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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 4 1455-1460
Copyright © 2000 by The Endocrine Society

Original Studies

Leucine 7 to Proline 7 Polymorphism in the Preproneuropeptide Y Is Associated with Birth Weight and Serum Triglyceride Concentration in Preschool-Aged Children1

Matti K. Karvonen, Markku Koulu, Ullamari Pesonen, Matti I. J. Uusitupa, Anne Tammi, Jorma Viikari, Olli Simell and Tapani Rönnemaa

Departments of Pharmacology and Clinical Pharmacology (M.K.K., M.K., U.P.) and Pediatrics (O.S.) and Cardiorespiratory Research Unit (A.T.), University of Turku, and Department of Medicine, Turku University Central Hospital (J.V., T.R.), FIN-20520 Turku; and Department of Clinical Nutrition, University of Kuopio (M.I.J.U.), FIN-70211 Kuopio, Finland

Address all correspondence and requests for reprints to: Dr. M. K. Karvonen, Department of Pharmacology and Clinical Pharmacology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. E-mail: makarvo{at}utu.fi


   Abstract
Top
 Abstract
Introduction
 Experimental Subjects
 Materials and Methods
 Results
 Discussion
 References
 
The Leu7Pro gene variant of the signal peptide part of neuropeptide Y (NPY), has been shown to affect cholesterol metabolism in obese adults. This study investigates whether the Leu7Pro polymorphism in the prepro-NPY has an impact on serum lipid concentrations in preschool-aged children at 5 and 7 yr of age. As birth weight may influence future lipid values, we also investigated whether Leu7Pro polymorphism is associated with birth weight. The study comprised 688 children participating in the Special Turku Coronary Risk Factor Intervention Project. Fasting lipid concentrations were determined first at the age of 5 yr and again at the age of 7 yr. The Leu7Pro polymorphism was not associated with serum total or low density lipoprotein cholesterol values in boys or in girls. However, Pro7 substitution in prepro-NPY was constantly associated with 14–17% higher mean serum triglyceride values in the boys at the ages of 5 and 7 yr (P = 0.023). In addition, boys with the Pro7 substitution had, on the average, a 193-g higher birth weight than boys homozygous for Leu7 (P = 0.03). The Leu7Pro polymorphism may thus be linked with serum triglyceride concentrations, but not with serum cholesterol concentrations, in gender-specific manner in preschoolers.


   Introduction
Top
 Abstract
 Introduction
Experimental Subjects
 Materials and Methods
 Results
 Discussion
 References
 
NEUROPEPTIDE Y (NPY) is a neurotransmitter widely expressed in the central (1) and peripheral (2) nervous systems. NPY favors energy storage, as it markedly promotes eating (3, 4) and inhibits brown adipose tissue thermogenesis (5). Central administration of NPY stimulates the activity of lipoprotein lipase (5, 6), a key enzyme for white fat metabolism and degradation of triglyceride-rich particles. NPY also regulates the release of insulin (7), which regulates hypothalamic NPY expression (8). NPY also participates in the control of the hypothalamic-pituitary-adrenal axis (9). In the periphery, NPY is costored with norepinephrine in noradrenergic nerve endings and is released during high frequency nerve stimulation (10).

We recently identified a common polymorphism in the human NPY gene that results in the Leu7 to Pro7 substitution in prepro-NPY (11). The Pro7 substitution in prepro-NPY was associated with higher serum total and low density lipoprotein (LDL) cholesterol concentrations than the wild-type Leu7 in obese subjects. Although the biochemical and physiological background of these associations remains unknown, our findings suggest that the Leu7Pro polymorphism of the NPY gene is a genetic marker for major cardiovascular risk factors.

Elevated serum cholesterol and triglyceride concentrations in youth are considered important determinants for future atherosclerosis (12, 13). Genetically determined defects in LDL receptor (14) or lipoprotein lipase (15) and apolipoprotein E4 (Apo E4) genotype (16) are currently known genetic determinants of increased serum LDL cholesterol, decreased high density lipoprotein (HDL) cholesterol, and increased triglyceride concentrations at an early age. This study was originally undertaken to determine whether the recently discovered Leu7Pro polymorphism in prepro-NPY modifies serum lipid levels in children. As birth weight may regulate the late development of cardiovascular heart disease (17), we also examined the possible relationship between NPY polymorphism and birth weight.


   Experimental Subjects
Top
 Abstract
 Introduction
 Experimental Subjects
Materials and Methods
 Results
 Discussion
 References
 
This study comprises 688 children, whose serum lipid and Apo concentrations were determined at the ages of 5 yr (367 boys and 321 girls) and 7 yr (298 boys and 260 girls). All children were participants of a randomized prospective intervention study aimed at decreasing intervention children’s exposure to environmental atherosclerosis risk factors, Special Turku Coronary Risk Factor Intervention Project (STRIP). Dietary counseling of the intervention children began at the age of 7 months after obtaining informed consent from the parents. Consequently, the STRIP study investigates long term effects of a supervised eucaloric, low saturated fat, low cholesterol diet on serum lipid and lipoprotein concentrations in the children. Details of the study have described previously in detail (18, 19). The joint committee on ethics of Turku University and Turku University Central Hospital approved the study.


   Materials and Methods
Top
 Abstract
 Introduction
 Experimental Subjects
 Materials and Methods
Results
 Discussion
 References
 
Lipid analyses

Blood samples in the STRIP project children at the ages of 5 and 7 yr were drawn after an overnight fast. Lipid and Apo A1 and B concentrations were determined at the laboratory of the Research and Development Unit of the Social Insurance Institution in Turku, Finland. Serum cholesterol concentrations were measured using cholesterol oxidase-p-aminophenazone method (Merck & Co., Inc., Darmstadt, Germany). Serum HDL cholesterol concentrations were measured after precipitation of LDL and very low density lipoprotein (VLDL) with dextran sulfate 500,000 (20). LDL and VLDL cholesterol levels were calculated using the Friedewald formula (21). Apo B was determined immunoturbidometrically using apolipoprotein B kit (22) (Orion Diagnostica, Helsinki, Finland). Apo E phenotyping using electrophoresis and isoelectric focusing was described previously in detail (23).

Genotype analysis

DNA samples were isolated from dried whole blood collected on filter paper. DNA was extracted using a DNA isolation kit (Gentra Systems, Minneapolis, MN) as suggested by the manufacturer. The prepro-NPY genotype was determined by PCR-restriction fragment length polymorphism analysis from extracted DNA by an investigator unaware of the anthropometric and lipid data of the children. Thymidine 1128 to cytosine 1128 substitution generates a BsiEI restriction site, which was used to genotype the subjects for the Leu7Pro polymorphism. The genotyping method was described previously in detail (11).

Statistical methods

Because only three subjects were Pro7/Pro7 homozygotes, they were combined with the Leu7/Pro7 heterozygote group for statistical analyses. Logarithmic transformation of data was used to normalize data distribution, if indicated by Levene’s test of homogeneity of variances. Because gender and dietary intervention markedly influence some of the serum lipid parameters (Table 1Go), the association of Leu7Pro polymorphism was analyzed separately for sex and diet intervention using Student’s t test, if indicated by the general linear models procedure. The impact of Apo E phenotype on the association of Leu7Pro polymorphism with serum total, LDL, and HDL cholesterol levels was analyzed using analysis of covariance. Serum triglyceride concentrations were analyzed at different time points with ANOVA for repeated measurements. P <= 0.05 was considered significant. All statistical analyses were conducted using SAS (release 6.08) programs (SAS Institute, Inc., Cary, NC).


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  		Table 1. The impact of sex and dietary intervention on serum cholesterol, apo B, and triglyceride levels

 

   Results
Top
 Abstract
 Introduction
 Experimental Subjects
 Materials and Methods
 Results
Discussion
 References
 
Prepro-NPY Leu7Pro polymorphism and serum total, LDL, and HDL cholesterol concentrations

Serum total, LDL, and HDL cholesterol concentrations were similar in children with the Leu7/Leu7 genotype and the Pro7/- genotype in both boys and girls at the age of 5 or 7 yr (Tables 2Go and 3Go). The result was not different even if the impact of the Apo E {epsilon}4-allele, also known to affect serum lipids (24), was taken into account (data not shown). There was no effect of dietary intervention on the association of Leu7Pro polymorphism with lipid parameters (data not shown).


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  		Table 2. Serum lipid levels and main body size characteristics (mean ± SD) in boys according to the prepro-NPY genotype and age

 

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  		Table 3. Serum lipid levels and main body size characteristics (mean ± SD) in girls according to the prepro-NPY genotype and age

 
Prepro-NPY Leu7Pro polymorphism and serum triglyceride concentrations

At the ages of 5 and 7 yr, the Leu7Pro polymorphism associated with the serum triglyceride concentration in boys (genotype: F = 5.23; P = 0.023; time: F = 0.01; P = 0.93; time x genotype interaction: F = 0.07; P = 0.79; by ANOVA for repeated measurements; Table 2Go and Fig. 1Go). At the age of 5 yr, boys with the Pro7/- genotype had, on the average, 14% higher serum triglyceride concentrations than boys with the Leu7/Leu7 genotype. At the age of 7 yr, the difference was 17%. However girls showed no association between the polymorphic forms of prepro-NPY and serum triglyceride values (genotype: F = 0.00; P = 0.99; time: F = 0.48; P = 0.49; time x genotype interaction: F = 0.51; P = 0.47; by ANOVA for repeated measurements). Cumulative distribution curves in boys showed that the below median triglyceride concentrations were essentially similar in the two genotype groups, but high triglyceride values occurred at both ages more frequently in boys with the Pro7 substitution (Fig. 2Go). There was no effect of dietary intervention on the association of Leu7Pro polymorphism with triglyceride (data not shown). Birth weight correlated poorly with serum triglyceride concentration in both genders.



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  		Figure 1. The mean serum triglyceride levels (±SEM) according to the NPY signal peptide genotype in boys and girls at the ages of 5 and 7 yr. The open symbols present the serum triglyceride levels in subjects with the Pro7 substitution in prepro-NPY, and the closed symbols present the serum triglyceride levels in subjects with the Leu7/Leu7 signal peptide genotype. *, F = 5.23; P = 0.023 (by ANOVA for repeated measurements for genotype effect).

 


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  		Figure 2. Cumulative distribution curves for serum triglyceride levels in boys at 5 yr (a) and 7 yr (b) of age presented separately for Leu7/Leu7 (solid line) and Pro7/- (dotted line) genotype groups.

 
Prepro-NPY Leu7Pro polymorphism, birth size, and parents’ sizes

The Leu7Pro polymorphism associated with birth weight and relative (Table 2Go) birth weight in boys, so that male infants with the Pro7 substitution were, on the average, 193 g heavier at birth than male infants with the Leu7/Leu7 genotype (Table 4Go). No such difference between girls with Pro7/- and those with Leu7/Leu7 was found. Birth height and gestational age at birth were also similar in boys with Pro7/- and Leu7/Leu7. The mean values of height, weight, and body mass index of the fathers and mothers of children with two different NPY signal peptide genotypes were also similar (Table 5Go).


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  		Table 4. Characteristics of the study subjects at birth (mean ± SD)

 

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  		Table 5. Parent’s BMI, weight, and height by children’s sex and children’s prepro-NPY genotype

 

   Discussion
Top
 Abstract
 Introduction
 Experimental Subjects
 Materials and Methods
 Results
 Discussion
References
 
Our primary aim was to analyze the impact of the Leu7Pro substitution on serum lipid concentrations in children. Clearly, the Pro7 substitution was not associated with the LDL or HDL cholesterol concentration, but was linked with elevated serum triglyceride concentrations in boys at the ages of both 5 and 7 yr. Intraindividual triglyceride tracking is low over the long term, and triglyceride concentrations present marked day to day variations. It is very unlikely that the difference between the Pro7/- and Leu7/Leu7 genotypes could have appeared at two separate age points 2 yr apart by chance. Currently, we do not know the mechanisms for the observed association between NPY genotype and elevated triglycerides and why this was present only in boys. There is an obvious gender difference in serum triglyceride concentrations that may contribute to the absence of the association of the Pro7 substitution with serum triglycerides in girls. Theoretically, differences in body composition at an early age (25) and also moderate differences in sex hormone levels at an early age (26) may alter the association of NPY genotype with triglyceride concentrations. The observed elevation in triglycerides might also be due to diminished lipoprotein lipase activity, which is under the stimulation of NPY (5, 6). In fact, the absolute elevation in triglyceride concentration in boys was moderate between the two genotype groups, but the difference was probably large enough to suggest that that it may have biological value. Birth weight or current weight did not explain the observed association in boys. Subjects with elevated serum triglyceride levels often express a lipoprotein profile characterized by elevated VLDL cholesterol and decreased HDL cholesterol concentration and sometimes also elevated LDL cholesterol concentration. These are all features of familial combined hyperlipidemia, which is the most common genetic form of hyperlipidemia. In this study there were no differences in LDL or HDL cholesterol levels at early ages. A recent study by Pajukanta et al. (27) linked familial combined hyperlipidemia to chromosome 1q21-q23. The human NPY gene is assigned to 7p15.1 (28).

Previously, we have found associations of Leu7Pro polymorphism with serum total and LDL cholesterol in obese adult subjects (11) and also been able to replicate the finding in a study cohort of obese middle-aged Caucasian men (Karvonen, M. K., et al., unpublished observation). In the present study we analyzed the effect of the Leu7Pro polymorphism on serum total and LDL cholesterol concentrations separately in the highest quartile of relative weight in boys and girls, but we observed no tendency for association (data not shown). Considering the underlying physiological link between NPY and cholesterol metabolism, this study conducted in children does not provide direct new mechanistic explanation. However, our findings are in favor of the idea that the serum cholesterol-elevating role of Pro7 substitution may require an increased cholesterol turnover rate, as in obesity (29, 30). It is possible that the effect of Leu7Pro polymorphism on the serum cholesterol concentration is not detectable in a study sample of preschool-aged children who may generally have lower cholesterol turnover at the age of 5–7 yr compared to obese adult subjects. It is possible that the Leu7Pro variant may have different effects on lipid metabolism depending on age and gender.

Coronary fatty streaks are found as early as the first decade of life, although they become more prevalent in adolescents and in early adulthood (31). Elevated serum lipid levels in early childhood are associated with increased fatty streak and fibrous plaque formation. There are also gender differences in the degree of arterial narrowing in children, with boys having, on the average, more narrowing than girls (32). The elevated triglyceride levels seen in boys with the Pro7 substitution may be one factor that contributes to fatty streak formation in childhood. NPY itself has been implicated in myocardial infarction (33, 34), and a recent study shows that NPY acts as an important angiogenic factor that promotes capillary tube formation and proliferation of human endothelial cells (35). Thus, NPY may regulate artery wall cell function leading to structural changes independently of lipid accumulation. This is also in accordance with our preliminary observation suggesting that the Pro7 substitution in the prepro-NPY may be an independent risk factor for accelerated carotid atherosclerosis in type 2 diabetics (36). To determine whether a similar association with atherosclerosis is present in children, it would be informative to evaluate the possible relation between the Leu7Pro polymorphism and early changes in arteries of accidentally deceased children.

A difference in the mean birth weight in boys between the two NPY genotype groups was observed. Boys with the Pro7 substitution were, on the average, 193 g (5%) heavier than boys with the Leu7/Leu7 genotype, and there were no differences in height or gestational age of the newborn boys. There was a difference in the relative weight, which expresses the weight deviation as a percentage from the mean weight of healthy Finnish children of the same height and gender (37). This suggests that the male infants with the Pro7 substitution have more adipose tissue at birth. In addition, there was no single newborn with very low birth weight in Pro7 group (Fig. 3Go), as in Leu7/Leu7 group. Because the birth weight closely correlates to the sizes of the parents we also analyzed the weights and heights of the parents (recorded when children were 3 yr old). There were no differences in height, weight, or body mass index of the parents of children with the Pro7 substitution compared to those of the parents of children with the Leu7/Leu7 genotype. As we have no data on mothers’ NPY genotype, we cannot exclude the possibility that the Pro7 substitution in mother affects male fetal growth. However, a major effect is unlikely, because the difference in birth weight is present only in boys. The impact of the Pro7 substitution on insulin metabolism and glucose utilization of the developing fetus is not known, and therefore, further studies are warranted to confirm our observation of higher birth weight in boys with the Pro7 substitution.



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  		Figure 3. The birth weight in boys according to the NPY signal peptide genotype. The mean ± SD level is presented beside each scattergram.

 
The impact of the Pro7 substitution on synthesis, storage, and release of prepro-NPY can only be speculated. In general, signal peptides target nascent proteins to the lumen of endoplasmic reticulum, where proteins fold and oligomerize, disulfide bonds are formed, and N-linked oligosaccharides are added. Proline and leucine have different chemical properties. Leucine, which has a hydrophobic aliphatic side-chain, is known to favor formation of {alpha}-helixes, whereas proline introduces breaks and kinks into {alpha}-helical parts of the peptide backbone. Therefore, the Pro7 substitution of Leu7 in the signal peptide may lead to alterations in cellular processing of the nascent prepro-NPY in the endoplasmic reticulum, which could lead to changes in the availability or kinetics of NPY release. Further studies are required to elucidate these mechanisms in detail.

In conclusion, the Leu7Pro polymorphism located in the signal peptide part of prepro-NPY is associated with constantly higher serum triglyceride levels in boys in early childhood. Furthermore, the Leu7Pro polymorphism may be associated with higher birth weight in boys, but not with body weight in preschool-aged children. If reproduced, these results indicate that the Leu7Pro polymorphism may be an important new gene marker for cardiovascular risk at an early age.


   Acknowledgments
 
We thank H. Torikka for statistical analyses and R. Kaartosalmi for technical assistance.


   Footnotes
 
1 This work was supported by the Research Foundation of Pharmacal and the Ida Montin Foundation (to M.K.K.) and by grants from the Turku University Hospital and the Technology Development Center of Finland (to M.K.). Back

Received August 19, 1999.

Revised December 1, 1999.

Accepted December 17, 1999.


   References
Top
 Abstract
 Introduction
 Experimental Subjects
 Materials and Methods
 Results
 Discussion
 References
 

  1. Gray TS, Morley JE. 1986 Neuropeptide Y: anatomical distribution and possible function in mammalian nervous system. Life Sci. 38:389–401.[CrossRef][Medline]
  2. Lundberg JM, Terenius L, Hokfelt T, et al. 1982 Neuropeptide Y (NPY)-like immunoreactivity in peripheral noradrenergic neurons and effects of NPY on sympathetic function. Acta Physiol Scand. 116:477–480.[Medline]
  3. Clark JT, Kalra PS, Crowley WR, Kalra SP. 1984 Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology. 115:427–429.[Abstract/Free Full Text]
  4. Stanley BG, Leibowitz SF. 1984 Neuropeptide Y: stimulation of feeding and drinking by injection into the paraventricular nucleus. Life Sci. 35:2635–2642.[CrossRef][Medline]
  5. Billington CJ, Briggs JE, Grace M, Levine AS. 1991 Effects of intracerebroventricular injection of neuropeptide Y on energy metabolism. Am J Physiol 260:R321–R327.
  6. Billington CJ, Briggs JE, Harker S, Grace M, Levine AS. 1994 Neuropeptide Y in hypothalamic paraventricular nucleus: a center coordinating energy metabolism. Am J Physiol. 266:R1765–R1770.
  7. Moltz JH, McDonald JK. 1985 Neuropeptide Y: direct and indirect action on insulin secretion in the rat. Peptides. 6:1155–1159.[CrossRef][Medline]
  8. Schwartz MW, Sipols AJ, Marks JL, et al. 1992 Inhibition of hypothalamic neuropeptide Y gene expression by insulin. Endocrinology. 130:3608–3616.[Abstract/Free Full Text]
  9. Wahlestedt C, Skagerberg G, Ekman R, Heilig M, Sundler F, Hakanson R. 1987 Neuropeptide Y (NPY) in the area of the hypothalamic paraventricular nucleus activates the pituitary-adrenocortical axis in the rat. Brain Res. 417:33–38.[CrossRef][Medline]
  10. Lundberg JM, Terenius L, Hokfelt T, Goldstein M. 1983 High levels of neuropeptide Y in peripheral noradrenergic neurons in various mammals including man. Neurosci Lett. 42:167–172.[CrossRef][Medline]
  11. Karvonen MK, Pesonen U, Koulu M, et al. 1998 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.[CrossRef][Medline]
  12. Anonymous. 1990 Relationship of atherosclerosis in young men to serum lipoprotein cholesterol concentrations and smoking. A preliminary report from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. JAMA. 264:3018–3024.[Abstract/Free Full Text]
  13. Berenson GS, Srinivasan SR, Bao W, Newman WP, Tracy RE, Wattigney WA. 1998 Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med. 338:1650–1656.[Abstract/Free Full Text]
  14. Hobbs HH, Brown MS, Goldstein JL. 1992 Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1:445–466.[CrossRef][Medline]
  15. Fisher RM, Humphries SE, Talmud PJ. 1997 Common variation in the lipoprotein lipase gene: effects on plasma lipids and risk of atherosclerosis. Atherosclerosis. 135:145–159.[CrossRef][Medline]
  16. Utermann G, Hees M, Steinmetz A. 1977 Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man. Nature. 269:604–607.[CrossRef][Medline]
  17. Barker DJ, Martyn CN, Osmond C, Hales CN, Fall CH. 1993 Growth in utero and serum cholesterol concentrations in adult life. Br Med J. 307:1524–1527.
  18. Lapinleimu H, Viikari J, Jokinen E, et al. 1995 Prospective randomised trial in 1062 infants of diet low in saturated fat and cholesterol. Lancet. 345:471–476.[CrossRef][Medline]
  19. Niinikoski H, Viikari J, Ronnemaa T, et al. 1996 Prospective randomized trial of low-saturated-fat, low-cholesterol diet during the first 3 years of life. The STRIP baby project. Circulation. 94:1386–1393.[Abstract/Free Full Text]
  20. Kostner GM. 1976 Enzymatic determination of cholesterol in high-density lipoprotein fractions prepared by polyanion precipitation. Clin Chem. 22:695.
  21. Friedewald WT, Levy RL, Fredrikson DS. 1972 Estimation of the concentration of low density lipoprotein cholesterol in plasma without the use of preparative ultracentifuge. Clin Chem. 18:499–502.[Abstract]
  22. Riepponen P, Marniemi J, Rautaoja T. 1987 Immunoturbidimetric determination of apolipoproteins A-1 and B in serum. Scand J Clin Lab Invest. 47:739–744.[Medline]
  23. Lehtimaki T, Moilanen T, Viikari J, et al. 1990 Apolipoprotein E phenotypes in Finnish youths: a cross-sectional and 6- year follow-up study. J Lipid Res. 31:487–495.[Abstract]
  24. Lapinleimu H, Viikari J, Ronnemaa T, et al. 1996 Apolipoprotein E polymorphism and serum lipids in a randomized, prospective trial of an infant diet with reduced saturated fat and cholesterol. Pediatrics. 98:757–762.[Abstract/Free Full Text]
  25. Mast M, Kortzinger I, Konig E, Muller MJ. 1998 Gender differences in fat mass of 5–7-year old children. Int J Obes Relat Metab Disord. 22:878–884.[CrossRef][Medline]
  26. Herruzo AJ, Mozas J, Alarcon JL, et al. 1993 Sex differences in serum hormone levels in umbilical vein blood. Int J Gynaecol Obstet. 41:37–41.[CrossRef][Medline]
  27. Pajukanta P, Nuotio I, Terwilliger JD, et al. 1998 Linkage of familial combined hyperlipidaemia to chromosome 1q21–q23. Nat Genet. 18:369–373.[CrossRef][Medline]
  28. Baker E, Hort YJ, Ball H, Sutherland GR, Shine J, Herzog H. 1995 Assignment of the human neuropeptide Y gene to chromosome 7p15.1 by nonisotopic in situ hybridization. Genomics. 26:163–164.[CrossRef][Medline]
  29. Miettinen TA. 1971 Cholesterol production in obesity. Circulation. 44:842–850.[Abstract/Free Full Text]
  30. Kesaniemi YA, Grundy SM. 1983 Increased low density lipoprotein production associated with obesity. Arteriosclerosis. 3:170–177.[Abstract/Free Full Text]
  31. Stary HC. 1989 Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Arteriosclerosis. 9:I19–I32.
  32. Pesonen E, Norio R, Hirvonen J, et al. 1990 Intimal thickening in the coronary arteries of infants and children as an indicator of risk factors for coronary heart disease. Eur Heart J. 11(Suppl E):53–60.
  33. Ullman B, Franco-Cereceda A, Hulting J, Lundberg JM, Sollevi A. 1990 Elevation of plasma neuropeptide Y-like immunoreactivity and noradrenaline during myocardial ischaemia in man. J Intern Med. 228:583–589.[Medline]
  34. Ullman B, Hulting J, Lundberg JM. 1994 Prognostic value of plasma neuropeptide-Y in coronary care unit patients with and without acute myocardial infarction. Eur Heart J. 15:454–461.[Abstract/Free Full Text]
  35. Zukowska-Grojec Z, Karwatowska-Prokopczuk E, Rose W, et al. 1998 Neuropeptide Y: a novel angiogenic factor from the sympathetic nerves and endothelium. Circ Res. 27:187–195.
  36. Niskanen L, Karvonen MK, Valve R, et al. 1999 Leucine 7 to proline 7 polymorphism in the NPY gene is associated with enhanced carotid atherosclerosis in elderly patients with type 2 diabetes and control subjects. Diabetologia. 42(Suppl 1):A318.
  37. Sorva R, Perheentupa J, Tolppanen EM. 1984 A novel format for a growth chart. Acta Paediatr Scand. 73:527–529.[Medline]



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