Smoking and selected DNA repair gene polymorphisms in controls: systematic review and meta-analysis

When the case-only study design is used to estimate statistical interaction between genetic (G) and environmental (E) exposures, G and E must be independent in the underlying population, or the case-only estimate of interaction (COR) will be biased. Few studies have examined the occurrence of G-E association in published control group data.

To examine the assumption of G-E independence in empirical data, we conducted a systematic review and meta-analysis of G-E associations in controls for frequently investigated DNA repair genes (XRCC1 Arg399Gln, Arg194Trp, or Arg280His, XPD Lys751Gln, and Asp312Asn, and XRCC3 Thr241Met), and smoking (ever/never smoking, current/not current smoker, smoking duration, smoking intensity, and pack-years).

Across the 55 included studies, single nucleotide polymorphisms SNP-smoking associations in controls (OR(z)) were not reliably at the null value of 1.0 for any SNP-smoking combinations. Two G-E combinations were too heterogeneous for summary estimates: XRCC1 399 and ever-never smoking (N = 21), and XPD 751 and pack-years (N = 12). OR(z) ranges for these combinations were: [OR(z) (95% confidence interval (CI)] 0.7 (0.4, 1.2)-1.9 (1.2, 2.8) and 0.8 (0.5, 1.3)-2.3 (0.8, 6.1), respectively). Estimates for studies considered homogeneous (Cochran's Q P-value <0.10) varied 2- to 5-fold. No study characteristics were identified that could explain heterogeneity.

We recommend the independence assumption be evaluated in the population underlying any potential case-only study, rather than in a proxy control group(s) or pooled controls.

These results suggest that G-E association in controls may be population-specific. Increased access to control data would improve evaluation of the independence assumption.