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Cheadle and colleagues (1) report that carrier status for a rare nonsynonymous variant in OGG1 (c.923G>A, rs113561019, G308E), confers susceptibility to colorectal cancer (CRC). Here, we report a wellpowered study that finds no evidence for the association. This has important clinical genetics implications because inappropriate screening or intervention might be recommended to carriers, particularly those with a heterozygous MUTYH mutation, if OGG1 (c.923G>A) were wrongly ascribed as a CRC risk variant. We analyzed 6856 case patients and 10 090 control subjects from six European populations. These comprised 1) 3666 (predominantly) English case patients (n = 250 from the CORGI study; n = 957 from the QUASAR study; n = 1168 from NSCCG; n = 1291 from a Leeds-based case–control series) and 6140 control patients (n = 5694 1958 Birth Cohort [1958BC]; n = 446 from a Leeds-based case–control series); 2) 2052 Scottish CRC case patients and 2004 Scottish control subjects (n = 1452 from the 1935 and 1928 Lothian Birth Cohorts; n = 552 from Generation Scotland); 3) 276 Spanish case patients and 284 control subjects; 4) 800 Dutch samples (n = 337 Leiden case patients and n = 337 control subjects; n = 74 Gronigen case patients and n = 52 control subjects); 5) 199 Portuguese case patients and 186 control subjects; and 6) 1339 German samples (n = 77 Heidelberg case patients and n = 88 control subjects; n = 175 Kiel case patients and n = 999 control subjects). This provides greater than 99.9% power (α = 0.05) to detect the effect size (odds ratio [OR] =2.92) reported by Smith et al. (1). We used Infinium HumanExome BeadChips (Illumina San Diego, CA) to genotype OGG1 c.923G>A (Supplementary Figure 1, available online) and validated genotyping by sequencing 541 randomly selected samples (n = 492 1958BC control subjects; n = 49 UK CRC case patients) showing complete concordance (r2 = 1.0; 531 both GG; 10 both GA). We used principal component analysis with HapMap 2 samples to assess ancestral comparability of case patients and control subjects (Supplementary Figure 2, available online). None of the six series showed a statistically significant difference in frequency of c.923G>A genotype between case patients and control subjects (Figure 1; Table 1). In a metaanalysis of data from all studies, we found no association between c.923A carrier status and CRC (OR = 0.94; 95% confidence interval [CI] = 0.72 to 1.21; P = .61; Pheterogenity = .99; I2 = 0%) (Figure 1). Principal component analysis adjustment using Eigenstrat software had no impact on these findings (Supplementary Table 1, available online). There are a number of possible explanations for the disparity of our findings and those reported by Smith et al. (1). First, population stratification could lead to spurious associations, especially CORRespONDeNCe

Re: Role of the Oxidative DNA Damage Repair Gene OGG1 in Colorectal Tumorigenesis