Breast Cancer Research and Treatment

, Volume 129, Issue 2, pp 593–606

Common genetic variation in adiponectin, leptin, and leptin receptor and association with breast cancer subtypes

  • Sarah J. Nyante
  • Marilie D. Gammon
  • Jay S. Kaufman
  • Jeannette T. Bensen
  • Dan Yu Lin
  • Jill S. Barnholtz-Sloan
  • Yijuan Hu
  • Qianchuan He
  • Jingchun Luo
  • Robert C. Millikan
Epidemiology

Abstract

Adipocytokines are produced by visceral fat, and levels may be associated with breast cancer risk. We investigated whether single nucleotide polymorphisms (SNPs) in adipocytokine genes adiponectin (ADIPOQ), leptin (LEP), and the leptin receptor (LEPR) were associated with basal-like or luminal A breast cancer subtypes. 104 candidate and tag SNPs were genotyped in 1776 of 2022 controls and 1972 (200 basal-like, 679 luminal A) of 2311 cases from the Carolina Breast Cancer Study (CBCS), a population-based case–control study of whites and African Americans. Breast cancer molecular subtypes were determined by immunohistochemistry. Genotype odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Haplotype ORs and 95% CIs were estimated using Hapstat. Interactions with waist-hip ratio were evaluated using a multiplicative interaction term. Ancestry was estimated from 144 ancestry informative markers (AIMs), and included in models to control for population stratification. Candidate SNPs LEPR K109R (rs1137100) and LEPR Q223R (rs1137101) were positively associated with luminal A breast cancer, whereas ADIPOQ +45 T/G (rs2241766), ADIPOQ +276 G/T (rs1501299), and LEPR K656N (rs8129183) were not associated with either subtype. Few patterns were observed among tag SNPs, with the exception of 3 LEPR SNPs (rs17412175, rs9436746, and rs9436748) that were in moderate LD and inversely associated with basal-like breast cancer. However, no SNP associations were statistically significant after adjustment for multiple comparisons. Haplotypes in LEP and LEPR were associated with both basal-like and luminal A subtypes. There was no evidence of interaction with waist-hip ratio. Data suggest associations between LEPR candidate SNPs and luminal A breast cancer in the CBCS and LEPR intron 2 tag SNPs and basal-like breast cancer. Replication in additional studies where breast cancer subtypes have been defined is necessary to confirm these potential associations.

Keywords

Adiponectin Leptin Leptin receptor Breast cancer Subtypes Single nucleotide polymorphism 

Supplementary material

10549_2011_1517_MOESM1_ESM.doc (482 kb)
Supplementary material 1 (DOC 482 kb)

References

  1. 1.
    Fulford LG, Easton DF, Reis-Filho JS, Sofronis A, Gillett CE, Lakhani SR, Hanby A (2006) Specific morphological features predictive for the basal phenotype in grade 3 invasive ductal carcinoma of breast. Histopathology 49(1):22–34PubMedCrossRefGoogle Scholar
  2. 2.
    Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, Perou CM (2006) Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol 19(2):264–271PubMedCrossRefGoogle Scholar
  3. 3.
    Kim MJ, Ro JY, Ahn SH, Kim HH, Kim SB, Gong G (2006) Clinicopathologic significance of the basal-like subtype of breast cancer: a comparison with hormone receptor and her2/neu-overexpressing phenotypes. Hum Pathol 37(9):1217–1226PubMedCrossRefGoogle Scholar
  4. 4.
    Rodriguez-Pinilla SM, Sarrio D, Honrado E, Hardisson D, Calero F, Benitez J, Palacios J (2006) Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin Cancer Res 12(5):1533–1539PubMedCrossRefGoogle Scholar
  5. 5.
    Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, Deming SL, Geradts J, Cheang MC, Nielsen TO, Moorman PG et al (2006) Race, breast cancer subtypes, and survival in the carolina breast cancer study. JAMA 295(21):2492–2502PubMedCrossRefGoogle Scholar
  6. 6.
    Kurebayashi J, Moriya T, Ishida T, Hirakawa H, Kurosumi M, Akiyama F, Kinoshita T, Takei H, Takahashi K, Ikeda M, Nakashima K (2007) The prevalence of intrinsic subtypes and prognosis in breast cancer patients of different races. Breast 16(Suppl 2):S72–S77PubMedCrossRefGoogle Scholar
  7. 7.
    Foulkes WD, Stefansson IM, Chappuis PO, Begin LR, Goffin JR, Wong N, Trudel M, Akslen LA (2003) Germline brca1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 95(19):1482–1485PubMedGoogle Scholar
  8. 8.
    Lakhani SR, Reis-Filho JS, Fulford L, Penault-Llorca F, van der Vijver M, Parry S, Bishop T, Benitez J, Rivas C, Bignon YJ, Chang-Claude J, Hamann U, Cornelisse CJ, Devilee P, Beckmann MW et al (2005) Prediction of brca1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res 11(14):5175–5180PubMedCrossRefGoogle Scholar
  9. 9.
    Turner NC, Reis-Filho JS (2006) Basal-like breast cancer and the brca1 phenotype. Oncogene 25(43):5846–5853PubMedCrossRefGoogle Scholar
  10. 10.
    Millikan RC, Newman B, Tse CK, Moorman PG, Conway K, Dressler LG, Smith LV, Labbok MH, Geradts J, Bensen JT, Jackson S, Nyante S, Livasy C, Carey L, Earp HS et al (2008) Epidemiology of basal-like breast cancer. Breast Cancer Res Treat 109(1):123–139PubMedCrossRefGoogle Scholar
  11. 11.
    Schaffler A, Scholmerich J, Buechler C (2007) Mechanisms of disease: adipokines and breast cancer-endocrine and paracrine mechanisms that connect adiposity and breast cancer. Nat Clin Pract Endocrinol Metab 3(4):345–354PubMedCrossRefGoogle Scholar
  12. 12.
    Rose DP, Komninou D, Stephenson GD (2004) Obesity, adipocytokines, and insulin resistance in breast cancer. Obes Rev 5(3):153–165PubMedCrossRefGoogle Scholar
  13. 13.
    Fredriksson J, Carlsson E, Orho-Melander M, Groop L, Ridderstrale M (2006) A polymorphism in the adiponectin gene influences adiponectin expression levels in visceral fat in obese subjects. Int J Obes (Lond) 30(2):226–232CrossRefGoogle Scholar
  14. 14.
    Vona-Davis L, Howard-McNatt M, Rose DP (2007) Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer. Obes Rev 8(5):395–408PubMedCrossRefGoogle Scholar
  15. 15.
    Kelesidis I, Kelesidis T, Mantzoros CS (2006) Adiponectin and cancer: a systematic review. Br J Cancer 94(9):1221–1225PubMedCrossRefGoogle Scholar
  16. 16.
    Mantzoros C, Petridou E, Dessypris N, Chavelas C, Dalamaga M, Alexe DM, Papadiamantis Y, Markopoulos C, Spanos E, Chrousos G, Trichopoulos D (2004) Adiponectin and breast cancer risk. J Clin Endocrinol Metab 89(3):1102–1107PubMedCrossRefGoogle Scholar
  17. 17.
    Chen DC, Chung YF, Yeh YT, Chaung HC, Kuo FC, Fu OY, Chen HY, Hou MF, Yuan SS (2006) Serum adiponectin and leptin levels in Taiwanese breast cancer patients. Cancer Lett 237(1):109–114PubMedCrossRefGoogle Scholar
  18. 18.
    Korner A, Pazaitou-Panayiotou K, Kelesidis T, Kelesidis I, Williams CJ, Kaprara A, Bullen J, Neuwirth A, Tseleni S, Mitsiades N, Kiess W, Mantzoros CS (2007) Total and high-molecular-weight adiponectin in breast cancer: in vitro and in vivo studies. J Clin Endocrinol Metab 92(3):1041–1048PubMedCrossRefGoogle Scholar
  19. 19.
    Miyoshi Y, Funahashi T, Kihara S, Taguchi T, Tamaki Y, Matsuzawa Y, Noguchi S (2003) Association of serum adiponectin levels with breast cancer risk. Clin Cancer Res 9(15):5699–5704PubMedGoogle Scholar
  20. 20.
    Kang JH, Yu BY, Youn DS (2007) Relationship of serum adiponectin and resistin levels with breast cancer risk. J Korean Med Sci 22(1):117–121PubMedCrossRefGoogle Scholar
  21. 21.
    Han CZ, Du LL, Jing JX, Zhao XW, Tian FG, Shi J, Tian BG, Liu XY, Zhang LJ (2008) Associations among lipids, leptin, and leptin receptor gene gin223arg polymorphisms and breast cancer in china. Biol Trace Elem Res 126(1–3):38–48PubMedCrossRefGoogle Scholar
  22. 22.
    Mantzoros CS, Bolhke K, Moschos S, Cramer DW (1999) Leptin in relation to carcinoma in situ of the breast: a study of pre-menopausal cases and controls. Int J Cancer 80(4):523–526PubMedCrossRefGoogle Scholar
  23. 23.
    Petridou E, Papadiamantis Y, Markopoulos C, Spanos E, Dessypris N, Trichopoulos D (2000) Leptin and insulin growth factor i in relation to breast cancer (greece). Cancer Causes Control 11(5):383–388PubMedCrossRefGoogle Scholar
  24. 24.
    Stattin P, Soderberg S, Biessy C, Lenner P, Hallmans G, Kaaks R, Olsson T (2004) Plasma leptin and breast cancer risk: a prospective study in northern Sweden. Breast Cancer Res Treat 86(3):191–196PubMedCrossRefGoogle Scholar
  25. 25.
    Cleveland RJ, Gammon MD, Long CM, Gaudet MM, Eng SM, Teitelbaum SL, Neugut AI, Santella RM (2010) Common genetic variations in the lep and lepr genes, obesity and breast cancer incidence and survival. Breast Cancer Res Treat 120(3):745–752. doi:10.1007/s10549-009-0503-1 PubMedCrossRefGoogle Scholar
  26. 26.
    Kaklamani VG, Sadim M, Hsi A, Offit K, Oddoux C, Ostrer H, Ahsan H, Pasche B, Mantzoros C (2008) Variants of the adiponectin and adiponectin receptor 1 genes and breast cancer risk. Cancer Res 68(9):3178–3184PubMedCrossRefGoogle Scholar
  27. 27.
    Snoussi K, Strosberg AD, Bouaouina N, Ben Ahmed S, Helal AN, Chouchane L (2006) Leptin and leptin receptor polymorphisms are associated with increased risk and poor prognosis of breast carcinoma. BMC Cancer 6:38PubMedCrossRefGoogle Scholar
  28. 28.
    Woo HY, Park H, Ki CS, Park YL, Bae WG (2006) Relationships among serum leptin, leptin receptor gene polymorphisms, and breast cancer in Korea. Cancer Lett 237(1):137–142PubMedCrossRefGoogle Scholar
  29. 29.
    Teras LR, Goodman M, Patel AV, Bouzyk M, Tang W, Diver WR, Feigelson HS (2009) No association between polymorphisms in lep, lepr, adipoq, adipor1, or adipor2 and postmenopausal breast cancer risk. Cancer Epidemiol Biomarkers Prev 18(9):2553–2557. doi:10.1158/1055-9965.EPI-09-0542 PubMedCrossRefGoogle Scholar
  30. 30.
    Okobia MN, Bunker CH, Garte SJ, Zmuda JM, Ezeome ER, Anyanwu SN, Uche EE, Kuller LH, Ferrell RE, Taioli E (2008) Leptin receptor gln223arg polymorphism and breast cancer risk in Nigerian women: a case control study. BMC Cancer 8:338PubMedCrossRefGoogle Scholar
  31. 31.
    Yang XR, Sherman ME, Rimm DL, Lissowska J, Brinton LA, Peplonska B, Hewitt SM, Anderson WF, Szeszenia-Dabrowska N, Bardin-Mikolajczak A, Zatonski W, Cartun R, Mandich D, Rymkiewicz G, Ligaj M et al (2007) Differences in risk factors for breast cancer molecular subtypes in a population-based study. Cancer Epidemiol Biomarkers Prev 16(3):439–443PubMedCrossRefGoogle Scholar
  32. 32.
    Kristensen VN, Borresen-Dale AL (2008) Snps associated with molecular subtypes of breast cancer: on the usefulness of stratified genome-wide association studies (gwas) in the identification of novel susceptibility loci. Mol Oncol 2(1):12–15PubMedCrossRefGoogle Scholar
  33. 33.
    Nordgard SH, Johansen FE, Alnaes GI, Naume B, Borresen-Dale AL, Kristensen VN (2007) Genes harbouring susceptibility snps are differentially expressed in the breast cancer subtypes. Breast Cancer Res 9(6):113PubMedCrossRefGoogle Scholar
  34. 34.
    Thorner AR, Hoadley KA, Parker JS, Winkel S, Millikan RC, Perou CM (2009) In vitro and in vivo analysis of b-myb in basal-like breast cancer. Oncogene 28(5):742–751PubMedCrossRefGoogle Scholar
  35. 35.
    Newman B, Moorman PG, Millikan R, Qaqish BF, Geradts J, Aldrich TE, Liu ET (1995) The Carolina breast cancer study: integrating population-based epidemiology and molecular biology. Breast Cancer Res Treat 35(1):51–60PubMedCrossRefGoogle Scholar
  36. 36.
    Millikan R, Eaton A, Worley K, Biscocho L, Hodgson E, Huang WY, Geradts J, Iacocca M, Cowan D, Conway K, Dressler L (2003) Her2 codon 655 polymorphism and risk of breast cancer in African Americans and whites. Breast Cancer Res Treat 79(3):355–364PubMedCrossRefGoogle Scholar
  37. 37.
    Weinberg CR, Sandler DP (1991) Randomized recruitment in case-control studies. Am J Epidemiol 134(4):421–432PubMedGoogle Scholar
  38. 38.
    Huang WY, Newman B, Millikan RC, Schell MJ, Hulka BS, Moorman PG (2000) Hormone-related factors and risk of breast cancer in relation to estrogen receptor and progesterone receptor status. Am J Epidemiol 151(7):703–714PubMedGoogle Scholar
  39. 39.
    Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M et al (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10(16):5367–5374PubMedCrossRefGoogle Scholar
  40. 40.
    Livasy CA, Perou CM, Karaca G, Cowan DW, Maia D, Jackson S, Tse CK, Nyante S, Millikan RC (2007) Identification of a basal-like subtype of breast ductal carcinoma in situ. Hum Pathol 38(2):197–204PubMedCrossRefGoogle Scholar
  41. 41.
    de Bakker PI, Yelensky R, Pe’er I, Gabriel SB, Daly MJ, Altshuler D (2005) Efficiency and power in genetic association studies. Nat Genet 37(11):1217–1223PubMedCrossRefGoogle Scholar
  42. 42.
    Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, Nickerson DA (2004) Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 74(1):106–120PubMedCrossRefGoogle Scholar
  43. 43.
    Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, Belmont JW, Boudreau A, Hardenbol P, Leal SM, Pasternak S, Wheeler DA, Willis TD, Yu F, Yang H et al (2007) A second generation human haplotype map of over 3.1 million snps. Nature 449(7164):851–861PubMedCrossRefGoogle Scholar
  44. 44.
    Barnholtz-Sloan JS, Shetty PB, Guan X, Nyante SJ, Luo J, Brennan DJ, Millikan RC (2010) Fgfr2 and other loci identified in genome-wide association studies are associated with breast cancer in african-american and younger women. Carcinogenesis 31(8):1417–1423. doi:10.1093/carcin/bgq128 PubMedCrossRefGoogle Scholar
  45. 45.
    Tian C, Hinds DA, Shigeta R, Kittles R, Ballinger DG, Seldin MF (2006) A genomewide single-nucleotide-polymorphism panel with high ancestry information for African American admixture mapping. Am J Hum Genet 79(4):640–649PubMedCrossRefGoogle Scholar
  46. 46.
    Barnholtz-Sloan JS, McEvoy B, Shriver MD, Rebbeck TR (2008) Ancestry estimation and correction for population stratification in molecular epidemiologic association studies. Cancer Epidemiol Biomarkers Prev 17(3):471–477PubMedCrossRefGoogle Scholar
  47. 47.
    Wigginton JE, Cutler DJ, Abecasis GR (2005) A note on exact tests of Hardy–Weinberg equilibrium. Am J Hum Genet 76(5):887–893PubMedCrossRefGoogle Scholar
  48. 48.
    Barnholtz-Sloan JS, Chakraborty R, Sellers TA, Schwartz AG (2005) Examining population stratification via individual ancestry estimates versus self-reported race. Cancer Epidemiol Biomarkers Prev 14(6):1545–1551PubMedCrossRefGoogle Scholar
  49. 49.
    Hall IJ, Newman B, Millikan RC, Moorman PG (2000) Body size and breast cancer risk in black women and white women: the carolina breast cancer study. Am J Epidemiol 151(8):754–764PubMedGoogle Scholar
  50. 50.
    Harvie M, Hooper L, Howell AH (2003) Central obesity and breast cancer risk: a systematic review. Obes Rev 4(3):157–173PubMedCrossRefGoogle Scholar
  51. 51.
    Connolly BS, Barnett C, Vogt KN, Li T, Stone J, Boyd NF (2002) A meta-analysis of published literature on waist-to-hip ratio and risk of breast cancer. Nutr Cancer 44(2):127–138PubMedCrossRefGoogle Scholar
  52. 52.
    Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of ld and haplotype maps. Bioinformatics 21(2):263–265PubMedCrossRefGoogle Scholar
  53. 53.
    Poole C (2001) Low P-values or narrow confidence intervals: which are more durable? Epidemiology 12(3):291–294PubMedCrossRefGoogle Scholar
  54. 54.
    Lettre G, Lange C, Hirschhorn JN (2007) Genetic model testing and statistical power in population-based association studies of quantitative traits. Genet Epidemiol 31(4):358–362PubMedCrossRefGoogle Scholar
  55. 55.
    Lin DY (2005) An efficient Monte Carlo approach to assessing statistical significance in genomic studies. Bioinformatics 21(6):781–787. doi:10.1093/bioinformatics/bti053 PubMedCrossRefGoogle Scholar
  56. 56.
    Lin DY, Zeng D, Millikan R (2005) Maximum likelihood estimation of haplotype effects and haplotype-environment interactions in association studies. Genet Epidemiol 29(4):299–312PubMedCrossRefGoogle Scholar
  57. 57.
    Lin DY, Zeng D (2006) Likelihood-based inference on haplotype effects in genetic association studies. J Am Stat Assoc 101(473):89–118CrossRefGoogle Scholar
  58. 58.
    Hu YJ, Lin DY, Zeng D (2010) A general framework for studying genetic effects and gene–environment interactions with missing data. Biostatistics 11(4):583–598. doi:10.1093/biostatistics/kxq015 PubMedCrossRefGoogle Scholar
  59. 59.
    Quinton ND, Lee AJ, Ross RJ, Eastell R, Blakemore AI (2001) A single nucleotide polymorphism (snp) in the leptin receptor is associated with BMI, fat mass and leptin levels in postmenopausal Caucasian women. Hum Genet 108(3):233–236PubMedCrossRefGoogle Scholar
  60. 60.
    van Rossum CT, Hoebee B, van Baak MA, Mars M, Saris WH, Seidell JC (2003) Genetic variation in the leptin receptor gene, leptin, and weight gain in young Dutch adults. Obes Res 11(3):377–386PubMedCrossRefGoogle Scholar
  61. 61.
    Wauters M, Mertens I, Chagnon M, Rankinen T, Considine RV, Chagnon YC, Van Gaal LF, Bouchard C (2001) Polymorphisms in the leptin receptor gene, body composition and fat distribution in overweight and obese women. Int J Obes Relat Metab Disord 25(5):714–720PubMedCrossRefGoogle Scholar
  62. 62.
    Kim SM, Kim SH, Lee JR, Jee BC, Ku SY, Suh CS, Choi YM, Kim JG, Moon SY (2008) Association of leptin receptor polymorphisms lys109arg and gln223arg with serum leptin profile and bone mineral density in Korean women. Am J Obstet Gynecol 198(4):e421–e428. doi:10.1016/j.ajog.2007.10.799 CrossRefGoogle Scholar
  63. 63.
    Ogawa T, Hirose H, Yamamoto Y, Nishikai K, Miyashita K, Nakamura H, Saito I, Saruta T (2004) 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 53(7):879–885PubMedCrossRefGoogle Scholar
  64. 64.
    Stratigopoulos G, Le Duc CA, Matsuoka N, Gutman R, Rausch R, Robertson SA, Myers MG Jr, Chung WK, Chua SC Jr, Leibel RL (2009) Functional consequences of the human leptin receptor (lepr) q223r transversion. Obesity (Silver Spring) 17(1):126–135. doi:10.1038/oby.2008.489 CrossRefGoogle Scholar
  65. 65.
    Ragin CC, Dallal C, Okobia M, Modugno F, Chen J, Garte S, Taioli E (2009) Leptin levels and leptin receptor polymorphism frequency in healthy populations. Infect Agent Cancer 4(Suppl 1):13. doi:10.1186/1750-9378-4-S1-S13 CrossRefGoogle Scholar
  66. 66.
    Ben Ali S, Kallel A, Sediri Y, Ftouhi B, Feki M, Slimene H, Jemaa R, Kaabachi N (2009) Lepr p.Q223r polymorphism influences plasma leptin levels and body mass index in Tunisian obese patients. Arch Med Res 40(3):186–190. doi:10.1016/j.arcmed.2009.02.008 PubMedCrossRefGoogle Scholar
  67. 67.
    Savitz DA (2003) Interpreting epidemiologic evidence. Oxford University Press, New YorkCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Sarah J. Nyante
    • 1
    • 2
    • 6
  • Marilie D. Gammon
    • 1
    • 2
  • Jay S. Kaufman
    • 3
  • Jeannette T. Bensen
    • 1
    • 2
  • Dan Yu Lin
    • 2
    • 4
  • Jill S. Barnholtz-Sloan
    • 5
  • Yijuan Hu
    • 4
  • Qianchuan He
    • 4
  • Jingchun Luo
    • 2
  • Robert C. Millikan
    • 1
    • 2
  1. 1.Department of EpidemiologyUniversity of North CarolinaChapel HillUSA
  2. 2.Lineberger Comprehensive Cancer CenterUniversity of North CarolinaChapel HillUSA
  3. 3.Department of Epidemiology, Biostatistics, & Occupational HealthMcGill UniversityMontrealCanada
  4. 4.Department of BiostatisticsUniversity of North CarolinaChapel HillUSA
  5. 5.Case Comprehensive Cancer CenterCase Western Reserve University School of MedicineClevelandUSA
  6. 6.Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaUSA

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