Nature Medicine
4, 1434 - 1437 (1998)
doi:10.1038/4027
Association of a leucine(7)-to-proline(7) polymorphism in the signal
peptide of neuropeptide Y with high serum cholesterol and LDL cholesterol
levelsMatti K. Karvonen1, Ullamari Pesonen1, Markku Koulu1, Leo Niskanen2, Markku Laakso2, Aila Rissanen3, Jacqueline M. Dekker4, Leen M ´t Hart5, Raisa Valve6
& Matti I.J. Uusitupa61
Department of Pharmacology and Clinical Pharmacology,
University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland
2
Department of Medicine, University of Kuopio,
P.O.Box 1777, FIN-70211 Kuopio, Finland
3
Eating Disorder Unit, University of Helsinki,
Paasikivenkatu 4, FIN-00250 Helsinki,
Finland
4
Institute for Research in Extramural Medicine, Vrije
Universiteit Amsterdam, Van der Boechorststraat 7,
1081 BT Amsterdam, The Netherlands
5
Leiden University Medical Center, Department of Molecular
Cellbiology, Wassenaarseweg 72, 2333 AL,
Leiden, The Netherlands
6
Department of Clinical Nutrition, University of Kuopio, P.O.Box 1627, FIN-70211 Kuopio,
Finland
Correspondence should be addressed to Markku Koulu mkoulu@utu.fi
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 systems1,
2, has an important role in the hypothalamic
regulation of energy balance by stimulating food intake3,
4,
5
and favoring energy storage through increased lipoprotein lipase activity
in white adipose tissue6,
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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