J Korean Surg Soc.  2012 Jul;83(1):7-13. 10.4174/jkss.2012.83.1.7.

Susceptibility of gastric cancer according to leptin and leptin receptor gene polymorphisms in Korea

• Kim EY
• Chin HM
• Park SM
• Jeon HM
• Chung WC
• Paik CN
• Jun KH

• KMID: 2212273
• DOI: http://doi.org/10.4174/jkss.2012.83.1.7

Abstract

PURPOSE
Leptin plays an important role in the control of body weight and also has a growth-factor-like function in epithelial cells. Abnormal expression of leptin and leptin receptor may be associated with cancer development and progression. We evaluated the relationship among leptin and leptin receptors polymorphisms, body mass index (BMI), serum leptin concentrations, and clinicopathologic features with gastric cancer and determined whether they could be the risk factor of gastric cancer.
METHODS
We measured the serum leptin concentrations of 48 Korean patients with gastric cancer and 48 age- and sex-matched controls. By polymerase chain reaction-restriction fragment length polymorphism, we investigated one leptin gene promoter G-2548A genotype and four leptin receptor gene polymorphisms at codons 223, 109, 343, and 656.
RESULTS
There was no significant difference between the mean leptin concentrations of the patient and control groups, while BMI was significantly lower in gastric cancer cases (22.9 +/- 3.6 vs. 24.5 +/- 2.8 kg/m2, P = 0.021). There was significant association between the LEPR Lys109Arg genotype and gastric cancer risk, heterozygotes for GA genotype had been proved to increased the risk of gastric cancer, and its corresponding odds ratio was 2.926 (95% confidence interval, 1.248 to 6.861).
CONCLUSION
Our results suggested that LEPR gene Lys109Arg polymorphism is associated with gastric cancer in Korean patients.

Keyword

Leptin; Leptin receptors; Gastric cancer

MeSH Terms

Body Mass Index
Body Weight
Codon
Epithelial Cells
Genotype
Heterozygote
Humans
Korea
Leptin
Odds Ratio
Receptors, Leptin
Risk Factors
Stomach Neoplasms
Codon
Leptin
Receptors, Leptin

Reference

1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994. 372:425–432.

2. Collins S, Kuhn CM, Petro AE, Swick AG, Chrunyk BA, Surwit RS. Role of leptin in fat regulation. Nature. 1996. 380:677.

3. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996. 334:292–295.

4. Señarís R, Garcia-Caballero T, Casabiell X, Gallego R, Castro R, Considine RV, et al. Synthesis of leptin in human placenta. Endocrinology. 1997. 138:4501–4504.

5. Jin L, Burguera BG, Couce ME, Scheithauer BW, Lamsan J, Eberhardt NL, et al. Leptin and leptin receptor expression in normal and neoplastic human pituitary: evidence of a regulatory role for leptin on pituitary cell proliferation. J Clin Endocrinol Metab. 1999. 84:2903–2911.

6. Briscoe CP, Hanif S, Arch JR, Tadayyon M. Leptin receptor long-form signalling in a human liver cell line. Cytokine. 2001. 14:225–229.

7. Mix H, Widjaja A, Jandl O, Cornberg M, Kaul A, Goke M, et al. Expression of leptin and leptin receptor isoforms in the human stomach. Gut. 2000. 47:481–486.

8. Schneider R, Bornstein SR, Chrousos GP, Boxberger S, Ehninger G, Breidert M. Leptin mediates a proliferative response in human gastric mucosa cells with functional receptor. Horm Metab Res. 2001. 33:1–6.

9. Sierra-Honigmann MR, Nath AK, Murakami C, Garcia-Cardena G, Papapetropoulos A, Sessa WC, et al. Biological action of leptin as an angiogenic factor. Science. 1998. 281:1683–1686.

10. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003. 348:1625–1638.

11. Stattin P, Lukanova A, Biessy C, Soderberg S, Palmqvist R, Kaaks R, et al. Obesity and colon cancer: does leptin provide a link? Int J Cancer. 2004. 109:149–152.

12. Stattin P, Soderberg S, Hallmans G, Bylund A, Kaaks R, Stenman UH, et al. Leptin is associated with increased prostate cancer risk: a nested case-referent study. J Clin Endocrinol Metab. 2001. 86:1341–1345.

13. Stephenson GD, Rose DP. Breast cancer and obesity: an update. Nutr Cancer. 2003. 45:1–16.

14. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature. 1996. 379:632–635.

15. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell. 1996. 84:491–495.

16. Gotoda T, Manning BS, Goldstone AP, Imrie H, Evans AL, Strosberg AD, et al. Leptin receptor gene variation and obesity: lack of association in a white British male population. Hum Mol Genet. 1997. 6:869–876.

17. Zhao L, Shen ZX, Luo HS, Shen L. Possible involvement of leptin and leptin receptor in developing gastric adenocarcinoma. World J Gastroenterol. 2005. 11:7666–7670.

18. Lewin MJ, Bado A. Gastric leptin. Microsc Res Tech. 2001. 53:372–376.

19. Ishikawa M, Kitayama J, Nagawa H. Expression pattern of leptin and leptin receptor (OB-R) in human gastric cancer. World J Gastroenterol. 2006. 12:5517–5522.

20. Zhao X, Huang K, Zhu Z, Chen S, Hu R. Correlation between expression of leptin and clinicopathological features and prognosis in patients with gastric cancer. J Gastroenterol Hepatol. 2007. 22:1317–1321.

21. Low S, Chin MC, Ma S, Heng D, Deurenberg-Yap M. Rationale for redefining obesity in Asians. Ann Acad Med Singapore. 2009. 38:66–69.

22. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med. 1995. 1:1155–1161.

23. Ben Ali S, Kallel A, Ftouhi B, Sediri Y, Feki M, Slimane H, et al. Association of G-2548A LEP polymorphism with plasma leptin levels in Tunisian obese patients. Clin Biochem. 2009. 42:584–588.

24. Mammes O, Betoulle D, Aubert R, Herbeth B, Siest G, Fumeron F. Association of the G-2548A polymorphism in the 5' region of the LEP gene with overweight. Ann Hum Genet. 2000. 64(Pt 5):391–394.

25. Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP, Bortoluzzi MN, et al. The stomach is a source of leptin. Nature. 1998. 394:790–793.

26. Blaser MJ, Atherton JC. Helicobacter pylori persistence: biology and disease. J Clin Invest. 2004. 113:321–333.

27. Azuma T, Suto H, Ito Y, Ohtani M, Dojo M, Kuriyama M, et al. Gastric leptin and Helicobacter pylori infection. Gut. 2001. 49:324–329.

28. Chung WK, Power-Kehoe L, Chua M, Chu F, Aronne L, Huma Z, et al. Exonic and intronic sequence variation in the human leptin receptor gene (LEPR). Diabetes. 1997. 46:1509–1511.

29. Woo HY, Park H, Ki CS, Park YL, Bae WG. Relationships among serum leptin, leptin receptor gene polymorphisms, and breast cancer in Korea. Cancer Lett. 2006. 237:137–142.

30. Ogawa T, Hirose H, Yamamoto Y, Nishikai K, Miyashita K, Nakamura H, et al. Relationships between serum soluble leptin receptor level and serum leptin and adiponectin levels, insulin resistance index, lipid profile, and leptin receptor gene polymorphisms in the Japanese population. Metabolism. 2004. 53:879–885.