Testing of multiplicative interaction terms demonstrated no statistically significant departures from multiplicative joint effects between the IRR for CFH Y402H and cigarette smoking (P=.72 for interaction) or obesity (P=.56 for interaction) or between the IRR for LOC387715 A69S and these factors (Table 5). However, because the lack of such statistical interaction on the multiplicative scale does not necessarily imply the absence of synergy in biological effects or translate well into public health messages,21,22 we also calculated the IRR for each genotype–risk factor combination to identify subjects at particularly high risk of AMD (Table 5). Although statistically consistent with multiplicative effects, these estimates indicate that, compared with nonobese subjects with no CFH Y402H risk alleles, there is a 4-fold increased risk among participants homozygous for CFH Y402H who are not obese, whereas the risk is 12-fold among homozygous participants who are also obese. Corresponding IRRs for nonsmoking vs smoking homozygous carriers of CFH Y402H are 4.23 and 8.69, respectively (Table 5). Similarly, for LOC387715 A69S, compared with nonsmoking subjects with no risk alleles, the estimated IRRs are 6.33 for homozygous A69S carriers who do not smoke and 22.47 among current smokers. We observed no statistically significant departures from multiplicative interaction between CFH Y402H and regular aspirin use (P=.88 for interaction), fruit intake (P=.44 for interaction), ω-6 to ω-3 fatty acid intake ratio (P=.81 for interaction), or alcohol consumption (P=.34 for interaction) or between LOC387715 A69S and these factors (P=.10, P=.77, P=.42, and P=.51 for interaction, for regular aspirin use, fruit intake, ω-6 to ω-3 fatty acid intake ratio, and alcohol consumption, respectively). For these factors, comparison of the stratum-specific IRR did not suggest large differences in risk conferred by either genotype among exposed vs unexposed participants, with the possible exception of LOC387715 and regular aspirin use. Compared with participants with no A69S risk alleles who used aspirin regularly, the risk of AMD was increased 7-fold among subjects homozygous for A69S who did not use aspirin regularly, but just more than 2-fold among regular aspirin users who were homozygous for A69S.