From Medscape Genomic Medicine > Viewpoints in Genomic Medicine

Are Diabetes and Colorectal Cancer Risk Genetically Linked?

Ali Torkamani, PhD

Authors and Disclosures

Posted: 01/03/2012

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Type 2 Diabetes Risk Variants and Colorectal Cancer Risk: The Multiethnic Cohort and PAGE Studies

Cheng I, Caberto CP, Lum-Jones A, et al
Gut. 2011;60:1703-1711

Summary

Colorectal cancer and type 2 diabetes are common chronic diseases sharing a number of risk factors including age, diet, obesity, and physical inactivity. Studies have shown that individuals with diabetes have a 19%-30% increased risk of developing colorectal cancer,^[1,2] and this association between colorectal cancer and type 2 diabetes remains after adjusting for shared risk factors, suggesting that a core set of nonenvironmental risk factors may underlie their co-occurrence.^[3] Investigators from the Population Architecture using Genomics and Epidemiology (PAGE) initiative drew study subjects from the multiethnic cohort to determine whether shared genetic risk variants might explain this co-occurrence.
The multiethnic cohort consists of 215,000 individuals drawn from 5 racial/ethnic groups: African American, Native Hawaiian, Japanese, Latino, and White. Of these individuals, 2011 patients diagnosed with colorectal cancer and 6049 control subjects were selected for genotyping. Case subjects were identified through population surveillance covering Hawaii and California to capture incident colorectal cancers, and control subjects consisted of individuals between the ages of 45 and 75 years old with no diagnosis of colorectal cancer prior to enrollment. All of these individuals were genotyped at 19 single nucleotide polymorphisms (SNPs) previously associated with type 2 diabetes.
After statistical associations corrected for age, sex, and race/ethnicity were performed via logistic regression, 4 SNPs associated with type 2 diabetes -- THADA, JAZF1, KCNJ11, and TSPAN8 -- were found to be nominally associated with colorectal cancer risk.

Viewpoint

Although 4 type 2 diabetes susceptibility SNPs were associated with colorectal cancer in this study, there are a number of concerns regarding the accuracy of these results.
First, with the exception of the THADA SNP, the associations are quite weak, resulting in P values only slightly below the threshold for significance.
Second, with the exception of the KCNJ11 SNP, the directions of the effects for type 2 diabetes vs colorectal cancer were swapped. In other words, type 2 diabetes risk variants were associated with decreased risk for colorectal cancer in these SNPs, which is inconsistent with the original hypothesis that type 2 diabetes and colorectal cancer co-occurrence are mediated by common genetic mechanisms.
Third, a number of the considered populations are admixed, suggesting that correction for overall ethnicity may not be sufficient. Fourth, when analyses were stratified by type 2 diabetes diagnosis status, associations were observed among individuals with colorectal cancer but without type 2 diabetes, rather than those subjects with concurrent diagnoses. Finally, no replication or attempt to otherwise confirm the results was reported.
While there are a number of concerns regarding the accuracy of these results, the strong association for the THADA SNP and the consistency of direction for the KCNJ11 SNP is intriguing. These associations also hold up, for the most part, when stratified by ethnicity, suggesting a true signal could be present at these loci. However, it is difficult to draw any solid conclusions regarding the relationship between type 2 diabetes susceptibility loci and colorectal cancer risk. Clearly, further studies need to be executed to clarify the genetic relationship between type 2 diabetes and colorectal cancer.

Are Diabetes and Colorectal Cancer Risk Genetically Linked?: Type 2 Diabetes Risk Variants and Colorectal Cancer Risk: The Multiethnic Cohort and PAGE Studies