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Haplotypes in the lipoprotein lipase gene influence high-density lipoprotein cholesterol response to statin therapy and progression of atherosclerosis in coronary artery bypass grafts

The Pharmacogenomics Journal volume 7, pages 66–73 (2007)Cite this article

Abstract

Lipoprotein lipase (LPL) hydrolyzes circulating triglycerides (TGs). We previously showed that 3′-end haplotypes in the LPL gene influence atherosclerosis and insulin resistance. This study asked whether these LPL haplotypes influence response to lipid-lowering therapy among 829 subjects from the Post-Coronary Artery Bypass Graft trial. Lipid profiles were obtained at baseline and 4–5 years after treatment with lovastatin. Haplotypes were based on 12 SNPs. The fourth most frequent haplotype, 12-4, was associated with a decreased increment in high-density lipoprotein-cholesterol (HDL-C) following treatment. Haplotypes 12-6, 12-7 and 12-8 were each associated with increased HDL-C response to therapy, and haplotype 12-2 with decreased TG response. The most common haplotype, 12-1, was protective against graft worsening or occlusion. Haplotype 12-4 reduced HDL-C response to lovastatin, possibly consistent with our prior observations of this haplotype as predisposing to coronary artery disease. LPL may influence atherosclerosis risk through pleiotropic effects on each aspect of the metabolic syndrome.

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Abbreviations

CABG:

coronary artery bypass graft

DBP:

diastolic blood pressure

HDL-C:

high-density lipoprotein cholesterol

HMG-CoA:

3-hydroxy-3-methylglutaryl-coenzyme A

LDL-C:

low-density lipoprotein cholesterol

LPL:

lipoprotein lipase

SBP:

systolic blood pressure

SNP:

single nucleotide polymorphism

TC:

total cholesterol

TG:

triglycerides

References

  1. Ahn YI, Ferrell RE, Hamman RF, Kamboh MI . Association of lipoprotein lipase gene variation with the physiological components of the insulin-resistance syndrome in the population of the San Luis Valley, Colorado. Diabetes Care 1993; 16: 1502–1506.

    Article  CAS  PubMed  Google Scholar 

  2. Holmer SR, Hengstenberg C, Mayer B, Döring A, Löwel H, Engel S et al. Lipoprotein lipase gene polymorphism, cholesterol subfractions and myocardial infarction in large samples of the general population. Cardiovasc Res 2000; 47: 806–812.

    Article  CAS  PubMed  Google Scholar 

  3. Heizmann C, Kirchgessner T, Kwiterovich PO, Ladias JA, Derby C, Antonarakis SE et al. DNA polymorphism haplotypes of the human lipoprotein lipase gene: possible association with high density lipoprotein levels. Hum Genet 1991; 86: 578–584.

    Article  CAS  PubMed  Google Scholar 

  4. Jemaa R, Tuzet S, Portos C, Betoulle D, Apfelbaum M, Fumeron F . Lipoprotein lipase gene polymorphisms: associations with hypertriglyceridemia and body mass index in obese people. Int J Obes Relat Metab Disord 1995; 19: 270–274.

    CAS  PubMed  Google Scholar 

  5. Allayee H, de Bruin TW, Michelle Dominguez K, Cheng LS, Ipp E, Cantor RM et al. Genome scan for blood pressure in Dutch dyslipidemic families reveals linkage to a locus on chromosome 4p. Hypertension 2001; 38: 773–778.

    Article  CAS  PubMed  Google Scholar 

  6. Wu DA, Bu X, Warden CH, Shen DD, Jeng CY, Sheu WH et al. Quantitative trait locus mapping of human blood pressure to a genetic region at or near the lipoprotein lipase gene locus on chromosome 8p22. J Clin Invest 1996; 97: 2111–2118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lee WJ, Sheu WH, Jeng CY, Young MS, Chen YT . Associations between lipoprotein lipase gene polymorphisms and insulin resistance in coronary heart disease. Chinese Med J 2000; 63: 563–572.

    CAS  Google Scholar 

  8. Goodarzi MO, Guo X, Taylor KD, Quinones MJ, Saad MF, Yang H et al. Lipoprotein lipase is a gene for insulin resistance in Mexican Americans. Diabetes 2004; 53: 214–220.

    Article  CAS  PubMed  Google Scholar 

  9. Humphries SE, Nicaud V, Margalef J, Tiret L, Talmud PJ . Lipoprotein lipase gene variation is associated with a paternal history of premature coronary artery disease and fasting and postprandial plasma triglycerides: the European Atherosclerosis Research Study (EARS). Arterioscler Thromb Vasc Biol 1998; 18: 526–534.

    Article  CAS  PubMed  Google Scholar 

  10. Mattu RK, Needham EW, Morgan R, Rees A, Hackshaw AK, Stocks J et al. DNA variants at the LPL gene locus associate with angiographically defined severity of atherosclerosis and serum lipoprotein levels in a Welsh population. Arterioscler Thromb Vasc Biol 1994; 14: 1090–1097.

    Article  CAS  Google Scholar 

  11. Goodarzi MO, Guo X, Taylor KD, Quiñones MJ, Samayoa C, Yang H et al. Determination and use of haplotypes: ethnic comparison and association of the lipoprotein lipase gene and coronary artery disease in Mexican-Americans. Genet Med 2003; 5: 322–327.

    Article  CAS  PubMed  Google Scholar 

  12. Goodarzi MO, Wong H, Quinones MJ, Taylor KD, Guo X, Castellani LW et al. The 3′ untranslated region of the lipoprotein lipase gene: haplotype structure and association with post-heparin plasma lipase activity. J Clin Endocrinol Metab 2005; 90: 4816–4823.

    Article  CAS  PubMed  Google Scholar 

  13. Jukema JW, van Boven AJ, Groenemeijer B, Zwinderman AH, Reiber JH, Bruschke AV et al. The Asp9 Asn mutation in the lipoprotein lipase gene is associated with increased progression of coronary atherosclerosis. REGRESS Study Group, Interuniversity Cardiology Institute, Utrecht, The Netherlands. Regression Growth Evaluation Statin Study. Circulation 1996; 94: 1913–1918.

    Article  CAS  PubMed  Google Scholar 

  14. Taylor KD, Scheuner MT, Yang H, Wang Y, Haritunians T, Fischel-Ghodsian N et al. Lipoprotein lipase locus and progression of atherosclerosis in coronary-artery bypass grafts. Genet Med 2004; 6: 481–486.

    Article  CAS  PubMed  Google Scholar 

  15. The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997; 336: 153–162.

  16. Murthy V, Julien P, Gagne C . Molecular pathobiology of the human lipoprotein lipase gene. Pharmacol Ther 1996; 70: 101–135.

    Article  CAS  PubMed  Google Scholar 

  17. Eisenberg S . High density lipoprotein metabolism. J Lipid Res 1984; 25: 1017–1058.

    CAS  PubMed  Google Scholar 

  18. Sato A, Watanabe K, Fukuzumi H, Hase K, Ishida F, Kamei T . Effect of simvastatin (MK-733) on plasma triacylglycerol levels in rats. Biochem Pharmacol 1991; 41: 1163–1172.

    Article  CAS  PubMed  Google Scholar 

  19. Kasim SE, LeBoeuf RC, Khilnani S, Tallapaka L, Dayananda D, Jen KL . Mechanisms of triglyceride-lowering effect of an HMG-CoA reductase inhibitor in a hypertriglyceridemic animal model, the Zucker obese rat. J Lipid Res 1992; 33: 1–7.

    CAS  PubMed  Google Scholar 

  20. Aoki T, Yamazaki H, Tamaki T, Sato F, Kitahara M, Saito Y . Triglyceride-lowering effect of pitavastatin in a guinea pig model of postprandial lipemia. Arzneimittelforschung 2003; 53: 154–158.

    PubMed  Google Scholar 

  21. Bey L, Maigret P, Laouenan H, Hamilton MT . Induction of lipoprotein lipase gene expression in 3T3-L1 preadipocytes by atorvastatin, a cholesterol- and triglyceride-lowering drug. Pharmacology 2002; 66: 51–56.

    Article  CAS  PubMed  Google Scholar 

  22. Schneider JG, von Eynatten M, Parhofer KG, Volkmer JE, Schiekofer S, Hamann A et al. Atorvastatin improves diabetic dyslipidemia and increases lipoprotein lipase activity in vivo. Atherosclerosis 2004; 175: 325–331.

    Article  CAS  PubMed  Google Scholar 

  23. Cabezas MC, de Bruin TW, Kock LA, Kortlandt W, Van Linde-Sibenius Trip M, Jansen H et al. Simvastatin improves chylomicron remnant removal in familial combined hyperlipidemia without changing chylomicron conversion. Metabolism 1993; 42: 497–503.

    Article  CAS  PubMed  Google Scholar 

  24. Endo K, Miyashita Y, Saiki A, Oyama T, Koide N, Ozaki H et al. Atorvastatin and pravastatin elevated pre-heparin lipoprotein lipase mass of type 2 diabetes with hypercholesterolemia. J Atheroscler Thromb 2004; 11: 341–347.

    Article  CAS  PubMed  Google Scholar 

  25. Kobayashi J, Maruyama T, Masuda M, Shinomiya M . Effect of atorvastatin treatment on lipoprotein lipase mass in the pre-heparin plasma in Japanese hyperlipidemic subjects. Clin Chim Acta 2001; 314: 261–264.

    Article  CAS  PubMed  Google Scholar 

  26. Sasaki J, Yamamoto K, Kobori S, Setoguchi Y, Sato Y, Matsunaga A et al. Effects of fluvastatin, a new inhibitor of HMG-CoA reductase, and niceritrol on serum lipids, lipoproteins and cholesterol ester transfer activity in primary hypercholesterolemic patients. Int J Clin Pharmacol Ther 1995; 33: 420–426.

    CAS  PubMed  Google Scholar 

  27. Mamputu JC, Levesque L, Renier G . Proliferative effect of lipoprotein lipase on human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2000; 20: 2212–2219.

    Article  CAS  PubMed  Google Scholar 

  28. Mamputu JC, Desfaits AC, Renier G . Lipoprotein lipase enhances human monocyte adhesion to aortic endothelial cells. J Lipid Res 1997; 38: 1722–1729.

    CAS  PubMed  Google Scholar 

  29. Mead JR, Ramji DP . The pivotal role of lipoprotein lipase in atherosclerosis. Cardiovasc Res 2002; 55: 261–269.

    Article  CAS  PubMed  Google Scholar 

  30. Templeton AR, Clark AG, Weiss KM, Nickerson DA, Boerwinkle E, Sing CF . Recombinational and mutational hotspots within the human lipoprotein lipase gene. Am J Hum Genet 2000; 66: 69–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Templeton AR, Weiss KM, Nickerson DA, Boerwinkle E, Sing CF . Cladistic structure within the human lipoprotein lipase gene and its implications for phenotypic association studies. Genetics 2000; 156: 1259–1275.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Neel JV, Weder AB, Julius S . Type II diabetes, essential hypertension, and obesity as ‘syndromes of impaired genetic homeostasis’: the ‘thrifty genotype’ hypothesis enters the 21st century. Perspect Biol Med 1998; 42: 44–74.

    Article  CAS  PubMed  Google Scholar 

  33. Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton Jr VP, Ridker PM . Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 2004; 291: 2821–2827.

    Article  CAS  PubMed  Google Scholar 

  34. Sambrook J, Fritsch E, Maniatis T . Molecular Cloning. Cold Spring Harbor Laboratory: New York, 1989.

    Google Scholar 

  35. Nickerson DA, Taylor SL, Weiss KM, Clark AG, Hutchinson RG, Stengård J et al. DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nat Genet 1998; 19: 233–240.

    Article  CAS  PubMed  Google Scholar 

  36. Livak KJ . Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genet Anal 1999; 14: 143–149.

    Article  CAS  PubMed  Google Scholar 

  37. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  PubMed  Google Scholar 

  38. Qin ZS, Niu T, Liu JS . Partition-ligation-expectation-maximization algorithm for haplotype inference with single-nucleotide polymorphisms. Am J Hum Genet 2002; 71: 1242–1247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by National Institutes of Health Program Project Grant HL-28481 and Pharmacogenetic Network Grant HL-69757. Further support came from the Cedars-Sinai Board of Governors' Chair in Medical Genetics (JIR) and the Cedars-Sinai General Clinical Research Center Grant RR000425.

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Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    M O Goodarzi & H J Antoine

  2. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    M O Goodarzi, K D Taylor, X Guo & J I Rotter

  3. RAND Corporation, Santa Monica, CA, USA

    M T Scheuner

  4. Department of Medicine, Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    P K Shah

  5. Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    M O Goodarzi, P K Shah & J I Rotter

  6. Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    K D Taylor, X Guo & J I Rotter

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  1. M O Goodarzi
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  2. K D Taylor
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Correspondence to M O Goodarzi.

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The authors declare that no conflict of interest exists.

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Goodarzi, M., Taylor, K., Scheuner, M. et al. Haplotypes in the lipoprotein lipase gene influence high-density lipoprotein cholesterol response to statin therapy and progression of atherosclerosis in coronary artery bypass grafts. Pharmacogenomics J 7, 66–73 (2007). https://doi.org/10.1038/sj.tpj.6500402

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