ASSOCIATION OF A POLYMORPHIC VARIANT OF THE WERNER HELICASE GENE WITHMYOCARDIAL-INFARCTION IN A JAPANESE POPULATION

The Werner syndrome (WS) is a rare autosomal recessive progeroid syndr ome characterized by the premature onset of multiple age-related disor ders, including atherosclerosis, cancer, non-insulin-dependent diabete s mellitus (NIDDM), ocular cataracts and osteoporosis [Epstein et al., 1966]. The major cause of death (at a median age of 47) is myocardial infarction (MI) [Epstein et al., 1966]. The WS mutation involves a me mber (WRN) of the RecQ family of helicases and may perturb DNA replica tion, repair, recombination, transcription, or chromosomal segregation [Yu et al., 1996]. We now report data on 149 MI cases and age-matched controls suggesting that a polymorphic WRN variant is associated with increased risk for MI. Based on our data, homozygosity for a cysteine at amino acid 1367 (the most prevalent genotype) predicts a 2.78 time s greater risk of MI (95% confidence intervals: 1.23 to 6.86). The var iant was not significantly associated with NIDDM. The two alleles (cys teine vs. arginine) could influence helicase activity, turnover, macro molecular interactions or, alternatively, could be markers for haploty pes influencing WRN regulation or reflecting gene action at linked loc i. However, given the caveats implicit in genetic association studies, it is imperative that the present results be replicated in independen t populations.