. (2016). Identification of a recurrent frameshift mutation at the LDLR exon 14 (c.2027delG, p.(G676Afs*33)) causing familial hypercholesterolemia in Saudi Arab homozygous children. Genomics, 107(1), 24-32. doi:10.1016/j.ygeno.2015.12.001

Al-Allaf, F. A., Athar, M., Abduljaleel, Z., Bouazzaoui, A., Taher, M. M., Own, R., . . . Alashwal, A. (2014). Identification of a novel nonsense variant c.1332dup, p.(D445*) in the LDLR gene that causes familial hypercholesterolemia. Hum Genome Var, 1, 14021. doi:10.1038/hgv.2014.21

Al-Allaf, F. A., Athar, M., Abduljaleel, Z., Taher, M. M., Khan, W., Ba-Hammam, F. A., . . . Alashwal, A. (2015). Next generation sequencing to identify novel genetic variants causative of autosomal dominant familial hypercholesterolemia associated with increased risk of coronary heart disease. Gene, 565(1), 76-84. doi:10.1016/j.gene.2015.03.064

Alallaf, F., FA, H. N., Alnefaie, M., Almaymuni, A., Rashidi, O. M., Alhabib, K., . . . Awan, Z. (2017). The Spectrum of Familial Hypercholesterolemia (FH) in Saudi Arabia: Prime Time for Patient FH Registry. Open Cardiovasc Med J, 11, 66-75. doi:10.2174/1874192401711010066

Aledo, R., Padro, T., Mata, P., Alonso, R., & Badimon, L. (2015). rs11613352 polymorphism (TT genotype) associates with a decrease of triglycerides and an increase of HDL in familial hypercholesterolemia patients. Rev Esp Cardiol (Engl Ed), 68(4), 305-309. doi:10.1016/j.rec.2014.04.015

Alharbi, K. K., Alharbi, F. K., Alharbi, F. K., Ghneim, H. K., Al-Sulaiman, A., Alodhayani, A. A., . . . Khan, I. A. (2016). Amendment of amino acid in Q192R genetic polymorphism of paraoxonase 1 is a conventional risk factor for type 2 diabetes mellitus in the Saudi population. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE, 9(8), 16605-16612.

Alharbi, K. K., Kashour, T. S., Al-Hussaini, W., Al-Nbaheen, M. S., Mohamed, S., Hasanato, R. M., . . . Khan, I. A. (2013). Association of angiotensin converting enzyme gene insertion/deletion polymorphism and familial hypercholesterolemia in the Saudi population. Lipids Health Dis, 12, 177. doi:10.1186/1476-511x-12-177

Alharbi, K. K., Kashour, T. S., Al-Hussaini, W., Nbaheen, M. S., Hasanato, R. M., Mohamed, S., . . . Khan, I. A. (2015). Screening for genetic mutations in LDLR gene with familial hypercholesterolemia patients in the Saudi population. Acta Biochim Pol, 62(3), 559-562. doi:10.18388/abp.2015_1015

Alharbi, K. K., Khan, I. A., & Syed, R. (2014). Association of apolipoprotein E polymorphism with type 2 diabetes mellitus in a Saudi population. DNA Cell Biol, 33(9), 637-641. doi:10.1089/dna.2014.2461

Angarica, V. E., Orozco, M., & Sancho, J. (2016). Exploring the complete mutational space of the LDL receptor LA5 domain using molecular dynamics: linking SNPs with disease phenotypes in familial hypercholesterolemia. Hum Mol Genet, 25(6), 1233-1246. doi:10.1093/hmg/ddw004

Arati, S., Sibin, M. K., Bhat, D. I., Narasingarao, K. V., & Chetan, G. K. (2016). Polymorphisms of apolipoprotein E and aneurysmal subarachnoid haemorrhage: A meta-analysis. Meta gene, 9, 151-158. doi:10.1016/j.mgene.2016.06.003

Awan, Z., Choi, H. Y., Stitziel, N., Ruel, I., Bamimore, M. A., Husa, R., . . . Genest, J. (2013). APOE p.Leu167del mutation in familial hypercholesterolemia. Atherosclerosis, 231(2), 218-222. doi:10.1016/j.atherosclerosis.2013.09.007

Benn, M., Watts, G. F., Tybjaerg-Hansen, A., & Nordestgaard, B. G. (2012). Familial hypercholesterolemia in the danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab, 97(11), 3956-3964. doi:10.1210/jc.2012-1563

Braenne, I., Reiz, B., Medack, A., Kleinecke, M., Fischer, M., Tuna, S., . . . Schunkert, H. (2014). Whole-exome sequencing in an extended family with myocardial infarction unmasks familial hypercholesterolemia. BMC Cardiovasc Disord, 14, 108. doi:10.1186/1471-2261-14-108

Cao, L., Wang, K., Gu, T., Du, B., & Song, J. (2014). Association between APOE epsilon 4 allele and postoperative cognitive dysfunction: a meta-analysis. International Journal of Neuroscience, 124(7), 478-485.

Carmena, R., Roederer, G., Mailloux, H., Lussier-Cacan, S., & Davignon, J. (1993). The response to lovastatin treatment in patients with heterozygous familial hypercholesterolemia is modulated by apolipoprotein E polymorphism. Metabolism, 42(7), 895-901.

Chan, D. C., Pang, J., Barrett, P. H. R., Sullivan, D. R., Burnett, J. R., van Bockxmeer, F. M., & Watts, G. F. (2016). ω-3 Fatty acid ethyl esters diminish postprandial lipemia in familial hypercholesterolemia. The Journal of Clinical Endocrinology & Metabolism, 101(10), 3732-3739.

Davignon, J., Bouthillier, D., Nestruck, A. C., & Sing, C. F. (1988). Apolipoprotein E polymorphism and atherosclerosis: insight from a study in octogenarians. Trans Am Clin Climatol Assoc, 99, 100-110.

Drogari, E., Ragia, G., Mollaki, V., Elens, L., Van Schaik, R. H., & Manolopoulos, V. G. (2014). POR*28 SNP is associated with lipid response to atorvastatin in children and adolescents with familial hypercholesterolemia. Pharmacogenomics, 15(16), 1963-1972. doi:10.2217/pgs.14.138

Eto, M., Watanabe, K., Chonan, N., & Ishii, K. (1988). Familial hypercholesterolemia and apolipoprotein E4. Atherosclerosis, 72(2-3), 123-128.

Fallaize, R., Celis-Morales, C., Macready, A. L., Marsaux, C. F., Forster, H., O'Donovan, C., . . . Lovegrove, J. A. (2016). The effect of the apolipoprotein E genotype on response to personalized dietary advice intervention: findings from the Food4Me randomized controlled trial. Am J Clin Nutr, 104(3), 827-836. doi:10.3945/ajcn.116.135012

Friedlander, Y., & Leitersdorf, E. (1996). Influence of apolipoprotein E genotypes on plasma lipid and lipoprotein concentrations: results from a segregation analysis in pedigrees with molecularly defined familial hypercholesterolemia. Genet Epidemiol, 13(2), 159-177. doi:10.1002/(SICI)1098-2272(1996)13:2<159::AID-GEPI3>3.0.CO;2-3

Futema, M., Plagnol, V., Li, K., Whittall, R. A., Neil, H. A., Seed, M., . . . Humphries, S. E. (2014). Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations. J Med Genet, 51(8), 537-544. doi:10.1136/jmedgenet-2014-102405

Garatachea, N., Marin, P. J., Santos-Lozano, A., Sanchis-Gomar, F., Emanuele, E., & Lucia, A. (2015). The ApoE gene is related with exceptional longevity: a systematic review and meta-analysis. Rejuvenation Res, 18(1), 3-13. doi:10.1089/rej.2014.1605

Gatt, J. M., Burton, K. L., Williams, L. M., & Schofield, P. R. (2015). Specific and common genes implicated across major mental disorders: a review of meta-analysis studies. J Psychiatr Res, 60, 1-13. doi:10.1016/j.jpsychires.2014.09.014

Graham, C. A., Latten, M. J., & Hart, P. J. (2017). Molecular diagnosis of familial hypercholesterolaemia. Curr Opin Lipidol, 28(4), 313-320. doi:10.1097/mol.0000000000000430

Gu, L., Su, L., Chen, Q., Liang, B., Qin, Y., Xie, J., . . . Wang, J. (2013). Association between the apolipoprotein E gene polymorphism and ischemic stroke in Chinese populations: New data and meta-analysis. Exp Ther Med, 5(3), 853-859. doi:10.3892/etm.2012.866

Haidich, A.-B. (2010). Meta-analysis in medical research. Hippokratia, 14(Suppl 1), 29.

Han, Y., Liu, T., & Lu, L. (2013). Apolipoprotein E gene polymorphism in psoriasis: a meta-analysis. Archives of medical research, 44(1), 46-53.

Hiddink, L., Dallinga-Thie, G. M., Hovingh, G. K., de Visser, M. C., Peer, P. G., Stalenhoef, A. F., & van Heerde, W. L. (2015). Annexin A5 haplotypes in familial hypercholesterolemia: lack of association with carotid intima-media thickness and cardiovascular disease risk. Atherosclerosis, 238(2), 195-200. doi:10.1016/j.atherosclerosis.2014.11.023

Hinchcliffe, M., Le, H., Fimmel, A., Molloy, L., Freeman, L., Sullivan, D., & Trent, R. J. (2014). Diagnostic validation of a familial hypercholesterolaemia cohort provides a model for using targeted next generation DNA sequencing in the clinical setting. Pathology, 46(1), 60-68. doi:10.1097/pat.0000000000000026

Ho, C. K., Musa, F. R., Bell, C., & Walker, S. W. (2015). LDLR gene synonymous mutation c.1813C>T results in mRNA splicing variation in a kindred with familial hypercholesterolaemia. Ann Clin Biochem, 52(Pt 6), 680-684. doi:10.1177/0004563215572702

Jensen, H. K. (2002). The molecular genetic basis and diagnosis of familial hypercholesterolemia in Denmark. Dan Med Bull, 49(4), 318-345.

Karahan, Z., Ugurlu, M., Ucaman, B., Ulug, A. V., Kaya, I., Cevik, K., . . . Iyem, H. (2015). Relation between Apolipoprotein E Gene Polymorphism and Severity of Coronary Artery Disease in Acute Myocardial Infarction. Cardiol Res Pract, 2015, 363458. doi:10.1155/2015/363458

Katsanis, S. H., & Katsanis, N. (2013). Molecular genetic testing and the future of clinical genomics. Nat Rev Genet, 14(6), 415-426. doi:10.1038/nrg3493

Khan, I. A., Vattam, K. K., Jahan, P., Hasan, Q., & Rao, P. (2016). Importance of glucokinase -258G/A polymorphism in Asian Indians with post-transplant and type 2 diabetes mellitus. Intractable Rare Dis Res, 5(1), 25-30. doi:10.5582/irdr.2015.01040

Leduc, V., Bourque, L., Poirier, J., & Dufour, R. (2016). Role of rs3846662 and HMGCR alternative splicing in statin efficacy and baseline lipid levels in familial hypercholesterolemia. Pharmacogenet Genomics, 26(1), 1-11. doi:10.1097/fpc.0000000000000178

Li, T., Shi, Y., Yin, J., Qin, Q., Wei, S., Nie, S., & Liu, L. (2015). The association between lipid metabolism gene polymorphisms and nephropathy in type 2 diabetes: a meta-analysis. Int Urol Nephrol, 47(1), 117-130.

Liao, R., Ye, M., & Xu, X. (2014). An updated meta-analysis: apolipoprotein E genotypes and risk of primary open-angle glaucoma. Mol Vis, 20, 1025-1036.

Lin, Y. J., Pan, J. L., Jiang, M. J., Tan, J. H., Zhong, W., Gong, T. K., . . . Wu, Y. J. (2014). Apo E gene polymorphism affects development of type 2 diabetic nephropathy in Asian populations, especially in East Asians: an updated meta-analysis. Med Sci Monit, 20, 1596-1603. doi:10.12659/msm.892111

Liu, M., Bian, C., Zhang, J., & Wen, F. (2014). Apolipoprotein E gene polymorphism and Alzheimer's disease in Chinese population: a meta-analysis. Sci Rep, 4, 4383. doi:10.1038/srep04383

Lye, S. H., Chahil, J. K., Bagali, P., Alex, L., Vadivelu, J., Ahmad, W. A., . . . Mohamed, R. (2013). Genetic polymorphisms in LDLR, APOB, PCSK9 and other lipid related genes associated with familial hypercholesterolemia in Malaysia. PloS one, 8(4), e60729. doi:10.1371/journal.pone.0060729

Maurera, F., Pradervandb, S., Guilleretb, I., Nanchend, D., Maghraouib, A., Chapatteb, L., . . . Harshmanc, K. (2016). Identification and molecular characterisation of Lausanne Institutional Biobank participants with familial hypercholesterolaemia–a proof-of-concept study. Swiss Med Wkly, 146, w14326.

Megale, R. Z., de Loyola Filho, A. I., Firmo, J. O., Lima-Costa, M. F., & Peixoto, S. V. (2016). Apolipoprotein E polymorphism and functional disability in Brazilian elders: the Bambui Health and Aging Study. Cad Saude Publica, 32(2), e00080115. doi:10.1590/0102-311x00080115

Meng, H.-x., Qi, M.-g., Yi, Y.-y., & Liu, Y.-p. (2013). Association between apolipoprotein E gene polymorphism and the risk of recurrent pregnancy loss: a meta-analysis. Journal of assisted reproduction and genetics, 30(12), 1547-1552.

Miao, J., Wang, F., Zheng, W., & Zhuang, X. (2015). Association of the Apolipoprotein E polymorphism with migraine: a meta-analysis. BMC Neurol, 15, 138. doi:10.1186/s12883-015-0385-2

Nikkola, E., Ko, A., Alvarez, M., Cantor, R. M., Garske, K., Kim, E., . . . Pajukanta, P. (2017). Family-specific aggregation of lipid GWAS variants confers the susceptibility to familial hypercholesterolemia in a large Austrian family. Atherosclerosis, 264, 58-66. doi:10.1016/j.atherosclerosis.2017.07.024

Nuglozeh, E. (2017). Whole-Exomes Sequencing Delineates Gene Variants Profile in a Young Saudi Male with Familial Hypercholesterolemia: Case Report. J Clin Diagn Res, 11(6), Gd01-gd06. doi:10.7860/jcdr/2017/28156.10143

Onorato, A., & Sturm, A. C. (2016). Heterozygous familial hypercholesterolemia. Circulation, 133(14), e587-e589.

Pajak, A., Szafraniec, K., Polak, M., Drygas, W., Piotrowski, W., Zdrojewski, T., & Jankowski, P. (2016). Prevalence of familial hypercholesterolemia: a meta-analysis of six large, observational, population-based studies in Poland. Archives of medical science: AMS, 12(4), 687.

Radovica-Spalvina, I., Latkovskis, G., Silamikelis, I., Fridmanis, D., Elbere, I., Ventins, K., . . . Klovins, J. (2015). Next-generation-sequencing-based identification of familial hypercholesterolemia-related mutations in subjects with increased LDL-C levels in a latvian population. BMC Med Genet, 16, 86. doi:10.1186/s12881-015-0230-x

Risch, N., & Merikangas, K. (1996). The future of genetic studies of complex human diseases. science, 273(5281), 1516-1517.

Rubino, E., Vacca, A., Govone, F., De Martino, P., Pinessi, L., & Rainero, I. (2013). Apolipoprotein E polymorphisms in frontotemporal lobar degeneration: a meta-analysis. Alzheimer's & Dementia, 9(6), 706-713.

Saavedra, Y. G., Dufour, R., Davignon, J., & Baass, A. (2014). PCSK9 R46L, lower LDL, and cardiovascular disease risk in familial hypercholesterolemia: a cross-sectional cohort study. Arterioscler Thromb Vasc Biol, 34(12), 2700-2705. doi:10.1161/atvbaha.114.304406

Salanti, G., Sanderson, S., & Higgins, J. P. (2005). Obstacles and opportunities in meta-analysis of genetic association studies. Genet Med, 7(1), 13-20. doi:10.109701.gim.0000151839.12032.1a

Sanchez Munoz-Torrero, J. F., Rivas, M. D., Zamorano, J., Alonso, R., Joya-Vazquez, P., Padro, T., & Mata, P. (2014). rs1801275 Interleukin-4 receptor alpha polymorphism in familial hypercholesterolemia. J Clin Lipidol, 8(4), 418-422. doi:10.1016/j.jacl.2014.04.003

Stoumpos, S., Hamodrakas, S. J., Anthopoulos, P. G., & Bagos, P. G. (2013). The association between apolipoprotein E gene polymorphisms and essential hypertension: a meta-analysis of 45 studies including 13,940 cases and 16,364 controls. J Hum Hypertens, 27(4), 245-255. doi:10.1038/jhh.2012.37

Sun, J.-H., Tan, L., Wang, H.-F., Tan, M.-S., Tan, L., Li, J.-Q., . . . Yu, J.-T. (2015). Genetics of vascular dementia: systematic review and meta-analysis. Journal of Alzheimer's Disease, 46(3), 611-629.

Tada, H., Kawashiri, M. A., Okada, H., Endo, S., Toyoshima, Y., Konno, T., . . . Hayashi, K. (2016). A Rare Coincidence of Sitosterolemia and Familial Mediterranean Fever Identified by Whole Exome Sequencing. J Atheroscler Thromb, 23(7), 884-890. doi:10.5551/jat.34827

Tian, Y., Wang, J., Ye, Y., Sun, L., Fan, Y., Wang, L., . . . Wang, K. (2014). Apolipoprotein E polymorphism and colorectal neoplasm: results from a meta-analysis. PloS one, 9(7), e102477. doi:10.1371/journal.pone.0102477

Utermann, G., Vogelberg, K. H., Steinmetz, A., Schoenborn, W., Pruin, N., Jaeschke, M., . . . Canzler, H. (1979). Polymorphism of apolipoprotein E. II. Genetics of hyperlipoproteinemia type III. Clin Genet, 15(1), 37-62.

van Lennep, J. E. R. (2016). Knowledge equals health; why all healthcare professionals should know about familial hypercholesterolemia. Atherosclerosis, 252, 188-189.

Vandrovcova, J., Thomas, E. R., Atanur, S. S., Norsworthy, P. J., Neuwirth, C., Tan, Y., . . . Aitman, T. J. (2013). The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia. Genet Med, 15(12), 948-957. doi:10.1038/gim.2013.55

Versmissen, J., Oosterveer, D. M., Yazdanpanah, M., Dehghan, A., Holm, H., Erdman, J., . . . Sijbrands, E. J. (2015). Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach. Eur J Hum Genet, 23(3), 381-387. doi:10.1038/ejhg.2014.101

Wang, W., Zhou, M., Huang, W., Chen, S., & Zhang, X. (2013). Lack of association of apolipoprotein E (Apo E) epsilon2/epsilon3/epsilon4 polymorphisms with primary open-angle glaucoma: a meta-analysis from 1916 cases and 1756 controls. PloS one, 8(9), e72644. doi:10.1371/journal.pone.0072644

Wang, Y., Zhou, Y.-F., Zhao, B.-Y., Gu, Z.-Y., & Li, S.-L. (2014). Apolipoprotein E gene ε4ε4 is associated with elevated risk of primary open angle glaucoma in Asians: a meta-analysis. BMC Med Genet, 15(1), 60.

Xu, H., Li, H., Liu, J., Zhu, D., Wang, Z., Chen, A., & Zhao, Q. (2014). Meta-analysis of apolipoprotein E gene polymorphism and susceptibility of myocardial infarction. PloS one, 9(8), e104608. doi:10.1371/journal.pone.0104608

Xu, H., Qian, Y., Guan, J., Yi, H., & Yin, S. (2015). No association between the ApoE epsilon2 and epsilon4 alleles and the risk of obstructive sleep apnea: A systematic review and meta-analysis. Biomed Rep, 3(3), 313-318. doi:10.3892/br.2015.425

Yin, Y.-W., Qiao, L., Sun, Q.-Q., Hu, A.-M., Liu, H.-L., Wang, Q., & Hou, Z.-Z. (2014). Influence of apolipoprotein E gene polymorphism on development of type 2 diabetes mellitus in Chinese Han population: a meta-analysis of 29 studies. Metabolism, 63(4), 532-541.

Yin, Y.-W., Sun, Q.-Q., Zhang, B.-B., Hu, A.-M., Liu, H.-L., Wang, Q., & Hou, Z.-Z. (2013). Association between apolipoprotein E gene polymorphism and the risk of coronary artery disease in Chinese population: evidence from a meta-analysis of 40 studies. PloS one, 8(6), e66924.

Yin, Y.-W., Zhang, Y.-D., Wang, J.-Z., Li, B.-H., Yang, Q.-W., Fang, C.-Q., . . . Zhang, L.-L. (2012). Association between apolipoprotein E gene polymorphism and the risk of multiple sclerosis: a meta-analysis of 6977 subjects. Gene, 511(1), 12-17.

Yousuf, F. A., & Iqbal, M. P. (2015). Review: Apolipoprotein E (Apo E) gene polymorphism and coronary heart disease in Asian populations. Pak J Pharm Sci, 28(4), 1439-1444.

Zeggini, E., & Ioannidis, J. P. (2009). Meta-analysis in genome-wide association studies. Pharmacogenomics, 10(2), 191-201. doi:10.2217/14622416.10.2.191

Zhang, C., Li, S., Zhang, X., Liu, H., & Luo, Y. (2015). Association of ApoE gene with type 2 diabetic nephropathy in a Chinese population: a meta-analysis of case-control studies. Ann Endocrinol (Paris), 76(5), 601-613. doi:10.1016/j.ando.2014.12.001

Zhang, M.-d., Gu, W., Qiao, S.-b., Zhu, E.-j., Zhao, Q.-m., & Lv, S.-z. (2014). Apolipoprotein E gene polymorphism and risk for coronary heart disease in the Chinese population: a meta-analysis of 61 studies including 6634 cases and 6393 controls. PloS one, 9(4), e95463.

Zhang, R., Wang, X., Tang, Z., Liu, J., Yang, S., Zhang, Y., . . . Li, J. (2014). Apolipoprotein E gene polymorphism and the risk of intracerebral hemorrhage: a meta-analysis of epidemiologic studies. Lipids Health Dis, 13(1), 47.

Zhao, D., Zhang, Z., Wu, G. B., Wang, H. Y., Gao, F., Duan, X. D., . . . Song, J. (2016). Apolipoprotein E gene polymorphism and the risk of subarachnoid hemorrhage: a meta-analysis of case-control studies. Acta Neurochir (Wien), 158(8), 1515-1522. doi:10.1007/s00701-016-2824-2

Zhu, H., Xue, H., Wang, H., Ma, Y., Liu, J., & Chen, Y. (2016). The association of apolipoprotein E (APOE) gene polymorphisms with atherosclerosis susceptibility: a meta-analysis. Minerva Cardioangiol, 64(1), 47-54.