Polymorphisms at the Werner locus: II. 1074Leu/Phe, 1367Cys/Arg, longevity, and atherosclerosis

Werner syndrome (WS) is a progeroid syndrome caused by autosomal recessive null mutations at the WRN locus. The WRN gene encodes a nuclear protein of 180 kD that contains both exonuclease and helicase domains. WS patients dev elop various forms of arteriosclerosis, particularly atherosclerosis, and m edial calcinosis, The most common cause of death in Caucasian subjects with WS is myocardial infarction, Previous studies have identified specific pol ymorphisms within WRN that may modulate the risk of atherosclerosis. Popula tion studies of the 1074Leu/Phe and 1367Cys/Arg polymorphisms were undertak en to evaluate the role of WRN in atherogenesis, Frequencies of the 1074Leu /Phe polymorphisms in Finnish and Mexican populations revealed an age-depen dent decline of 1074Phe/Phe genotype. In Mexican newborns, but not in Finni sh newborns, the 1074Leu/Phe and 1367Cys/Arg polymorphisms were in linkage disequilibrium, Among coronary artery disease subjects, there was a tendenc y for the 1074Phe allele to be associated with coronary stenosis in a gene dose-dependent manner. Furthermore, the 1367Arg/Arg genotype predicted a lo wer degree of coronary artery occlusion, as measured by NV50, when compared to the 1367Cys/Cys or 1367Cys/Arg genotypes, However, these tendencies did not achieve statistical significance. Samples from Mexican patients with i schemic stroke showed a trend of haplotype frequencies different from that in a control group of Mexican adults. These data support the hypothesis tha t WRN may mediate not only WS, but may also modulate more common age-relate d disorders and, perhaps, a basic aging process, (C) 2000 Wiley-Liss, Inc.