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Linkage of serum leptin levels in families with sleep apnea

International Journal of Obesity volume 29, pages 260–267 (2005)Cite this article

Abstract

OBJECTIVE:

To identify regions on the genome linked to plasma leptin levels.

DESIGN:

Full genome scan with 402 microsatellite markers, spaced ∼10 cM apart. Data were analyzed using the Haseman–Elston regression linkage analysis.

SUBJECTS:

A total of 160 sibling pairs from 59 predominantly African American, obese families recruited to participate in a genetic-epidemiological study of obstructive sleep apnea.

MEASUREMENTS:

Serum leptin levels adjusted for age, sex, race and body mass index (BMI).

RESULTS:

Suggestive linkage peaks were observed on chromosomes 2 (P=0.00170; marker D2S1384), 3 (P=0.00007; marker D3S3034), 4 (P=0.00020; marker D4S1652) and 21 (P=0.00053; marker D21s1411).

CONCLUSION:

The peak on chromosome 3 is near the gene for glycogensynthase kinase 2 beta, an important factor in glucose homeostasis. Linkage was generally stronger after BMI adjustment, suggesting the potential influence of a number of metabolic pathways on leptin levels other than those that directly determine obesity levels. The evidence of linkage for leptin levels is consistent with prior linkage analyses for cholesterol, hypertension and other metabolic phenotypes.

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References

  1. Strohl KP, Novak RD, Singer W, Cahan C, Boehm KD, Denko CW, Hoffstem VS . Insulin levels, blood pressure and sleep apnea. Sleep 1994; 17: 614–618.

    Article  CAS  Google Scholar 

  2. Newman AB, Nieto FJ, Guidry U, Lind BK, Redline S, Shahar E, Pickering TG, Quan SF . Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. Am J Epidemiol 2001; 154: 50–59.

    Article  CAS  Google Scholar 

  3. Wilcox I, McNamara SG, Collins FL, Grunstein RR, Sullivan CE . ‘Syndrome Z’: the interaction of sleep apnoea, vascular risk factors and heart disease. Thorax 1998; 53 (Suppl 3): S25–S28.

    PubMed  PubMed Central  Google Scholar 

  4. Yokoe T, Minoguchi K, Matsuo H, Oda N, Minoguchi H, Yoshino G, Hirano T, Adachi M . Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 2003; 107: 1129–1134.

    Article  CAS  Google Scholar 

  5. Palmer LJ, Redline S . Genomic approaches to understanding obstructive sleep apnea. Respir Physiol Neurobiol 2003; 135: 187–205.

    Article  CAS  Google Scholar 

  6. Havel PJ . Update on adipocyte hormones: regulation of energy balance and carbohydrate/lipid metabolism. Diabetes 2004; 53 (Suppl 1): S143–S151.

    Article  CAS  Google Scholar 

  7. O'Donnell CP, Tankersley CG, Polotsky VP, Schwartz AR, Smith PL . Leptin, obesity, and respiratory function. Respir Physiol 2000; 119: 163–170.

    Article  CAS  Google Scholar 

  8. Hixson JE, Almasy L, Cole S, Birnbaum S, Mitchell BD, Mahaney MC, Stern MP, MacCluer JW, Blangero J, Comuzzie AG . Normal variation in leptin levels in associated with polymorphisms in the proopiomelanocortin gene, POMC. J Clin Endocrinol Metab 1999; 84: 3187–3191.

    CAS  Google Scholar 

  9. Palmer LJ, Buxbaum SG, Larkin E, Patel SR, Elston RC, Tishler PV, Redline S . A whole-genome scan for obstructive sleep apnea and obesity. Am J Hum Genet 2003; 72: 340–350.

    Article  CAS  Google Scholar 

  10. Comuzzie AG, Hixson JE, Almasy L, Mitchell BD, Mahaney MC, Dyer TD, Stern MP, MacCluer JW, Blangero J . A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat Genet 1997; 15: 273–276.

    Article  CAS  Google Scholar 

  11. Palmer LJ, Buxbaum SG, Larkin E, Patel SR, Elston RC, Tishler PV, Redline S . A whole-genome scan for obstructive sleep apnea and obesity. Am J Hum Genet 2003; 72: 340–350.

    Article  CAS  Google Scholar 

  12. Comuzzie AG, Hixson JE, Almasy L, Mitchell BD, Mahaney MC, Dyer TD, Stern MP, MacCluer JW, Blangero J . A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat Genet 1997; 15: 273–276.

    Article  CAS  Google Scholar 

  13. Kissebah AH, Sonnenberg GE, Myklebust J, Goldstein M, Broman K, James RG, Marks JA, Krakower GR, Jacob HJ, Weber J, Martin L, Blangero J, Comuzzie AG . Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proc Natl Acad Sci USA 2000; 97: 14478–14483.

    Article  CAS  Google Scholar 

  14. Martin LJ, Kissebah AH, Sonnenberg GE, Blangero J, Comuzzie AG . Genotype-by-smoking interaction for leptin levels in the Metabolic Risk Complications of Obesity Genes Project. Int J Obes Relat Metab Disord 2003; 27: 334–340.

    Article  CAS  Google Scholar 

  15. Walder K, Hanson RL, Kobes S, Knowler WC, Ravussin E . An autosomal genomic scan for loci linked to plasma leptin concentration in Pima Indians. Int J Obes Relat Metab Disord 2000; 24: 559–565.

    Article  CAS  Google Scholar 

  16. Buxbaum SG, Elston RC, Tishler PV, Redline S . Genetics of the apnea hypopnea index in Caucasians and African Americans: I. Segregation analysis. Genet Epidemiol 2002; 22: 243–253.

    Article  Google Scholar 

  17. S.A.G.E. Statistical Analysis for Genetic Epidemiology. 2002, http://darwin.cwru.edu/sage.

  18. Franceschini R, Corsini G, Cataldi A, Fiorucci A, Tenerelli P, Rolandi E, Barreca T . Twenty-four-hour variation in serum leptin in the elderly. Metabolism 1999; 48: 1011–1014.

    Article  CAS  Google Scholar 

  19. Wiesner G, Vaz M, Collier G, Seals D, Kaye D, Jennings G, Lambert G, Wilkinson D, Esler M . Leptin is released from the human brain: influence of adiposity and gender. J Clin Endocrinol Metab 1999; 84: 2270–2274.

    CAS  PubMed  Google Scholar 

  20. Rayner DV, Trayhurn P . Regulation of leptin production: sympathetic nervous system interactions. J Mol Med 2001; 79: 8–20.

    Article  CAS  Google Scholar 

  21. Wiesner G, Vaz M, Collier G, Seals D, Kaye D, Jennings G, Lambert G, Wilkinson D, Esler M . Leptin is released from the human brain: influence of adiposity and gender. J Clin Endocrinol Metab 1999; 84: 2270–2274.

    CAS  PubMed  Google Scholar 

  22. Walder K, Hanson RL, Kobes S, Knowler WC, Ravussin E . An autosomal genomic scan for loci linked to plasma leptin concentration in Pima Indians. Int J Obes Relat Metab Disord 2000; 24: 559–565.

    Article  CAS  Google Scholar 

  23. Hodge AM, Boyko EJ, de Courten M, Zimmet PZ, Chitson P, Tuomilehto J, Alberti KG . Leptin and other components of the Metabolic Syndrome in Mauritius—a factor analysis. Int J Obes Relat Metab Disord 2001; 25: 126–131.

    Article  CAS  Google Scholar 

  24. Winick JD, Stoffel M, Friedman JM . Identification of microsatellite markers linked to the human leptin receptor gene on chromosome 1. Genomics 1996; 36: 221–222.

    Article  CAS  Google Scholar 

  25. Hixson JE, Almasy L, Cole S, Birnbaum S, Mitchell BD, Mahaney MC, Stern MP, MacCluer JW, Blangero J, Comuzzie AG . Normal variation in leptin levels in associated with polymorphisms in the proopiomelanocortin gene, POMC. J Clin Endocrinol Metab 1999; 84: 3187–3191.

    CAS  Google Scholar 

  26. Kissebah AH, Sonnenberg GE, Myklebust J, Goldstein M, Broman K, James RG, Marks JA, Krakower GR, Jacob HJ, Weber J, Martin L, Blangero J, Comuzzie AG . Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proc Natl Acad Sci USA 2000; 97: 14478–14483.

    Article  CAS  Google Scholar 

  27. Comuzzie AG, Hixson JE, Almasy L, Mitchell BD, Mahaney MC, Dyer TD, Stern MP, MacCluer JW, Blangero J . A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat Genet 1997; 15: 273–276.

    Article  CAS  Google Scholar 

  28. Heo M, Leibel RL, Fontaine KR, Boyer BB, Chung WK, Koulu M, Karvonen MK, Pesonen U, Rissanen A, Laakso M, Uusitupa MI, Chagnon Y, Bouchard C, Donohoue PA, Burns TL, Shuldiner AR, Silver K, Andersen RE, Pedersen O, Echwald S, Sorensen TI, Behn P, Permutt MA, Jacobs KB, Elston RC, Hoffman DJ, Gropp E, Allison DB . A meta-analytic investigation of linkage and association of common leptin receptor (LEPR) polymorphisms with body mass index and waist circumference. Int J Obes Relat Metab Disord 2002; 26: 640–646.

    Article  CAS  Google Scholar 

  29. Ceddia RB, Koistinen HA, Zierath JR, Sweeney G . Analysis of paradoxical observations on the association between leptin and insulin resistance. FASEB J 2002; 16: 1163–1176.

    Article  CAS  Google Scholar 

  30. Szanto I, Kahn CR . Selective interaction between leptin and insulin signaling pathways in a hepatic cell line. Proc Natl Acad Sci USA 2000; 97: 2355–2360.

    Article  CAS  Google Scholar 

  31. Frame S, Cohen P, Biondi RM . A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol Cell 2001; 7: 1321–1327.

    Article  CAS  Google Scholar 

  32. Wilk JB, Myers RH, Zhang Y, Lewis CE, Atwood L, Hopkins PN, Ellison RC . Evidence for a gene influencing heart rate on chromosome 4 among hypertensives. Hum Genet 2002; 111: 207–213.

    Article  CAS  Google Scholar 

  33. Facchini FS, Stoohs RA, Reaven GM . Enhanced sympathetic nervous system activity. The linchpin between insulin resistance, hyperinsulinemia, and heart rate. Am J Hypertens 1996; 9: 1013–1017.

    Article  CAS  Google Scholar 

  34. Palatini P . Elevated heart rate as a predictor of increased cardiovascular morbidity. J Hypertens 1999; 17 (Suppl 3): S3–S10.

    CAS  Google Scholar 

  35. Lindsay RS, Funahashi T, Krakoff J, Matsuzawa Y, Tanaka S, Kobes S, Bennett PH, Tataranni PA, Knowler WC, Hanson RL . Genome-wide linkage analysis of serum adiponectin in the Pima Indian population. Diabetes 2003; 52: 2419–2425.

    Article  CAS  Google Scholar 

  36. Singh MK, Krisan AD, Crain AM, Collins DE, Yaspelkis III BB . High-fat diet and leptin treatment alter skeletal muscle insulin-stimulated phosphatidylinositol 3-kinase activity and glucose transport. Metabolism 2003; 52: 1196–1205.

    Article  CAS  Google Scholar 

  37. Chagnon YC, Rankinen T, Snyder EE, Weisnagel SJ, Perusse L, Bouchard C . The human obesity gene map: the 2002 update. Obes Res 2003; 11: 313–367.

    Article  CAS  Google Scholar 

  38. Morrison AC, Brown A, Kardia SL, Turner ST, Boerwinkle E . Evaluating the context-dependent effect of family history of stroke in a genome scan for hypertension. Stroke 2003; 34: 1170–1175.

    Article  Google Scholar 

  39. Hsueh WC, Mitchell BD, Schneider JL, Wagner MJ, Bell CJ, Nanthakumar E, Shuldiner AR . QTL influencing blood pressure maps to the region of PPH1 on chromosome 2q31–34 in Old Order Amish. Circulation 2000; 101: 2810–2816.

    Article  CAS  Google Scholar 

  40. Tang W, Miller MB, Rich SS, North KE, Pankow JS, Borecki IB, Myers RH, Hopkins PN, Leppert M, Arnett DK . Linkage analysis of a composite factor for the multiple metabolic syndrome: the National Heart, Lung, and Blood Institute Family Heart Study. Diabetes 2003; 52: 2840–2847.

    Article  CAS  Google Scholar 

  41. Wilk JB, Myers RH, Zhang Y, Lewis CE, Atwood L, Hopkins PN, Ellison RC . Evidence for a gene influencing heart rate on chromosome 4 among hypertensives. Hum Genet 2002; 111: 207–213.

    Article  CAS  Google Scholar 

  42. Coon H, Leppert MF, Eckfeldt JH, Oberman A, Myers RH, Peacock JM, Province MA, Hopkins PN, Heiss G . Genome-wide linkage analysis of lipids in the Hypertension Genetic Epidemiology Network (HyperGEN) Blood Pressure Study. Arterioscler Thromb Vasc Biol 2001; 21: 1969–1976.

    Article  CAS  Google Scholar 

  43. North KE, Miller MB, Coon H, Martin L, Zhang B, Province MA, Oberman A, Almasy L, Blangero J, Arnett DK, Peacock JM, Elston RC, Heiss G . Gene influences cholesterol and triglycerides on chromosome 21q. 12th Annual Meeting of the International Genetic Epidemiology Society, Vol 46, 11-3-2003.

  44. Luke A, Wu X, Zhu X, Kan D, Su Y, Cooper R . Linkage for BMI at 3q27 region confirmed in an African-American population. Diabetes 2003; 52: 1284–1287.

    Article  CAS  Google Scholar 

  45. Kissebah AH, Sonnenberg GE, Myklebust J, Goldstein M, Broman K, James RG, Marks JA, Krakower GR, Jacob HJ, Weber J, Martin L, Blangero J, Comuzzie AG . Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proc Natl Acad Sci USA 2000; 97: 14478–14483.

    Article  CAS  Google Scholar 

  46. Luke A, Wu X, Zhu X, Kan D, Su Y, Cooper R . Linkage for BMI at 3q27 region confirmed in an African-American population. Diabetes 2003; 52: 1284–1287.

    Article  CAS  Google Scholar 

  47. Panhuysen CI, Cupples LA, Wilson PW, Herbert AG, Myers RH, Meigs JB . A genome scan for loci linked to quantitative insulin traits in persons without diabetes: the Framingham Offspring Study. Diabetologia 2003; 46: 579–587.

    Article  CAS  Google Scholar 

  48. Imperatore G, Knowler WC, Pettitt DJ, Kobes S, Fuller JH, Bennett PH, Hanson RL . A locus influencing total serum cholesterol on chromosome 19p: results from an autosomal genomic scan of serum lipid concentrations in Pima Indians. Arterioscler Thromb Vasc Biol 2000; 20: 2651–2656.

    Article  CAS  Google Scholar 

  49. Punjabi NM, Ahmed MM, Polotsky VY, Beamer BA, O'Donnell CP . Sleep-disordered breathing, glucose intolerance, and insulin resistance. Respir Physiol Neurobiol 2003; 136: 167–178.

    Article  CAS  Google Scholar 

  50. Phillips BG, Kato M, Narkiewicz K, Choe I, Somers VK . Increases in leptin levels, sympathetic drive, and weight gain in obstructive sleep apnea. Am J Physiol Heart Circ Physiol 2000; 279: H234–H237.

    Article  CAS  Google Scholar 

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Acknowledgements

Genotyping was conducted by the NHLBI Mammalian Genotyping Service, Marshfield, Wisconsin. This work was supported by Grants T32-HL07567, RO1HL46380 and M01-RR00080. This work was also supported in part by a US Public Health Service Resource Grant (RR03655) from the National Center for Research Resources and Research Grant (GM28356) from the National Institute of General Medical Sciences. We are deeply indebted to Joan Aylor, Kathryn Clark and Heather Rosebrock for their tremendous efforts in data collection.

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Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA

    E K Larkin & R C Elston

  2. Department of Pediatrics, Rainbow Babies and Children's Hospital and Case Western Reserve University, Cleveland, OH, USA

    E K Larkin & S Redline

  3. Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA

    S R Patel & P V Tishler

  4. Western Australian Institute for Medical Research, Centre for Medical Research, University of Western Australia, Perth, Australia

    L J Palmer

  5. Department of Pathology, University of Vermont, Burlington, VT, USA

    N S Jenny

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  1. E K Larkin
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Correspondence to E K Larkin.

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Larkin, E., Elston, R., Patel, S. et al. Linkage of serum leptin levels in families with sleep apnea. Int J Obes 29, 260–267 (2005). https://doi.org/10.1038/sj.ijo.0802872

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  • DOI: https://doi.org/10.1038/sj.ijo.0802872

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