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[eugene-march]

Abstract.

Several lines of evidence implicate mitochondrial dysfunction in the development of cancer. To test the hypothesis that common mtDNA variation influences the risk of colorectal cancer (CRC), we genotyped 132 tagging mtDNA variants in a sample of 2854 CRC cases and 2822 controls. The variants examined capture ~80% of mtDNA common variation (excluding the hypervariable D-loop). We first tested for single marker associations; the strongest association detected was with A5657G (P=0.06). Overall the distribution of association P-values was consistent with a null distribution. Next, we classified individuals into the nine common European haplogroups and compared their distribution in cases and controls. This analysis also provided no evidence of an association between mitochondrial variation and CRC risk. In conclusion, our results provide little evidence that mitochondrial genetic background plays a role in modifying an individual's risk of developing CRC.

Results.

Out of the 5701 DNA samples submitted for genotyping, 5676 samples were successfully processed. Genotyping failed in 25 individuals, leaving genotype data for 2854 cases and 2822 controls.

Of the 132 variants for which genotyping were attempted, 125 were satisfactorily genotyped (94.7%), with mean SNP call rates of 99.9 and 99.8% in cases and controls, respectively. Of these 125 SNPs, eight were monomorphic and an additional 54 had the minor variant observed in less than 1% of samples and were excluded from further analysis, leaving 63 polymorphic variants. Only one SNP (A15925G) was triallelic in samples analysed with one heterozygote observed among cases. This genotype was treated as missing for the analysis. Genotypes from duplicate samples displayed 100% concordance.

One variant (G10590A), polymorphic in our samples was not observed by (Saxena et al, 2006), and nine variants observed to be polymorphic in their study were either monomorphic or had very low frequency in our samples (Supplementary Table 2). Given these caveats, our data indicated that 79.3% of polymorphic variants were captured with r2>0.8, whereas 92.2% of variants with MAF>5% were captured with r2>0.8.

Four SNPs showed nominal levels of association with CRC risk (P<0.1; Table 2). The most strongly associated was A5657G, with a P-value of 0.06; non-significant after adjustment for multiple testing by permutation. All nine common European haplogroups (H, I, J, K, T, U, V, W and X) were observed in both cases and controls. Haplogroup J was slightly over-represented in cases, whereas haplogroup K was slightly under-represented, although these observations were statistically non-significant (Table 3). Adjustment for age and gender did not impact on the findings.



Interactions between the four SNPs that showed an association with CRC risk at the 10% level of significance were examined by fitting full logistic regression models for each pair, generating six models, and comparing with the main effects model for each pair. Owing to small MAFs, it was only possible to evaluate the interaction for three of the pairs. For each of these there was no significant evidence of interactive effects. Furthermore, there was no evidence of any differential effect of genotype by either age or gender.

For all 2854 genotyped cases, information was available on site of CRC (1743 colonic, 1111 rectal tumours) and family history (398 individuals with at least one first-degree relative affected by CRC, 2456 with no recorded family history), and 1222 of the cases had been evaluated for MSI status (151 MSI, 1071 MSS cases). Subgroup analysis by site indicated stronger evidence of association between mtDNA variants and colon cancer, with five variants showing significant association (P<0.05) whereas there was no evidence for an association between any variant and rectal cancer (P>0.1 for all variants). The variant A5657G was most strongly associated with the risk of colonic tumour (P=0.02), albeit non-significant after adjustment for multiple testing. Stratification by MSI status showed that three variants were associated with risk of CRC for MSI cases, with the strongest association for T4562C (P=4.6 × 10−3), non-significant after adjustment for multiple testing. There was no evidence for association between any SNP and CRC in MSS cases (P>0.05 for all variants). Stratification by family history status did not alter the overall findings.

http://www.nature.co...l/6604805a.html