Introduction: Obesity is a well-established postmenopausal breast cancer risk factor, and an indicator of poor prognosis. The adipokines, adiponectin and leptin, may be essential to our understanding these associations. Plasma concentrations of adiponectin are inversely correlated, while plasma concentrations of leptin are positively correlated with obesity. Epidemiological studies of these adipokines and breast cancer risk are suggestive of a positive association for plasma leptin and an inverse association for plasma adiponectin. We studied whether genetic variation in several adipokine genes, leptin (LEP), leptin receptor (LEPR), adiponectin (ADIPOQ), and adiponectin receptors 1 and 2 (ADIPOR1/2) was associated with adipokine concentrations measured in plasma and breast tissue in a study of healthy women.
Methods: Breast tissues and plasma were collected from 85 women undergoing reduction mammoplasty between 1997 and 2009. Plasma and breast adiponectin and leptin concentrations were measured by commercially-available ELISA kits. DNA was extracted from dissected breast tissues and common, functional SNPs in LEP (rs2167270), LEPR (rs1137101), ADIPOQ (rs1501299), ADIPOR1 (rs2275737), and ADIPOR2 (rs1044471) were genotyped. Differences in least-squares mean concentration of plasma and breast adipokines, adjusted for age, race, and body mass index (kg/m2), were compared using an F test. Associations between genotypes and adipokines measured in plasma and tissue were estimated using adjusted regression models, with log-transformed adipokines as dependent variables. Results for each genotype are given as eβ, representing the ratio of plasma adipokines among those carrying a variant genotype relative to those carrying the wild-type.
Results: Genotype of rs2167270 was significantly associated with plasma adiponectin and leptin, and breast leptin concentrations. Compared to the wild-type, homozygous variant allele carriers of the LEP A19G polymorphism had 27% lower plasma adiponectin (Ratio 0.73, 95% CI: 0.54, 0.98; P=0.03) and plasma leptin (Ratio 0.73, 95% CI: 0.55, 0.96; P=0.02). Additionally, compared to wild-type, heterozygous variant allele carriers of this polymorphism had 39% lower breast leptin (Ratio 0.61, 95% CI: 0.39, 0.97; P=0.03), although there appeared to be higher breast leptin among homozygous variant allele carriers (Ratio 1.67, 95% CI: 0.86, 3.26). No associations were observed for LEPR (rs1137101), ADIPOQ (rs1501299), ADIPOR1 (rs2275737), or ADIPOR2 (rs1044471) and adipokines measured in plasma or tissue.
Conclusion: Variant alleles of rs2167270 were associated with lower plasma adiponectin and leptin concentrations, as well as lower breast leptin concentrations. This study provides evidence for a role of variation in adipokine genes in endogenous adipokine concentrations both in circulation and within local breast tissues.
Citation Format: Adana A. Llanos, Theodore M. Brasky, Kepher H. Makambi, Jo L. Freudenheim, Peter G. Shields. Association between variation in LEP A19G and adipokine concentrations in plasma and breast tissues. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 116. doi:10.1158/1538-7445.AM2013-116