In this clinic-based case-control analysis, we found an association between 1 SNP of the ADIPOQ gene (rs266729) and colorectal cancer risk in 2 separate case-control studies, as well as in the combined analysis of both studies after adjustment for age, sex, and other SNPs.
There is considerable emerging evidence pointing to the importance of adiponectin signaling in colorectal carcinogenesis. Colonic tissue expresses both ADIPOR1
Two recent studies have shown an association between serum adiponectin levels and colorectal cancer risk,12,14
with a 47% reduction in risk in the highest vs the lowest quintile.14
However, another investigation did not find an association.24
The link between adiponectin and colorectal cancer may be the IGF pathway. Hyperinsulinemia reduces circulating levels of IGFBP1, which may lead to higher levels of unbound IGF1. High levels of circulating IGF1, which increase cellular proliferation and inhibit apoptosis,25,26
have been associated with increased risk of several common cancers, including colorectal cancer.6,27,28
We also recently reported that high levels of insulin (as reflected by increased C-peptide) or high levels of bioavailable IGF1 (assessed by the ratio of IGF1 to IGFBP3) independently predicted increased risk for colorectal cancer; high levels of both were not associated with higher risk.9
In the 2 sets of cases and controls that included a total of 1497 individuals, we observed a consistent association between rs266729 and colorectal cancer risk. More specifically, individuals with the GG/GC genotype have a 27% lower odds of colorectal cancer than those with the CC genotype. It has been shown that the G allele is associated with lower adiponectin levels.19
The haplotype-tagging SNP rs266729 is located in the 5′ flanking region of the gene at position −11365 within the promoter region. Polymorphisms within the promoter region have been associated with adiponectin levels and risk of diabetes.21
Furthermore, rs266729 has been associated with the risk of coronary artery bypass graft and percutaneous transluminal coronary angioplasty.29
Other polymorphisms in this region, including rs2117985 (−18003), rs822387 (−14811), and rs860291 (−12891), also have been significantly associated with adiponectin levels.17
In addition, individuals with the genotypes rs17300539 (−11391) AA/AG have 64% higher adiponectin levels (P
In our current study, we chose to study only 1 polymorphisms of the 5′ flanking region. Our data as well as data from other investigators highlight the importance of this region, both for gene function and as a disease-causing region in the adiponectin gene. Interestingly, combined analysis of the 2 studies presented in this article showed a borderline association between rs822395 and colorectal cancer risk, which suggests that several SNPs within this region may be associated with colorectal cancer risk.
We recently evaluated 10 SNPs of the adiponectin pathway with regard to breast cancer risk.30
Our findings showed that a different region in the adiponectin gene was an important modifier of breast cancer risk. More specifically, we found that +45 T→G (rs2241766) and +276 G→T (rs1501299) are associated with breast cancer risk. Both polymorphisms belong to block 2; rs2241766 is located in exon 2 whereas rs1501299 is located in intron 2. We also found 1 polymorphism of ADIPOR1
(+10225 C→G [rs7539542]) to be significantly associated with breast cancer risk. The haplotype-tagging SNPs used in these studies represent genomic regions putatively associated with cancer risk but the functionally significant SNPs and/or mutations are likely different from these haplotype-tagging SNPs. Additional fine mapping studies will be needed to determine if the functional SNPs associated with breast cancer risk are different from the SNPs associated with colorectal cancer risk.
This study has several strengths. Case-control study 1 included a large number of cases and controls (N=1099) with the same ethnic status and from the same geographic area. All cases and controls recruited in case-control study 2 were recruited at the same institution, and were matched for age, sex, and ethnic status. One of the 4 genotypic combinations associated with colorectal cancer in study 1 was confirmed in study 2 despite differences in the age, ethnic status, and proportion of males and females between the 2 studies. The magnitude of the association of rs266729 with colorectal cancer was comparable in the 2 studies. Furthermore, a combined analysis of both studies showed that the significant association of rs266729 with colorectal cancer risk persisted after adjustment for age, sex, race, and SNPs within the same gene. Using prevalence of 0.48 (prevalence of GG/CG for SNP rs266729 in controls), our study had good power to detect an OR of 2 (combined study: power = 0.99; matched study: power = 0.93; unmatched study: power=0.99).
While rs226729 was associated with colorectal cancer risk in both studies, this SNP only represents a genomic region putatively associated with risk. It is likely that the functionally significant SNPs/mutations are different. Additional studies that include resequencing of this genomic region and dense SNP analysis will be needed to identify these SNPs/mutations and determine their impact on the expression levels of ADIPOQ.
Our study also has several limitations. The epidemiological design is relatively informal, with possibly different case and control populations. Cases and controls in study 1 differed significantly in sex and age in that the median age of cases was slightly higher than that of controls. It is possible that age differences in cases and controls affected the allele frequencies observed. Furthermore, inaccurate information with respect to any variable classification would result in nondifferential misclassification, which also would be expected to result in a conservative bias in measures of association. A common limitation to both studies is the absence of information on family history of colorectal cancer as well as other risk factors for colorectal cancer. Another limitation is the difference between the 2 studies as to the patient population included. All cases and controls were white and of Ashkenazi Jewish background in study 1, whereas case-control study 2 included several ethnic groups. The additional SNPs associated with colorectal cancer risk in study 1 may be specific to Ashkenazi Jews, a population with increased colorectal cancer risk. Of note, APC I1307K,
a gene associated with increased colorectal cancer risk in Ashkenazi Jews,31
maps to 5q21–22. If 1 or more of the 3 SNPs associated with colorectal cancer in study 1 are validated in another population of Ashkenazi Jews, it will be interesting to study gene-gene interactions between these SNPs and APC I1307K
. In addition, we did not make any formal adjustment of our results for the multiple comparisons made in the study with 10 SNPs. This adjustment, however, would not have materially changed the conclusions of our study.
To our knowledge, this is the first study reporting an association of polymorphisms of the adiponectin pathway with colorectal cancer risk. Our study did not attempt to provide a comprehensive evaluation of all genes involved in the adiponectin pathway. Our findings, however, suggest that ADIPOQ rs266729 is associated with colorectal cancer risk. Importantly, they suggest that the 5′ region of the ADIPOQ gene harbor SNPs/mutations susceptible to modify colorectal cancer risk. If these exciting results can be confirmed in other studies, the adiponectin axis may emerge as an important modifier of colorectal cancer risk. Future studies will need to address the potential impact of adiponectin and its SNPs in the prognosis of colorectal cancer and also may be incorporated in genetic risk models for the disease.