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Association of a leucine(7)-to-proline(7) polymorphism in the signal peptide of neuropeptide Y with high serum cholesterol and LDL cholesterol levels

Nature Medicine volume 4, pages 1434–1437 (1998)Cite this article

Abstract

High serum levels of total and LDL cholesterol are important risk factors in the development of atherosclerotic coronary artery disease. Cholesterol metabolism is affected by nutritional, environmental and genetic factors. Neuropeptide Y (NPY), which is widely expressed in both the central and peripheral nervous systems 1, 2 , has an important role in the hypothalamic regulation of energy balance by stimulating food intake 3, 4, 5 and favoring energy storage through increased lipoprotein lipase activity in white adipose tissue 6, 7 . As a part of ongoing study of the genetic basis of obesity, we screened the NPY gene for sequence variants. We report here the identification of a common Leu(7)-to-Pro(7) polymorphism in the signal peptide of NPY. Presence of this Pro(7) in NPY was associated with higher serum levels of total and LDL cholesterol in obese subjects participating in two independent Finnish and Dutch studies. Furthermore, normal-weight Finns with Pro(7) also had higher serum levels of total and LDL cholesterol than did subjects with Leu(7)/Leu(7), as analyzed in three subsequent determinations at 5-year intervals during a 10-year follow-up period. The NPY polymorphism was not associated with higher cholesterol levels in normal-weight Dutch. Our study provides evidence that NPY is linked to cholesterol metabolism and that the polymorphism producing Pro(7) in NPY is one of the strongest genetic factors identified thus far affecting serum cholesterol, particularly in obese subjects.

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Figure 1: Fasting serum total cholesterol and LDL cholesterol levels in obese Finns (a) and obese Dutchmen (b).
Figure 2: Predicted probability (solid line) with 95 % confidence limits (dashed line) of having Pro(7) in NPY, calculated by logistic regression analysis with respect to serum total cholesterol level in obese Finns.

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Acknowledgements

We thank H. Helenius (Department of Biostatistics, University of Turku) for his help and comments concerning the statistical analyses. The study was partly supported by a grant to M.I.J.U. from the Council for Health Research, Academy of Finland.

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Authors and Affiliations

  1. Department of Pharmacology and Clinical Pharmacology University of Turku, Kiinamyllynkatu 10, Turku, FIN-20520, Finland

    Matti K. Karvonen, Ullamari Pesonen & Markku Koulu

  2. Department of Medicine, University of Kuopio, P.O.Box 1777, Kuopio, FIN-70211, Finland

    Leo Niskanen & Markku Laakso

  3. Eating Disorder Unit, University of Helsinki, Paasikivenkatu 4, Helsinki, FIN-00250, Finland

    Aila Rissanen

  4. Institute for Research in Extramural Medicine, Vrije Universiteit Amsterdam, Van der Boechorststraat 7, Amsterdam, 1081 BT, The Netherlands

    Jacqueline M. Dekker

  5. Department of Molecular Cellbiology, Leiden University Medical Center, Wassenaarseweg 72, Leiden, 2333 AL, The Netherlands

    Leen M ´t Hart

  6. Department of Clinical Nutrition, University of Kuopio, P.O.Box 1627, Kuopio, FIN-70211, Finland

    Raisa Valve & Matti I.J. Uusitupa

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  1. Matti K. Karvonen
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Correspondence to Markku Koulu.

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Karvonen, M., Pesonen, U., Koulu, M. et al. Association of a leucine(7)-to-proline(7) polymorphism in the signal peptide of neuropeptide Y with high serum cholesterol and LDL cholesterol levels. Nat Med 4, 1434–1437 (1998). https://doi.org/10.1038/4027

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