Skip to main content
SpringerLink
Log in

Direct sequencing for comprehensive screening of LDLR genetic polymorphisms among five ethnic populations

  • Research Article
  • Published:
Genes & Genomics Aims and scope Submit manuscript

Abstract

Low density lipoprotein receptor (LDLR) plays an important role in plasma lipoprotein metabolism and pharmacological responses. Although mutations of LDLR and their functional associations with plasma LDL cholesterol concentrations have been described, no comprehensive comparisons of LDLR variants among populations are established. The aim of this study is to define the distribution of single nucleotide polymorphisms (SNPs) of LDLR and to discover novel variants across population groups. A total of 288 DNAs from 96 Korean, 48 Chinese, 48 Japanese, 48 African-American, and 48 European-American subjects were resequenced. A total of 59 SNPs (18 in the coding regions, 37 in the introns, and 4 in the 3′-untranslated region) were identified, including eight novel variants. Polymorphisms of LDLR showed significantly different distributions in comparisons among ethnic population groups (P < 0.05, Fisher’s exact test). Moreover, almost all of these differently distributed SNPs were common variants. Notably, prevalent variations—rs1003723, rs1799898, rs688, rs5925, rs6413504 in Europeans, nonsynonymous rs11669576 (Ala391Thr) in Africans, and rs14158 in Asians—were observed. In further in silico analyses for the novel SNPs, 2 intronic variants (+17716G>A in the intron 5 and +38569A>C in the intron 16) were predicted as potential branch point sites for alternative splicing. Although this study is not free from limitations such as insufficient sample size and no functional studies on the novel SNPs, our findings provides supporting information about LDLR genetic variability among ethnic groups and pharmacogenetics studies for plasma lipoprotein metabolism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Adeyemo A, Bentley AR, Meilleur KG, Doumatey AP, Chen G, Zhou J, Shriner D, Huang H, Herbert A, Gerry NP et al (2012) Transferability and fine mapping of genome-wide associated loci for lipids in African Americans. BMC Med Genet 13:88

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ahn YI, Kamboh MI, Aston CE, Ferrell RE, Hamman RF (1994) Role of common genetic polymorphisms in the LDL receptor gene in affecting plasma cholesterol levels in the general population. Arterioscler Thromb 14:663–670

    Article  CAS  PubMed  Google Scholar 

  • Albers JJ, Day JR, Wolfbauer G, Kennedy H, Vuletic S, Cheung MC (2011) Impact of site-specific N-glycosylation on cellular secretion, activity and specific activity of the plasma phospholipid transfer protein. Biochim Biophys Acta 1814:908–911

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Andreotti G, Chen J, Gao YT, Rashid A, Chen BE, Rosenberg P, Sakoda LC, Deng J, Shen MC, Wang BS et al (2008) Polymorphisms of genes in the lipid metabolism pathway and risk of biliary tract cancers and stones: a population-based case-control study in Shanghai, China. Cancer Epidemiol Biomark Prev 17:525–534

    Article  CAS  Google Scholar 

  • Benjannet S, Hamelin J, Chretien M, Seidah NG (2012) Loss- and gain-of-function PCSK9 variants: cleavage specificity, dominant negative effects, and low density lipoprotein receptor (LDLR) degradation. J Biol Chem 287:33745–33755

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bieghs V, Van Gorp PJ, Wouters K, Hendrikx T, Gijbels MJ, van Bilsen M, Bakker J, Binder CJ, Lutjohann D, Staels B et al (2012) LDL receptor knock-out mice are a physiological model particularly vulnerable to study the onset of inflammation in non-alcoholic fatty liver disease. PLoS One 7:e30668

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Brown MS, Goldstein JL (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232:34–47

    Article  CAS  PubMed  Google Scholar 

  • Cardona A, Pagani L, Antao T, Lawson DJ, Eichstaedt CA, Yngvadottir B, Shwe MT, Wee J, Romero IG, Raj S et al (2014) Genome-wide analysis of cold adaptation in indigenous Siberian populations. PLoS One 9:e98076

    Article  PubMed Central  PubMed  Google Scholar 

  • Chasman DI, Giulianini F, MacFadyen J, Barratt BJ, Nyberg F, Ridker PM (2012) Genetic determinants of statin-induced low-density lipoprotein cholesterol reduction: the justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin (Jupiter) trial. Circ Cardiovasc Genet 5:257–264

    Article  CAS  PubMed  Google Scholar 

  • Cheng D, Huang R, Lanham IS, Cathcart HM, Howard M, Corder EH, Poduslo SE (2005) Functional interaction between APOE4 and LDL receptor isoforms in Alzheimer’s disease. J Med Genet 42:129–131

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cross DS, Ivacic LC, Stefanski EL, McCarty CA (2010) Population based allele frequencies of disease associated polymorphisms in the Personalized Medicine Research Project. BMC Genet 11:51

    Article  PubMed Central  PubMed  Google Scholar 

  • Dammerman M, Breslow JL (1995) Genetic basis of lipoprotein disorders. Circulation 91:505–512

    Article  CAS  PubMed  Google Scholar 

  • Davis HR Jr, Lowe RS, Neff DR (2011) Effects of ezetimibe on atherosclerosis in preclinical models. Atherosclerosis 215:266–278

    Article  CAS  PubMed  Google Scholar 

  • Di Lello FA, Caruz A, Rallon NI, Rivero-Juarez A, Neukam K, Barreiro P, Camacho A, Garcia-Rey S, Rivero A, Soriano V et al (2013) Effects of the genetic pattern defined by low-density lipoprotein receptor and IL28B genotypes on the outcome of hepatitis C virus infection. Eur J Clin Microbiol Infect Dis 32:1427–1435

    Article  PubMed  Google Scholar 

  • Fouchier SW, Kastelein JJ, Defesche JC (2005) Update of the molecular basis of familial hypercholesterolemia in The Netherlands. Hum Mutat 26:550–556

    Article  CAS  PubMed  Google Scholar 

  • Gao F, Ihn HE, Medina MW, Krauss RM (2013) A common polymorphism in the LDL receptor gene has multiple effects on LDL receptor function. Hum Mol Genet 22:1424–1431

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Go GW, Mani A (2012) Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis. Yale J Biol Med 85:19–28

    PubMed Central  CAS  PubMed  Google Scholar 

  • Guenard F, Houde A, Bouchard L, Tchernof A, Deshaies Y, Biron S, Lescelleur O, Biertho L, Marceau S, Perusse L et al (2012) Association of LIPA gene polymorphisms with obesity-related metabolic complications among severely obese patients. Obes (Silver Spring) 20:2075–2082

    Article  CAS  Google Scholar 

  • Hobbs HH, Brown MS, Goldstein JL (1992) Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1:445–466

    Article  CAS  PubMed  Google Scholar 

  • Holla OL, Nakken S, Mattingsdal M, Ranheim T, Berge KE, Defesche JC, Leren TP (2009) Effects of intronic mutations in the LDLR gene on pre-mRNA splicing: comparison of wet-lab and bioinformatics analyses. Mol Genet Metab 96:245–252

    Article  CAS  PubMed  Google Scholar 

  • Humphries S, Coviello DA, Masturzo P, Balestreri R, Orecchini G, Bertolini S (1991) Variation in the low density lipoprotein receptor gene is associated with differences in plasma low density lipoprotein cholesterol levels in young and old normal individuals from Italy. Arterioscler Thromb 11:509–516

    Article  CAS  PubMed  Google Scholar 

  • Ishibashi S, Brown MS, Goldstein JL, Gerard RD, Hammer RE, Herz J (1993) Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest 92:883–893

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havulinna AS et al (2008) Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 40:189–197

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Klausen IC, Hansen PS, Gerdes LU, Rudiger N, Gregersen N, Faergeman O (1993) A PvuII polymorphism of the low density lipoprotein receptor gene is not associated with plasma concentrations of low density lipoproteins including LP(a). Hum Genet 91:193–195

    Article  CAS  PubMed  Google Scholar 

  • Leren TP (2014) Sorting an LDL receptor with bound PCSK9 to intracellular degradation. Atherosclerosis 237:76–81

    Article  CAS  PubMed  Google Scholar 

  • Linsel-Nitschke P, Gotz A, Erdmann J, Braenne I, Braund P, Hengstenberg C, Stark K, Fischer M, Schreiber S, El Mokhtari NE et al (2008) 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 3:e2986

    Article  PubMed Central  PubMed  Google Scholar 

  • Mahley RW, Rall SC Jr (2000) Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1:507–537

    Article  CAS  PubMed  Google Scholar 

  • Martinelli N, Girelli D, Lunghi B, Pinotti M, Marchetti G, Malerba G, Pignatti PF, Corrocher R, Olivieri O, Bernardi F (2010) Polymorphisms at LDLR locus may be associated with coronary artery disease through modulation of coagulation factor VIII activity and independently from lipid profile. Blood 116:5688–5697

    Article  CAS  PubMed  Google Scholar 

  • Miljkovic I, Yerges-Armstrong LM, Kuller LH, Kuipers AL, Wang X, Kammerer CM, Nestlerode CS, Bunker CH, Patrick AL, Wheeler VW et al (2010) Association analysis of 33 lipoprotein candidate genes in multi-generational families of African ancestry. J Lipid Res 51:1823–1831

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pineda JA, Caruz A, Di Lello FA, Camacho A, Mesa P, Neukam K, Rivero-juarez A, Macias J, Gomez-Mateos J, Rivero A (2011) Low-density lipoprotein receptor genotyping enhances the predictive value of IL28B genotype in HIV/hepatitis C virus-coinfected patients. Aids 25:1415–1420

    Article  CAS  PubMed  Google Scholar 

  • Pullinger CR, Kane JP, Malloy MJ (2003) Primary hypercholesterolemia: genetic causes and treatment of five monogenic disorders. Expert Rev Cardiovasc Ther 1:107–119

    Article  CAS  PubMed  Google Scholar 

  • Sanna S, Li B, Mulas A, Sidore C, Kang HM, Jackson AU, Piras MG, Usala G, Maninchedda G, Sassu A et al (2011) Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. PLoS Genet 7:e1002198

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schaefer JR, Kurt B, Sattler A, Klaus G, Soufi M (2012) Pharmacogenetic aspects in familial hypercholesterolemia with the special focus on FHMarburg (FH p. W556R). Clin Res Cardiol Suppl 7:2–6

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Seidelmann SB, De Luca C, Leibel RL, Breslow JL, Tall AR, Welch CL (2005) Quantitative trait locus mapping of genetic modifiers of metabolic syndrome and atherosclerosis in low-density lipoprotein receptor-deficient mice: identification of a locus for metabolic syndrome and increased atherosclerosis on chromosome 4. Arterioscler Thromb Vasc Biol 25:204–210

    PubMed Central  CAS  PubMed  Google Scholar 

  • Skropeta D, Settasatian C, McMahon MR, Shearston K, Caiazza D, McGrath KC, Jin W, Rader DJ, Barter PJ, Rye KA (2007) N-Glycosylation regulates endothelial lipase-mediated phospholipid hydrolysis in apoE- and apoA-I-containing high density lipoproteins. J Lipid Res 48:2047–2057

    Article  CAS  PubMed  Google Scholar 

  • Slimani A, Jelassi A, Jguirim I, Najah M, Rebhi L, Omezzine A, Maatouk F, Hamda KB, Kacem M, Rabes JP et al (2012) Effect of mutations in LDLR and PCSK9 genes on phenotypic variability in Tunisian familial hypercholesterolemia patients. Atherosclerosis 222:158–166

    Article  CAS  PubMed  Google Scholar 

  • Thompson D, Stram D, Goldgar D, Witte JS (2003) Haplotype tagging single nucleotide polymorphisms and association studies. Hum Hered 56:48–55

    Article  PubMed  Google Scholar 

  • Tishkoff SA, Williams SM (2002) Genetic analysis of African populations: human evolution and complex disease. Nat Rev Genet 3:611–621

    Article  CAS  PubMed  Google Scholar 

  • Wang B, Zhao H, Zhou L, Dai X, Wang D, Cao J, Niu W (2009) Association of genetic variation in apolipoprotein E and low density lipoprotein receptor with ischemic stroke in Northern Han Chinese. J Neurol Sci 276:118–122

    Article  CAS  PubMed  Google Scholar 

  • Willer CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, Heath SC, Timpson NJ, Najjar SS, Stringham HM et al (2008) Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 40:161–169

    Article  CAS  PubMed  Google Scholar 

  • Xue C, Liu X, Gong Y, Zhao Y, Fu YX (2013) Significantly fewer protein functional changing variants for lipid metabolism in Africans than in Europeans. J Transl Med 11:67

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang L, Yuan F, Liu P, Fei L, Huang Y, Xu L, Hao L, Qiu X, Le Y, Yang X et al (2013) Association between PCSK9 and LDLR gene polymorphisms with coronary heart disease: case-control study and meta-analysis. Clin Biochem 46:727–732

  • Zhu H, Tucker HM, Grear KE, Simpson JF, Manning AK, Cupples LA, Estus S (2007) A common polymorphism decreases low-density lipoprotein receptor exon 12 splicing efficiency and associates with increased cholesterol. Hum Mol Genet 16:1765–1772

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zou F, Gopalraj RK, Lok J, Zhu H, Ling IF, Simpson JF, Tucker HM, Kelly JF, Younkin SG, Dickson DW et al (2008) Sex-dependent association of a common low-density lipoprotein receptor polymorphism with RNA splicing efficiency in the brain and Alzheimer’s disease. Hum Mol Genet 17:929–935

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by a grant (11182MFDS658) from Ministry of Food and Drug Safety in 2011.

Conflict of interest

The authors declare that there are no conflicts of interests.

Author information

Authors and Affiliations

  1. Research Institute for Basic Science, Sogang University, Seoul, Republic of Korea

    Jeong-Hyun Kim & Hyoung Doo Shin

  2. Department of Genetic Epidemiology, SNP Genetics, Inc, Seoul, Republic of Korea

    Hyun Sub Cheong, Lyoung Hyo Kim & Hyoung Doo Shin

  3. Department of Toxicological Evaluation and Research National Institute of Food and Drug Safety Evaluation, Osong Health Technology Administration Complex, Heungdeok-gu, Chungcheongbuk-do, Republic of Korea

    Hee Jung Shin, Han Sung Na & Myeon Woo Chung

  4. Department of Life Science, Sogang University, Seoul, 121-742, Republic of Korea

    Hyoung Doo Shin

Authors
  1. Jeong-Hyun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyun Sub Cheong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lyoung Hyo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hee Jung Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Han Sung Na
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Myeon Woo Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hyoung Doo Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hyoung Doo Shin.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 440 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, JH., Cheong, H.S., Kim, L.H. et al. Direct sequencing for comprehensive screening of LDLR genetic polymorphisms among five ethnic populations. Genes Genom 37, 247–255 (2015). https://doi.org/10.1007/s13258-014-0244-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13258-014-0244-3

Keywords

Search

Navigation