Heterozygosity in LDLR rs2228671 and rs72658855 Gene is Associated with Increased Risk of Developing Coronary Artery Disease in India –A Case-Control Study

Author(s): Chandan K. Jha, Rashid Mir*, Shaheena Banu, Imadeldin Elfaki, Sukh M.S. Chahal

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
(Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders)

Volume 20 , Issue 3 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Objective: Coronary artery disease (CAD) is one of the most common causes of death worldwide. Risk factors of CAD include high LDL-C, low high-density lipoprotein (HDL), hypertension, lack of exercise, genetic factors, etc. Polymorphisms of the LDLR gene have been associated with CAD in previous studies.

Methods: The LDLR-rs72658855 C>T genotyping was detected by using allele-specific PCR (ASPCR). The association of rs2228671 and rs72658855 with CAD in a south Indian cohort (200 CAD patients and 200 matched healthy controls was studied.

Results: Our findings showed that rs2228671 gene variability is associated with increased susceptibility to coronary artery disease in the codominant inheritance model for variant CC vs. CT OR 3.42(1.09-10.7), with P<0.034. A non-significant association was reported in the recessive inheritance model for the variant (CC+CT) vs. TT OR 0.56(0.16-1.95), at P<0.36. and in the dominant inheritance model for variant CC vs. (CT+TT) OR 2.8(1.07-7.34), at P<0.032 .In case of allelic comparison, it was indicated that the LDLR rs2228671-T allele was associated with an increased risk of developing CAD compared to C allele OR=2.4, with 95% CI (1.05-5.64) and P< 0.036 . Our findings showed that LDLR rs72658855 C>T gene variability was associated with an increased susceptibility to coronary artery disease in the codominant inheritance model for variant CC vs. CT OR 1.7(1.1-2.6), at P<0.015 and in the dominant inheritance model for variant CC vs. (CT+TT) OR 1.66(1.07-2.58), at P<0.0.02.. In case of allelic comparison, a non-significant association was reported in LDLR rs72658855-T and C allele.

Conclusion: We concluded that the heterozygosity in LDLR-rs72658855 and rs2228671 and T allele in LDLR rs2228671 are strongly associated with increased susceptibility to coronary artery disease. These results must be validated by future well-designed studies with larger sample sizes and different populations.

Keywords: Coronary Artery Disease (CAD), Low-Density Lipoprotein Receptor (LDLR), hypercholesterolemia, atherosclerosis, myocardial infarction, Peripheral Arterial Disease (PAD)

[1]
C KJ. Mir R, Elfaki I, Banu S, Chahal SMS: LDLR Gene Polymorphisms (rs5925 and rs1529729) Are Associated with Susceptibility to Coronary Artery Disease in a South Indian Population. Med. Sci. (Basel), 2019, 7(7)
[2]
Herrington, W.; Lacey, B.; Sherliker, P.; Armitage, J.; Lewington, S. Epidemiology of Atherosclerosis and the Potential to Reduce the Global Burden of Atherothrombotic Disease. Circ. Res., 2016, 118(4), 535-546.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.307611] [PMID: 26892956]
[3]
Sanchis-Gomar, F.; Perez-Quilis, C.; Leischik, R.; Lucia, A. Epidemiology of coronary heart disease and acute coronary syndrome. Ann. Transl. Med., 2016, 4(13), 256.
[http://dx.doi.org/10.21037/atm.2016.06.33] [PMID: 27500157]
[4]
Reschen, M.E.; Lin, D.; Chalisey, A.; Soilleux, E.J.; O’Callaghan, C.A. Genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene PHACTR1. Atherosclerosis, 2016, 250, 95-105.
[http://dx.doi.org/10.1016/j.atherosclerosis.2016.04.025] [PMID: 27187934]
[5]
Rafieian-Kopaei, M.; Setorki, M.; Doudi, M.; Baradaran, A.; Nasri, H. Atherosclerosis: process, indicators, risk factors and new hopes. Int. J. Prev. Med., 2014, 5(8), 927-946.
[PMID: 25489440]
[6]
Gu, Y.; Liu, Z.; Li, L.; Guo, C.Y.; Li, C.J.; Wang, L.S.; Yang, Z.J.; Ma, W.Z.; Jia, E.Z. OLR1, PON1 and MTHFR gene polymorphisms, conventional risk factors and the severity of coronary atherosclerosis in a Chinese Han population. Cell. Physiol. Biochem., 2013, 31(1), 143-152.
[http://dx.doi.org/10.1159/000343356] [PMID: 23391848]
[7]
Xie, X.; Shi, X.; Liu, M. The Roles of TLR Gene Polymorphisms in Atherosclerosis: A Systematic Review and Meta-Analysis of 35,317 Subjects. Scand. J. Immunol., 2017, 86(1), 50-58.
[http://dx.doi.org/10.1111/sji.12560] [PMID: 28474755]
[8]
Elfaki, I.; Mir, R.; Almutairi, F.M.; Duhier, F.M.A. Cytochrome P450: Polymorphisms and Roles in Cancer, Diabetes and Atherosclerosis. Asian Pac. J. Cancer Prev., 2018, 19(8), 2057-2070.
[PMID: 30139042]
[9]
Mir, R.; Jha, C.K.; Elfaki, I.; Rehman, S.; Javid, J.; Khullar, N.; Banu, S.; Chahal, S.M.S. MicroRNA-224 (rs188519172 A>G) gene variability is associated with a decreased susceptibility to Coronary Artery Disease: A Case-Control Study. MicroRNA, 2018.
[PMID: 30539710]
[10]
Jha, C.K.; Mir, R.; Elfaki, I.; Javid, J.; Babakr, A.T.; Banu, S.; Chahal, S.M.S. Evaluation of the Association of Omentin 1 rs2274907 A>T and rs2274908 G>A Gene Polymorphisms with Coronary Artery Disease in Indian Population: A Case Control Study. J. Pers. Med., 2019, 9(2), 30.
[http://dx.doi.org/10.3390/jpm9020030] [PMID: 31174318]
[11]
Mir, R.; Jha, C.K.; Elfaki, I.; Javid, J.; Rehman, S.; Khullar, N.; Banu, S.; Chahal, S.M.S. Incidence of MicroR-4513C/T Gene Variability in Coronary Artery Disease - A Case-Control Study. Endocr. Metab. Immune Disord. Drug Targets, 2019, 19(8), 1216-1223.
[http://dx.doi.org/10.2174/1871530319666190417111940] [PMID: 31038082]
[12]
Ambrose, JA; Singh, M Pathophysiology of coronary artery disease leading to acute coronary syndromes. F1000Prime Rep, 2015, 7, 08.
[http://dx.doi.org/10.12703/P7-08]
[13]
Gu, H.M.; Zhang, D.W. Hypercholesterolemia, low density lipoprotein receptor and proprotein convertase subtilisin/kexin-type 9. J. Biomed. Res., 2015, 29(5), 356-361.
[PMID: 26445568]
[14]
Goldstein, J.L.; Brown, M.S. The LDL receptor. Arterioscler. Thromb. Vasc. Biol., 2009, 29(4), 431-438.
[http://dx.doi.org/10.1161/ATVBAHA.108.179564] [PMID: 19299327]
[15]
Ochiai, A.; Miyata, S.; Iwase, M.; Shimizu, M.; Inoue, J.; Sato, R. Kaempferol stimulates gene expression of low-density lipoprotein receptor through activation of Sp1 in cultured hepatocytes. Sci. Rep., 2016, 6, 24940.
[http://dx.doi.org/10.1038/srep24940] [PMID: 27109240]
[16]
Ye, H.; Zhao, Q.; Huang, Y.; Wang, L.; Liu, H.; Wang, C.; Dai, D.; Xu, L.; Ye, M.; Duan, S. Meta-analysis of low density lipoprotein receptor (LDLR) rs2228671 polymorphism and coronary heart disease. BioMed Res. Int., 2014, 2014564940
[http://dx.doi.org/10.1155/2014/564940] [PMID: 24900971]
[17]
van Zyl, T.; Jerling, J.C.; Conradie, K.R.; Feskens, E.J.M. Common and rare single nucleotide polymorphisms in the LDLR gene are present in a black South African population and associate with low-density lipoprotein cholesterol levels. J. Hum. Genet., 2014, 59(2), 88-94.
[http://dx.doi.org/10.1038/jhg.2013.123] [PMID: 24284361]
[18]
Jha, C.K.; Chahal, S.M.S.; Khullar, N.; Banu, S. Mir. R: High-Quality Genomic DNA Extraction From Long Term Stored (LTS) Whole Blood Samples Using Glass Bead Method. Int. J. Health Sci. Res., 2016, 6(5), 288-292.
[19]
De Castro-Orós, I.; Pocoví, M.; Civeira, F. The genetic basis of familial hypercholesterolemia: inheritance, linkage, and mutations. Appl. Clin. Genet., 2010, 3, 53-64.
[PMID: 23776352]
[20]
Do, R.; Stitziel, N.O.; Won, H.H.; Jørgensen, A.B.; Duga, S.; Angelica Merlini, P.; Kiezun, A.; Farrall, M.; Goel, A.; Zuk, O.; Guella, I.; Asselta, R.; Lange, L.A.; Peloso, G.M.; Auer, P.L.; Girelli, D.; Martinelli, N.; Farlow, D.N.; DePristo, M.A.; Roberts, R.; Stewart, A.F.; Saleheen, D.; Danesh, J.; Epstein, S.E.; Sivapalaratnam, S.; Hovingh, G.K.; Kastelein, J.J.; Samani, N.J.; Schunkert, H.; Erdmann, J.; Shah, S.H.; Kraus, W.E.; Davies, R.; Nikpay, M.; Johansen, C.T.; Wang, J.; Hegele, R.A.; Hechter, E.; Marz, W.; Kleber, M.E.; Huang, J.; Johnson, A.D.; Li, M.; Burke, G.L.; Gross, M.; Liu, Y.; Assimes, T.L.; Heiss, G.; Lange, E.M.; Folsom, A.R.; Taylor, H.A.; Olivieri, O.; Hamsten, A.; Clarke, R.; Reilly, D.F.; Yin, W.; Rivas, M.A.; Donnelly, P.; Rossouw, J.E.; Psaty, B.M.; Herrington, D.M.; Wilson, J.G.; Rich, S.S.; Bamshad, M.J.; Tracy, R.P.; Cupples, L.A.; Rader, D.J.; Reilly, M.P.; Spertus, J.A.; Cresci, S.; Hartiala, J.; Tang, W.H.; Hazen, S.L.; Allayee, H.; Reiner, A.P.; Carlson, C.S.; Kooperberg, C.; Jackson, R.D.; Boerwinkle, E.; Lander, E.S.; Schwartz, S.M.; Siscovick, D.S.; McPherson, R.; Tybjaerg-Hansen, A.; Abecasis, G.R.; Watkins, H.; Nickerson, D.A.; Ardissino, D.; Sunyaev, S.R.; O’Donnell, C.J.; Altshuler, D.; Gabriel, S.; Kathiresan, S. NHLBI Exome Sequencing Project. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature, 2015, 518(7537), 102-106.
[http://dx.doi.org/10.1038/nature13917] [PMID: 25487149]
[21]
Mega, J.L.; Stitziel, N.O.; Smith, J.G.; Chasman, D.I.; Caulfield, M.; Devlin, J.J.; Nordio, F.; Hyde, C.; Cannon, C.P.; Sacks, F.; Poulter, N.; Sever, P.; Ridker, P.M.; Braunwald, E.; Melander, O.; Kathiresan, S.; Sabatine, M.S. Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials. Lancet, 2015, 385(9984), 2264-2271.
[http://dx.doi.org/10.1016/S0140-6736(14)61730-X] [PMID: 25748612]
[22]
Elfaki, I.; Almutairi, F.M.; Mir, R.; Khan, R.; Abu-Duhier, F. Cytochrome P450 CYP1B1*2 gene and its Association with T2D in Tabuk Population, Northwestern Region of Saudi Arabia. Asian Journal of Pharmaceutical and Clinical Research, 2018, 11(1), 55-59.
[http://dx.doi.org/10.22159/ajpcr.2018.v11i1.21657]
[23]
Almutairi, F.M.; Mir, R.; Abu-Duhier, F.; Khan, R.; Harby, K.; Elfaki, I. SLC2A2 Gene (Glucose Transporter 2) Variation is Associated with an Increased Risk of Developing T2d in an Ethnic Population of Saudi Arabia. Indian Journal of Public Health Research & Development, 2019, 10(1), 600-605.
[http://dx.doi.org/10.5958/0976-5506.2019.00118.9]
[24]
Deng, N.; Zhou, H.; Fan, H.; Yuan, Y. Single nucleotide polymorphisms and cancer susceptibility. Oncotarget, 2017, 8(66), 110635-110649.
[http://dx.doi.org/10.18632/oncotarget.22372] [PMID: 29299175]
[25]
Jha, C.K.; Mir, R.; Khullar, N.; Banu, S.; Chahal, S.M.S. LDLR rs688 TT Genotype and T Allele Are Associated with Increased Susceptibility to Coronary Artery Disease-A Case-Control Study. J. Cardiovasc. Dev. Dis., 2018, 5(2)E31
[http://dx.doi.org/10.3390/jcdd5020031] [PMID: 29843469]
[26]
Benjamin, E.J.; Blaha, M.J.; Chiuve, S.E.; Cushman, M.; Das, S.R.; Deo, R.; de Ferranti, S.D.; Floyd, J.; Fornage, M.; Gillespie, C.; Isasi, C.R.; Jiménez, M.C.; Jordan, L.C.; Judd, S.E.; Lackland, D.; Lichtman, J.H.; Lisabeth, L.; Liu, S.; Longenecker, C.T.; Mackey, R.H.; Matsushita, K.; Mozaffarian, D.; Mussolino, M.E.; Nasir, K.; Neumar, R.W.; Palaniappan, L.; Pandey, D.K.; Thiagarajan, R.R.; Reeves, M.J.; Ritchey, M.; Rodriguez, C.J.; Roth, G.A.; Rosamond, W.D.; Sasson, C.; Towfighi, A.; Tsao, C.W.; Turner, M.B.; Virani, S.S.; Voeks, J.H.; Willey, J.Z.; Wilkins, J.T.; Wu, J.H.; Alger, H.M.; Wong, S.S.; Muntner, P. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. Circulation, 2017, 135(10), e146-e603.
[http://dx.doi.org/10.1161/CIR.0000000000000485] [PMID: 28122885]
[27]
Prabhakaran, D.; Jeemon, P.; Roy, A. Cardiovascular Diseases in India: Current Epidemiology and Future Directions. Circulation, 2016, 133(16), 1605-1620.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.114.008729] [PMID: 27142605]
[28]
Ríos-González, B.E.; Ibarra-Cortés, B.; Ramírez-López, G.; Sánchez-Corona, J.; Magaña-Torres, M.T. Association of polymorphisms of genes involved in lipid metabolism with blood pressure and lipid values in mexican hypertensive individuals. Dis. Markers, 2014, 2014150358
[http://dx.doi.org/10.1155/2014/150358] [PMID: 25587205]
[29]
Strøm, T.B.; Tveten, K.; Laerdahl, J.K.; Leren, T.P. Mutation G805R in the transmembrane domain of the LDL receptor gene causes familial hypercholesterolemia by inducing ectodomain cleavage of the LDL receptor in the endoplasmic reticulum. FEBS Open Bio, 2014, 4, 321-327.
[http://dx.doi.org/10.1016/j.fob.2014.03.007] [PMID: 24918045]
[30]
Linsel-Nitschke, P.; Götz, A.; Erdmann, J.; Braenne, I.; Braund, P.; Hengstenberg, C.; Stark, K.; Fischer, M.; Schreiber, S.; El Mokhtari, N.E.; Schaefer, A.; Schrezenmeir, J.; Rubin, D.; Hinney, A.; Reinehr, T.; Roth, C.; Ortlepp, J.; Hanrath, P.; Hall, A.S.; Mangino, M.; Lieb, W.; Lamina, C.; Heid, I.M.; Doering, A.; Gieger, C.; Peters, A.; Meitinger, T.; Wichmann, H.E.; König, I.R.; Ziegler, A.; Kronenberg, F.; Samani, N.J.; Schunkert, H. Wellcome Trust Case Control Consortium (WTCCC); Cardiogenics Consortium. Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease--a Mendelian Randomisation study. PLoS One, 2008, 3(8) e2986
[http://dx.doi.org/10.1371/journal.pone.0002986] [PMID: 18714375]
[31]
Ortlepp, J.R.; von Korff, A.; Hanrath, P.; Zerres, K.; Hoffmann, R. Vitamin D receptor gene polymorphism BsmI is not associated with the prevalence and severity of CAD in a large-scale angiographic cohort of 3441 patients. Eur. J. Clin. Invest., 2003, 33(2), 106-109.
[http://dx.doi.org/10.1046/j.1365-2362.2003.01124.x] [PMID: 12588283]
[32]
Krawczak, M.; Nikolaus, S.; von Eberstein, H.; Croucher, P.J.; El Mokhtari, N.E.; Schreiber, S. PopGen: population-based recruitment of patients and controls for the analysis of complex genotype-phenotype relationships. Community Genet., 2006, 9(1), 55-61.
[PMID: 16490960]
[33]
Samani, N.J.; Erdmann, J.; Hall, A.S.; Hengstenberg, C.; Mangino, M.; Mayer, B.; Dixon, R.J.; Meitinger, T.; Braund, P.; Wichmann, H.E.; Barrett, J.H.; König, I.R.; Stevens, S.E.; Szymczak, S.; Tregouet, D.A.; Iles, M.M.; Pahlke, F.; Pollard, H.; Lieb, W.; Cambien, F.; Fischer, M.; Ouwehand, W.; Blankenberg, S.; Balmforth, A.J.; Baessler, A.; Ball, S.G.; Strom, T.M.; Braenne, I.; Gieger, C.; Deloukas, P.; Tobin, M.D.; Ziegler, A.; Thompson, J.R.; Schunkert, H. WTCCC and the Cardiogenics Consortium. Genomewide association analysis of coronary artery disease. N. Engl. J. Med., 2007, 357(5), 443-453.
[http://dx.doi.org/10.1056/NEJMoa072366] [PMID: 17634449]
[34]
Schunkert, H.; Götz, A.; Braund, P.; McGinnis, R.; Tregouet, D.A.; Mangino, M.; Linsel-Nitschke, P.; Cambien, F.; Hengstenberg, C.; Stark, K.; Blankenberg, S.; Tiret, L.; Ducimetiere, P.; Keniry, A.; Ghori, M.J.; Schreiber, S.; El Mokhtari, N.E.; Hall, A.S.; Dixon, R.J.; Goodall, A.H.; Liptau, H.; Pollard, H.; Schwarz, D.F.; Hothorn, L.A.; Wichmann, H.E.; König, I.R.; Fischer, M.; Meisinger, C.; Ouwehand, W.; Deloukas, P.; Thompson, J.R.; Erdmann, J.; Ziegler, A.; Samani, N.J. Cardiogenics Consortium. Repeated replication and a prospective meta-analysis of the association between chromosome 9p21.3 and coronary artery disease. Circulation, 2008, 117(13), 1675-1684.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.107.730614] [PMID: 18362232]
[35]
Erdmann, J.; Grosshennig, A.; Braund, P.S.; König, I.R.; Hengstenberg, C.; Hall, A.S.; Linsel-Nitschke, P.; Kathiresan, S.; Wright, B.; Trégouët, D.A.; Cambien, F.; Bruse, P.; Aherrahrou, Z.; Wagner, A.K.; Stark, K.; Schwartz, S.M.; Salomaa, V.; Elosua, R.; Melander, O.; Voight, B.F.; O’Donnell, C.J.; Peltonen, L.; Siscovick, D.S.; Altshuler, D.; Merlini, P.A.; Peyvandi, F.; Bernardinelli, L.; Ardissino, D.; Schillert, A.; Blankenberg, S.; Zeller, T.; Wild, P.; Schwarz, D.F.; Tiret, L.; Perret, C.; Schreiber, S.; El Mokhtari, N.E.; Schäfer, A.; März, W.; Renner, W.; Bugert, P.; Klüter, H.; Schrezenmeir, J.; Rubin, D.; Ball, S.G.; Balmforth, A.J.; Wichmann, H.E.; Meitinger, T.; Fischer, M.; Meisinger, C.; Baumert, J.; Peters, A.; Ouwehand, W.H.; Deloukas, P.; Thompson, J.R.; Ziegler, A.; Samani, N.J.; Schunkert, H. Italian Atherosclerosis, Thrombosis, and Vascular Biology Working Group; Myocardial Infarction Genetics Consortium; Wellcome Trust Case Control Consortium; Cardiogenics Consortium. New susceptibility locus for coronary artery disease on chromosome 3q22.3. Nat. Genet., 2009, 41(3), 280-282.
[http://dx.doi.org/10.1038/ng.307] [PMID: 19198612]
[36]
Martinelli, N.; Girelli, D.; Lunghi, B.; Pinotti, M.; Marchetti, G.; Malerba, G.; Pignatti, P.F.; Corrocher, R.; Olivieri, O.; Bernardi, F. Polymorphisms at LDLR locus may be associated with coronary artery disease through modulation of coagulation factor VIII activity and independently from lipid profile. Blood, 2010, 116(25), 5688-5697.
[http://dx.doi.org/10.1182/blood-2010-03-277079] [PMID: 20810930]
[37]
A. Smyth N; Hayat M Kerr R Raal F Ramsay M. Genetic Associations of LDLR, APOB and LDLRAP1 Variants with LDL-cholesterol Levels Among Africans. 2018, 32.
[38]
Hayat, M. VARIANTS IN FOUR GENES ASSOCIATED WITH LIPID LEVELS: A STUDY IN AFRICAN POPULATIONS; University of Witwatersrand: Johannesburg, 2018.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 3
Year: 2020
Page: [388 - 399]
Pages: 12
DOI: 10.2174/1871530319666191015164505
Price: $65

Article Metrics

PDF: 13
HTML: 2
EPUB: 1
PRC: 1