Table 3.
Evaluation of genetic evidence for variants identified in the selected G×E interactions
| Genetic variant | Gene (or near gene) | Reference | Discovery sample size | Replication sample size / Number of studies in meta‐analysis | Reported OR (95% CI) | p Value for genetic main effect | Heterogeneity, I 2 | Venice criteria | Evidence class1 |
|---|---|---|---|---|---|---|---|---|---|
| rs4143094 | 10p14/GATA3 | Figueiredo JC, 2014 | 9,287 cases and 9,117 controls of European ancestry from USA, Australia, Canada and Germany | Meta‐analysis, 10 studies | NR | 0.26 | NR | NA | No association |
| Slow/intermediate/rapid | NAT2 | Zhang L, 2012 | 13,606 cases and 17,957 controls of Africans, Asians, Caucasians and mixed populations | Meta‐analysis, 39 studies | Slow vs. rapid phenotype: 0.96 (0.90, 1.01) | No association | I 2 = 17.8% | NA | No association |
| Slow/intermediate/rapid | NAT2 | Wang H, 2015 | 2,186 cases and 3,736 controls of Japanese; 466 cases and 4,356 controls of African Americans | Meta‐analysis, 7 studies | Rapid vs. slow phenotype: Japanese: 1.05 (0.87, 1.27); African Americans: 0.75 (0.50, 1.14); Combined: 0.99 (0.83, 1.18) |
Japanese: 0.77; African Americans: 0.19; Combined: 0.81 |
NR | NA | No association |
| rs9409565 | 9q22.32/HIATL1 | Schumacher FR, 20152 | 18,299 cases and 19,656 controls of European ancestry from North America, Australia and Europe | Meta‐analysis, 4,725 cases and 9,969 controls of East Asian ancestry from Republic of Korea, China and Japan | 0.98 (0.95, 1.01) | 0.127 | NR | NA | No association |
| rs16892766 | 8q23.3/EIF3H | Li M, 2015 | 41,728 cases and 44,393 controls | Meta‐analysis, 11 studies | 1.22 (1.18, 1.27) | 1.39 × 10−24 | I 2 = 4% | AAA | Strong |
| rs6983267 | 8q24.21 | Tanskanen T, 2017 | 1,701 Finnish cases and 14,082 population‐based, cancer‐free controls | Meta‐analysis, 13,348 cases and 26,438 controls of European ancestry | 0.84 (0.80, 0.88) | 7.45 × 10−13 | I 2 = 37.7% | ABA (equivalent to AAA) | Strong |
| C1420T | SHMT1 | Wang Q, 2014 | 3,912 cases and 4,954 controls | Meta‐analysis, 7 studies | TT vs. CC: 0.84 (0.73, 0.97); CT vs. CC: 1.01 (0.92, 1.10); TT + CT vs. CC: 0.97 (0.89, 1.06); TT vs. CT + CC: 0.84 (0.73, 0.96) |
TT vs. CC: 0.020; CT vs. CC: 0.903; TT + CT vs. CC: 0.476; TT vs. CT + CC: 0.013 |
TT vs. CC: I
2 = 3.8%; CT vs. CC: I 2 = 0%; TT + CT vs. CC: I 2 = 0%; TT vs. CT + CC: I 2 = 0% |
NA | No association |
| rs2965667 | 12p12.3/PIK3C2G | Orlando G, 2016 | 8,749 cases and 18,245 controls from Europe | Meta‐analysis, 7 studies | 0.97 (0.87, 1.08) | 0.552 | I 2 = 4.8% | NA | No association |
| rs16973225 | 15q25.2/interleukin 16 | Orlando G, 2016 | 8,749 cases and 18,245 controls from Europe | Meta‐analysis, 7 studies | 1.05 (0.97, 1.15) | 0.242 | I 2 = 0% | NA | No association |
| rs964293 | 20q13.2/CYP24A1 | Orlando G, 2016 | 8,749 cases and 18,245 controls from Europe | Meta‐analysis, 7 studies | 0.97 (0.93, 1.01) | 0.156 | I 2 = 6.3% | NA | No association |
| Including 7 variants3 | 10p12.1/PTCHD3 | Timofeeva M, 2015 | 8,100 cases and 21,820 controls from Europe | Meta‐analysis, 6 studies | NR | 0.352 | NR | NA | No association |
| Including 8 variants4 | 17p13.2/MINK1 | Timofeeva M, 2015 | 8,100 cases and 21,820 controls from Europe | Meta‐analysis, 6 studies | NR | 0.381 | NR | NA | No association |
| rs1944511 | 11q23.3 | Siegert S, 2013 | 259 cases and 1,002 controls | Genome‐wide G×E interaction analysis | 1.07 | 0.536 | NR | NA | No association |
Abbreviations: CI, confidence interval; G×E, gene–environment; NA, not applicable; NR, not reported; OR, odds ratio; vs., versus.
Evidence class was decided on the basis of the Human Genome Epidemiology Network's Venice criteria: No association indicates evidence for main genetic effects with p > 10−5. Only genetic effects with p < 10−5 were considered for evaluation. On the basis of a combination of 3 criteria (amount of evidence, degree of replication, and protection from bias) (each of which can be scored A, B, or C), the epidemiological evidence for an effect of the genotype is classified as strong, moderate, or weak. For amount of evidence, a grade of A, B, or C was assigned when the sample size for the rarer genotype in the meta‐analyses was greater than 1,000, 100–1,000, or less than 100, respectively. For replication consistency, we used I 2 < 25% to assign grade A, 25–50% to assign grade B, and > 50% or a p value for heterogeneity <0.10 to assign grade C. For protection from bias, a grade of A means that bias, if present, may change the magnitude but not the presence of an association; a grade of B means that there is no evidence of bias that would invalidate an association, but important information is missing; and a grade of C means that there is a strong possibility of bias that would render the finding of an association invalid. For the genetic variants that reached genome‐wide significance threshold, the evidence class of the genetic variant was only based on the amount of evidence based on the clarification of Venice Criteria (Khoury MJ et al, 2009).
Current study exploring the marginal association of rs9409565 was used since it is about twice as large as Gong et al. (2016).
Seven variants at 10p12.1 were included in the analysis that explored main genetic effects by Timofeeva M et al, 2015. However, the interaction analysis (by Jiao S et al, 2015) included 8 variants: chr10:27687284, chr10:27687437, chr10:27687638, chr10:27687775, chr10:27687989, chr10:27688101, chr10:27702174 and chr10:27702624.
Eight variants at 17p13.2 were included in the analysis that explored main genetic effects Timofeeva M et al, 2015. However, the interaction analysis (by Jiao S et al, 2015) included 4 variants: chr17:4794313, chr17:4794407, chr17:4796839 and chr17:4797910.