Journal of Biomedical Science

, Volume 12, Issue 4, pp 651–658 | Cite as

Lipoprotein Lipase Gene is Linked and Associated with Hypertension in Taiwan Young-onset Hypertension Genetic Study

  • Pei Chen
  • Yuh-Shan Jou
  • Cathy S.J. Fann
  • Jaw-Wen Chen
  • Sheng-Yeu Wu
  • Wen-Harn Pan
Article

Summary

Hypertriglyceridemia has been extensively associated with hypertension. However, the mechanism behind it is poorly understood. A positive linkage signal between Lipoprotein lipase (LPL) and young-onset hypertension has been identified by us as the strongest among 18 candidate genes. Here we report our fine mapping works with seven microsatellite markers flanking LPL, sequencing results for its promoter and exons, and an extended association study with the identified single nucleotide polymorphisms(SNP). First, using data from 213 individuals in 59 nuclear families of young-onset hypertension, multipoint analysis revealed a NPL score of 3.02 for the LPL (GZ-14/GZ-15) marker in intron 6. LPL marker (p<10−12) and the haplotypes containing its allele 1 (p<0.0001) were also significantly associated with young hypertension by transmission disequilibrium test. In-depth sequencing revealed no mutation in promoter and exon regions, except two cSNP: 7754C→ A (C/A: 0.91/0.09), a silent mutation in exon 8 and S447X (C/G: 0.92/0.08), a stop codon mutation in exon 9. Other 11 cSNPs documented in NCBI GenBank are absent in our sample. Constructed from the above 2 cSNPs, haplotype AC showed a moderate TDT association with elevated triglyceride (p=0.02) and with hypertension and elevated triglyceride combined (p=0.06). Again, in an extended case-control study, a significant association was found between S447X and patients with persistent hypertension and elevated triglyceride (p=0.02). We conclude that LPL variants may play a causal role in the development of hypertension in Taiwan Han Chinese. The moderate association with SNP haplotype suggests that other regulatory LPL variant may exist.

Key words:

lipoprotein lipase young-onset hypertension linkage transmission disequilibrium test SNP haplotype S447X 

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References

  1. 1.
    Mein, C.A., Caulfield, M.J., Dobson, R.J., Munroe, P.B. (2004) "Genetics of essential hypertension" Hum. Mol. Genet. 13: R169-175CrossRefPubMedGoogle Scholar
  2. 2.
    Pan, W.H., Chen, Y.C., Yu, S.L., Sun, J.A., Chang, Y.S., Chen, C.J. (1994) "Correlates and predictive models for blood pressure values in residents of two communities in Taiwan" J. Formos. Med. Assoc. 93: 582-591PubMedGoogle Scholar
  3. 3.
    Julius, S., Jamerson, K., Mejia, A., Krause, L., Schork, N., Jones, K. (1990) "The association of borderline hypertension with target organ changes and higher coronary risk. Tecumseh Blood Pressure study" JAMA 264: 354-358CrossRefPubMedGoogle Scholar
  4. 4.
    Fisher, R.M., Humphries, S.E., Talmud, P.J. (1997) "Common variation in the lipoprotein lipase gene: effects on plasma lipids and risk of atherosclerosis" Atherosclerosis 135: 145-159CrossRefPubMedGoogle Scholar
  5. 5.
    Liu, A., Lee, L., Zhan, S., Cao, W., Lv, J., Guo, X., Hu, Y. (2004) "The S447X polymorphism of the lipoprotein lipase gene is associated with lipoprotein lipid and blood pressure levels in Chinese patients with essential hypertension" J. Hypertens. 22: 1503-1509CrossRefPubMedGoogle Scholar
  6. 6.
    Li, B., Ge, D., Wang, Y., Zhao, W., Zhou, X., Gu, D., Chen, R. (2004) "Lipoprotein lipase gene polymorphisms and blood pressure levels in the Northern Chinese Han population" Hypertens. Res. 27: 373-378CrossRefPubMedGoogle Scholar
  7. 7.
    Kastelein, J.J., Groenemeyer, B.E., Hallman, D.M., Henderson, H., Reymer, P.W., Gagne, S.E., Jansen, H., Seidell, J.C., Kromhout, D., Jukema, J.W., Bruschke, A.V., Boerwinkle, E., Hayden, M.R. (1998) "The Asn9 variant of lipoprotein lipase is associated with the –93G promoter mutation and an increased risk of coronary artery disease. The regress study group" Clin. Genet. 53: 27-33CrossRefPubMedGoogle Scholar
  8. 8.
    Bruin, T.W., Mailly, F., Barlingen, H.H., Fisher, R., Castro Cabezas, M., Talmud, P., Dallinga-Thie, G.M., Humphries, S.E. (1996) "Lipoprotein lipase gene mutations D9N and N291S in four pedigrees with familial combined hyperlipidaemia" Eur. J. Clin. Invest. 26: 631-639PubMedGoogle Scholar
  9. 9.
    Tu, X., Tu, J., Wen, X., Wang, J., Zhang, D. (2005) "A study of lipoprotein lipase gene intron 8 polymorphisms in Chinese Han race essential hypertension patients" Int. J. Cardiol. 99: 263-267CrossRefPubMedGoogle Scholar
  10. 10.
    Clee, S.M., Loubser, O., Collins, J., Kastelein, J.J., Hayden, M.R. (2001) "The LPL S447X cSNP is associated with decreased blood pressure and plasma triglycerides, and reduced risk of coronary artery disease" Clin. Genet. 60: 293-300CrossRefPubMedGoogle Scholar
  11. 11.
    Wu, D.A., Bu, X., Warden, C.H., Shen, D.D.C., Jeng, C.Y., Sheu, W.H.H., Fuh, M.M.T., Katsuya, T., Dzau, V.J., Reaven, G.M. et al. (1996) "Quantitative trait locus mapping of human blood pressure to a genetic region at or near the lipoprotein lipase gene locus on chromosome 8p22" Clin. Invest. 97: 2111-2118CrossRefGoogle Scholar
  12. 12.
    Yang, W., Huang, J., Ge, D., Yao, C., Duan, X., Gan, W., Huang, G., Zhao, J., Hui, R., Shen, Y. et al. (2003) "Variation near the region of the lipoprotein lipase gene and hypertension or blood pressure levels in Chinese" Hypertens. Res. 26: 459-464CrossRefPubMedGoogle Scholar
  13. 13.
    Yang, W.J., Huang, J.F., Yao, C.L., Fan, Z.J., Ge, D.L., Gan, W.Q., Huang, G.Y., Hui, R.T., Shen, Y., Qiang, B.Q., Gu, D.F. (2003) "Evidence for linkage and association of the markers near the LPL gene with hypertension in Chinese families" J. Med. Genet. 40: e57, 2003CrossRefGoogle Scholar
  14. 14.
    Yang, W., Huang, J., Ge, D., Yao, C., Duan, X., Shen, Y., Qiang, B., Gu, D. (2004) "Lipoprotein lipase gene is in linkage with blood pressure phenotypes in Chinese pedigrees" Hum. Genet. 115: 8-12CrossRefPubMedGoogle Scholar
  15. 15.
    Yang, W., Huang, J., Yao, C., Su, S., Liu, D., Ge, D., Gu, D. (2005) "Linkage and linkage disequilibrium analysis of the lipoprotein lipase gene with lipids profile in Chinese hypertensive families" Clin. Sci. 108: 137-142CrossRefPubMedGoogle Scholar
  16. 16.
    Hunt, S.C., Province, M.A., Atwood, L.D., Sholinsky, P., Lalouel, J.M., Rao, D.C., Williams, R.R., Leppert, M.F. (1999) "No linkage of the lipoprotein lipase locus to hypertension in Caucasians" J. Hypertens. 17: 39-43PubMedCrossRefGoogle Scholar
  17. 17.
    Pan, W.H., Chen, J.W., Fann, C., Jou, Y.S., Wu, S.Y. (2000) "Linkage analysis with candidate genes the Taiwan young-onset hypertension genetic study" Hum. Genet. 107: 210-215CrossRefPubMedGoogle Scholar
  18. 18.
    Wu, S.Y., Fann, C.S., Jou, Y.S., Chen, J.W., Pan, W.H. (2002) "Association between markers in chromosomal region 17q23 and young onset hypertension a TDT study" J. Med. Genet. 39: 42-44CrossRefPubMedGoogle Scholar
  19. 19.
    The sixth report of the Joint National Committee on Prevention, Detection, Evalution, and treatment of High Blood Pressure. Arch. Intern. Med. 157: 2413–2446, 1997Google Scholar
  20. 20.
    Kruglyak, L., Daly, M.J., Reeve-Daly, M.P., Lander, E.S. (1996) "Parametric and Nonparametric linkage analysis: a unified multipoint approach" Am. J. Hum. Genet. 58: 1347-1363PubMedGoogle Scholar
  21. 21.
    Spielman, R.S., McGinnis, R.E., Ewens, W.J. (1993) "Transmission Test for Linkage Disequilibrium: The Insulin Gene Region and Insulin-Dependent Diabetes Mellitus (IDDM)" Am. J. Hum. Genet. 52: 506-516PubMedGoogle Scholar
  22. 22.
    Spielman, R.S., Ewens, W.J. (1998) "A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test" Am. J. Hum. Genet. 62: 450-458CrossRefPubMedGoogle Scholar
  23. 23.
    Clayton, D., Jones, H. (1999) "Transmission/disequilibrium test for extended marker haplotypes" Am. J. Hum. Genet. 65: 1161-1169CrossRefPubMedGoogle Scholar
  24. 24.
    Yeh, C.J., Pan, W.H., Jong, Y.S., Kuo, Y.Y., Lo, C.H. (2001) "Incidence and predictors of isolated systolic hypertension and isolated diastolic hypertension in Taiwan" J. Formos. Med. Assoc. 100: 668-675PubMedGoogle Scholar
  25. 25.
    Nickerson, D.A., Taylor, S.L., Weiss, K.M., Clark, A.G., Hutchinson, R.G., Stengard, J., Salomaa, V., Vartiainen, E., Boerwinkle, E., Sing, C.F. (1998) "DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene" Nat. Genet. 19: 233-240CrossRefPubMedGoogle Scholar
  26. 26.
    Chen, J.W., Wu, S.Y., Pan, W.H. (2004) "Clinical characteristics of young-onset hypertension–implications for different genders" Int. J. Cardiol. 96: 65-71CrossRefPubMedGoogle Scholar
  27. 27.
    Goodarzi, M.O., Guo, X., Taylor, K.D., Quiñones, M.J., Saad, M.F., Yang, H., Hsueh, W.A., Rotter, J.I. (2004) "Lipoprotein lipase is a gene for insulin resistance in Mexican Americans" Diabetes 53: 214-220PubMedCrossRefGoogle Scholar
  28. 28.
    Jemaa, R., Tuzet, S., Portos, C., Betoulle, D., Apfelbaum, M., Fumeron, F. (1995) "Lipoprotein lipase gene polymorphisms: associations with hypertriglyceridemia and body mass index in obese people" Int. J. Obes. Relat. Metab. Disord. 19: 270-274PubMedGoogle Scholar
  29. 29.
    Moller, D.E., Kaufman, K.D. (2005) "Metabolic syndrome: a clinical and molecular perspective" Annu. Rev. Med. 56: 45-62CrossRefPubMedGoogle Scholar
  30. 30.
    Beauchamp, M.C., Michaud, S.E., Li, L., Sartippour, M.R., Renier, G. (2004) "Advanced glycation end products potentiate the stimulatory effect of glucose on macrophage lipoprotein lipase expression" J. Lipid. Res. 45: 1749-1757CrossRefPubMedGoogle Scholar
  31. 31.
    Michaud, S.E., Renier, G. (2001) "Direct regulatory effect of fatty acids on macrophage lipoprotein lipase: potential role of PPARs" Diabetes 50: 660-666PubMedCrossRefGoogle Scholar
  32. 32.
    Brown, C.M., Layman, D.K. (1988) "Lipoprotein lipase activity and chylomicron clearance in rats fed a high fat diet" J. Nutr. 118: 1294-1298PubMedGoogle Scholar
  33. 33.
    Sadur, C.N., Yost, T.J., Eckel, R.H. (1984) "Fat feeding decreases insulin responsiveness of adipose tissue lipoprotein lipase" Metabolism 33: 1043-1047CrossRefPubMedGoogle Scholar

Copyright information

© National Science Council, Taipei 2005

Authors and Affiliations

  • Pei Chen
    • 1
    • 2
  • Yuh-Shan Jou
    • 2
  • Cathy S.J. Fann
    • 2
  • Jaw-Wen Chen
    • 3
  • Sheng-Yeu Wu
    • 2
  • Wen-Harn Pan
    • 2
  1. 1.Graduate Institute of Life SciencesNational Defense Medical CenterTaiwan
  2. 2.Institute of Biomedical SciencesAcademia SinicaNankangTaiwan
  3. 3.Department of Cardiology, Taipei Veterans General Hospital, and Cardiovascular Research CenterNational Yang-Ming UniversityTaiwan

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