Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The effect of leptin on blood pressure considering smoking status: a Mendelian randomization study


Studies on leptin and blood pressure (BP) associations have yielded inconsistent findings. The current study aimed to evaluate the effect of genetically determined leptin on BP and to explore whether smoking status modified this effect. We conducted a Mendelian randomization analysis using the baseline data of 3860 participants in the Framingham Heart Study 3rd generation cohort. Pairwise associations among leptin genetic risk score (GRS), log-transformed leptin (log-leptin), and BP were assessed by multivariate linear regression models. Age and sex were adjusted in the base model, and education, smoking, drinking, and physical activity were adjusted in the full model. The interaction between leptin GRS and smoking was evaluated by adding an interaction term, GRS × smoking, in the fully adjusted model. In the age- and sex-adjusted analyses, log-leptin was positively associated with systolic BP (SBP) (P = 2.35 × 10−79), diastolic BP (DBP) (P = 6.19 × 10−76), mean arterial pressure (MAP) (P = 1.10 × 10−90), and pulse pressure (P = 4.38 × 10−19). Leptin GRS significantly increased log-leptin (P = 0.00001). Leptin GRS was associated with reduced SBP (P = 0.04), DBP (P = 0.006), and MAP (P = 0.008) among current smokers. In the fully adjusted model, significant interactions between GRS and smoking were identified for SBP (P = 0.02), DBP (P = 0.002), and MAP (P = 0.003). Sensitivity analyses among participants not taking antihypertensive or glucose-lowering medications revealed similar associations. Our study provided evidence for a potentially causal relationship between leptin and BP among current smokers.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Muntner P, Carey RM, Gidding S, Jones DW, Taler SJ, Wright JT, et al. Potential US population impact of the 2017 ACC/AHA High Blood Pressure Guideline. Circulation. 2018;137:109–18.

    Article  Google Scholar 

  2. 2.

    Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ Res. 2015;116:991–1006.

    CAS  Article  Google Scholar 

  3. 3.

    Simonds SE, Pryor JT, Ravussin E, Greenway FL, Dileone R, Allen AM, et al. Leptin mediates the increase in blood pressure associated with obesity. Cell. 2014;159:1404–16.

    CAS  Article  Google Scholar 

  4. 4.

    Huby AC, Otvos L, Belin de Chantemèle EJ. Leptin induces hypertension and endothelial dysfunction via aldosterone-dependent mechanisms in obese female mice. Hypertension. 2016;67:1020–8.

    CAS  Article  Google Scholar 

  5. 5.

    Allison MA, Ix JH, Morgan C, McClelland RL, Rifkin D, Shimbo D, et al. Higher leptin is associated with hypertension: the multi-ethnic study of atherosclerosis. J Hum Hypertens. 2013;27:617–22.

    CAS  Article  Google Scholar 

  6. 6.

    Sheu WH, Lee WJ, Chen YT. High plasma leptin concentrations in hypertensive men but not in hypertensive women. J Hypertens. 1999;17:1289–95.

    CAS  Article  Google Scholar 

  7. 7.

    Kokot F, Adamczak M, Wiecek A, Cieplok J. Does leptin play a role in the pathogenesis of essential hypertension? Kidney Blood Press Res. 1999;22:154–60.

    CAS  Article  Google Scholar 

  8. 8.

    Schorr U, Blaschke K, Turan S, Distler A, Sharma AM. Relationship between angiotensinogen, leptin and blood pressure levels in young normotensive men. J Hypertens. 1998;16:1475–80.

    CAS  Article  Google Scholar 

  9. 9.

    Ma D, Feitosa MF, Wilk JB, Laramie JM, Yu K, Leiendecker-Foster C, et al. Leptin is associated with blood pressure and hypertension in women from the National Heart, Lung, and Blood Institute Family Heart Study. Hypertension. 2009;53:473–9.

    CAS  Article  Google Scholar 

  10. 10.

    Smith W, Schutte R, Huisman HW, Van Rooyen JM, Ware LJ, Fourie CM, et al. Leptin is positively associated with blood pressure in african men with a low body mass index: the SAfrEIC study. Horm Metab Res. 2015;47:145–51.

    CAS  PubMed  Google Scholar 

  11. 11.

    Schutte R, Huisman HW, Schutte AE, Malan NT. Leptin is independently associated with systolic blood pressure, pulse pressure and arterial compliance in hypertensive African women with increased adiposity: the POWIRS study. J Hum Hypertens. 2005;19:535–41.

    CAS  Article  Google Scholar 

  12. 12.

    Brown RJ, Meehan CA, Gorden P. Leptin does not mediate hypertension associated with human obesity. Cell. 2015;162:465–6.

    CAS  Article  Google Scholar 

  13. 13.

    Kamimura D, Suzuki T, Wang W, deShazo M, Hall JE, Winniford MD, et al. Higher plasma leptin levels are associated with reduced left ventricular mass and left ventricular diastolic stiffness in black women: insights from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Hypertens Res. 2018;41:629–38.

    CAS  Article  Google Scholar 

  14. 14.

    Reseland JE, Mundal HH, Hollung K, Haugen F, Zahid N, Anderssen SA, et al. Cigarette smoking may reduce plasma leptin concentration via catecholamines. Prostaglandins, Leukotrienes, Essent Fat Acids. 2005;73:43–9.

    CAS  Article  Google Scholar 

  15. 15.

    Kryfti M, Dimakou K, Toumbis M, Daniil Z, Hatzoglou C, Gourgoulianis KI. Effects of smoking cessation on serum leptin and adiponectin levels. Tob Induc Dis. 2015;13:30.

    Article  Google Scholar 

  16. 16.

    Nagayasu S, Suzuki S, Yamashita A, Taniguchi A, Fukushima M, Nakai Y, et al. Smoking and adipose tissue inflammation suppress leptin expression in Japanese obese males: potential mechanism of resistance to weight loss among Japanese obese smokers. Tob Induc Dis. 2012;10:3.

    CAS  Article  Google Scholar 

  17. 17.

    Hughes K, Leong WP, Sothy SP, Lun KC, Yeo PP. Relationships between cigarette smoking, blood pressure and serum lipids in the Singapore general population. Int J Epidemiol. 1993;22:637–43.

    CAS  Article  Google Scholar 

  18. 18.

    Primatesta P, Falaschetti E, Gupta S, Marmot MG, Poulter NR. Association between smoking and blood pressure: evidence from the health survey for England. Hypertension. 2001;37:187–93.

    CAS  Article  Google Scholar 

  19. 19.

    Li J, Cui R, Eshak ES, Yamagishi K, Imano H, Muraki I, et al. Association of cigarette smoking with radial augmentation index: the Circulatory Risk in Communities Study (CIRCS). Hypertens Res. 2018;41:1054–62.

    CAS  Article  Google Scholar 

  20. 20.

    Splansky GL, Corey D, Yang Q, Atwood LD, Cupples LA, Benjamin EJ, et al. The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination. Am J Epidemiol. 2007;165:1328–35.

    Article  Google Scholar 

  21. 21.

    Kilpeläinen TO, Carli JF, Skowronski AA, Sun Q, Kriebel J, Feitosa MF, et al. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels. Nat Commun. 2016;7:10494.

    Article  Google Scholar 

  22. 22.

    Beaumont RN, Warrington NM, Cavadino A, Tyrrell J, Nodzenski M, Horikoshi M, et al. Genome-wide association study of offspring birth weight in 86577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics. Hum Mol Genet. 2018;27:742–56.

  23. 23.

    Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, et al. A global reference for human genetic variation. Nature. 2015; 526:68–74.

  24. 24.

    Das S, Forer L, Schönherr S, Sidore C, Locke AE, Kwong A, et al. Next-generation genotype imputation service and methods. Nat Genet. 2016;48:1284–7.

    CAS  Article  Google Scholar 

  25. 25.

    Andersson C, Lyass A, Larson MG, Robins SJ, Vasan RS. Low-density-lipoprotein cholesterol concentrations and risk of incident diabetes: epidemiological and genetic insights from the Framingham Heart Study. Diabetologia. 2015;58:2774–80.

    CAS  Article  Google Scholar 

  26. 26.

    Zachariah JP, Quiroz R, Nelson KP, Teng Z, Keaney JF, Sullivan LM, et al. Prospective relation of circulating adipokines to incident metabolic syndrome: the Framingham Heart Study. J Am Heart Assoc. 2017;6.

  27. 27.

    von Jeinsen B, Short MI, Xanthakis V, Carneiro H, Cheng S, Mitchell GF, et al. Association of circulating adipokines with echocardiographic measures of cardiac structure and function in a community-based cohort. J Am Heart Assoc. 2018;7.

  28. 28.

    Li C, Kim YK, Dorajoo R, Li H, Lee IT, Cheng CY, et al. Genome-wide association study meta-analysis of long-term average blood pressure in East Asians. Circ Cardiovasc Genet. 2017;10:e001527.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Li C, He J, Chen J, Zhao J, Gu D, Hixson JE, et al. Genome-wide gene-potassium interaction analyses on blood pressure: the GenSalt Study (Genetic Epidemiology Network of Salt Sensitivity). Circ Cardiovasc Genet. 2017;10.

  30. 30.

    Kannel WB, Sorlie P. Some health benefits of physical activity. The Framingham Study. Arch Intern Med. 1979;139:857–61.

    CAS  Article  Google Scholar 

  31. 31.

    Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39:175–91.

    Article  Google Scholar 

  32. 32.

    Faul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods. 2009;41:1149–60.

    Article  Google Scholar 

  33. 33.

    Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA. 1999;282:1568–75.

    CAS  Article  Google Scholar 

  34. 34.

    Fei H, Okano HJ, Li C, Lee GH, Zhao C, Darnell R, et al. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc Natl Acad Sci USA. 1997;94:7001–5.

    CAS  Article  Google Scholar 

  35. 35.

    Morris DL, Rui L. Recent advances in understanding leptin signaling and leptin resistance. Am J Physiol Endocrinol Metab. 2009;297:E1247–59.

    CAS  Article  Google Scholar 

  36. 36.

    Tu H, Kastin AJ, Hsuchou H, Pan W. Soluble receptor inhibits leptin transport. J Cell Physiol. 2008;214:301–5.

    CAS  Article  Google Scholar 

  37. 37.

    Pan W, Kastin AJ. Adipokines and the blood-brain barrier. Peptides. 2007;28:1317–30.

    CAS  Article  Google Scholar 

  38. 38.

    Al Mutairi SS, Mojiminiyi OA, Shihab-Eldeen AA, Al Sharafi A, Abdella N. Effect of smoking habit on circulating adipokines in diabetic and non-diabetic subjects. Ann Nutr Metab. 2008;52:329–34.

    CAS  Article  Google Scholar 

  39. 39.

    Park HK, Ahima RS. Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism. 2015;64:24–34.

    CAS  Article  Google Scholar 

  40. 40.

    Kraja AT, Vaidya D, Pankow JS, Goodarzi MO, Assimes TL, Kullo IJ, et al. A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium. Diabetes. 2011;60:1329–39.

    CAS  Article  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Changwei Li.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shen, L., Cordero, J.F., Wang, JS. et al. The effect of leptin on blood pressure considering smoking status: a Mendelian randomization study. Hypertens Res 43, 342–349 (2020).

Download citation


  • Leptin
  • Blood pressure
  • Smoking
  • Genetic risk score


Quick links