Abstract A123: Common polymorphisms in adiponectin and adiponectin receptor genes and prostate cancer survival
Authors: Stark Jennifer R. , Mucci Lorelei A. , Penney Kathryn L. , Dhillon Preet , Loda Massimo , Sesso Howard D. , Stampfer Meir J. , Ma Jing 
Published: May 2012

Abstract
Background: Adiponectin, an adipokine with anti-inflammatory and insulin-sensitizing properties, is inversely associated with adiposity. Our group previously showed that high circulating levels of adiponectin were inversely associated with prostate cancer (PCa) risk and progression. Moreover, four polymorphisms in ADIPOQ, a gene encoding adiponectin, were significantly associated with overall PCa risk, two of which were also associated with plasma adiponectin levels. However, the role of genetic variation in ADIPOQ and the adiponectin receptor genes ADIPOR1 and ADIPOR2 in PCa progression remains unknown. We related polymorphisms in ADIPOQ, ADIPOR1, and ADIPOR2 to PCa survival, ADIPOR2 expression, and a biomarker of proliferation.
Methods: Using genotype data from 1286 cases from the Physicians' Health Study, we evaluated 29 common SNPs in ADIPOQ, ADIPOR1 and ADIPOR2 with the development of lethal PCa, defined as progression to bony metastases or PCa-specific death, during 25 years of follow-up. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs). We assumed a codominant genotype model and assessed the association between each genotype and PCa survival by a p-value from a likelihood ratio test comparing models with and without the heterozygote and rare homozygote indicator variables. Using ANOVA, we also evaluated each genotype with tumor expression of ki67 (n=203), a marker of cellular proliferation, and ADIPOR2 (n=180) for a subset of cases.
Results: Two polymorphisms, one in ADIPOR1 and one in ADIPOR2, were significantly associated with time to lethal PCa. Compared to wildtype homozygotes for ADIPOR1 SNP rs16850799, the HRs for lethal PCa were 1.1 (95% CI: 0.8, 1.6) for heterozygotes and 2.5 (95% CI: 1.4, 4.4) for rare homozygotes (p=0.02). The variant allele for rs16850799 was also associated with increased cellular proliferation in prostate tumors (p=0.004). For ADIPOR2 rs1044471, the HRs compared to wildtype homozygotes were 0.6 (95% CI: 0.4, 0.9) for heterozygotes and 0.9 (95% CI: 0.6, 1.3) for rare homozygotes (p=0.03). The variant allele for rs1044471 was associated with lower expression levels of ADIPOR2 (p=0.03).
Conclusions: Of 29 SNPs evaluated in ADIPOQ, ADIPOR1 and ADIPOR2, we found two polymorphic loci (ADIPOR1 rs16850799 and ADIPOR2 rs1044471) to be associated with PCa progression and death. Variant allele carriers of the rs16850799 polymorphism in ADIPOR1 were more likely to develop lethal PCa and exhibited phenotypic changes consistent with disease aggressiveness in their tumors. Variant allele status in ADIPOR2 rs1044471 predicted ADIPOR2 expression levels. None of the four SNPs in ADIPOQ that we previously found to be associated with PCa risk were associated with time to lethal PCa. Our work suggests a potential role of adiponectin and its receptors in mediating the association between obesity and aggressive PCa.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A123.