Relative to the reference group that included subjects with high estradiol level and carried COMT Val/Val genotypes and SULT1E1 G alleles, those whose estradiol level was low and carried either COMT Met allele or SULT1E1 A/A genotype had 6.13-fold risk of ischemic stroke, showing a significant joint effect on risk of young ischemic stroke (P for interaction = 0.0174). The gene discussed is COMT; the disease is ischemic stroke.