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 develop various forms of arteriosclerosis, particularly atherosclerosis, and medial calcinosis. The most common cause of death in Caucasian subjects with WS is myocardial infarction. Previous studies have identified specific polymorphisms within WRN that may modulate the risk of atherosclerosis. Population studies of the 1074Leu/Phe and 1367Cys/Arg polymorphisms were undertaken to evaluate the role of WRN in atherogenesis. Frequencies of the 1074Leu/Phe polymorphisms in Finnish and Mexican populations revealed an age-dependent decline of 1074Phe/Phe genotype. In Mexican newborns, but not in Finnish newborns, the 1074Leu/Phe and 1367Cys/ Arg polymorphisms were in linkage disequilibrium. Among coronary artery disease subjects, there was a tendency for the 1074Phe allele to be associated with coronary stenosis in a gene dose-dependent manner. Furthermore, the 1367Arg/Arg genotype predicted a lower 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 ischemic stroke showed a trend of haplotype frequencies different from that in a control group of Mexican adults. These data support the hypothesis that WRN may mediate not only WS, but may also modulate more common age-related disorders and, perhaps, a basic aging process.
Castro
E
E
Department of Pathology, University of Washington, Seattle, USA.
Edland
S D
SD
Lee
L
L
Ogburn
C E
CE
Deeb
S S
SS
Brown
G
G
Panduro
A
A
Riestra
R
R
Tilvis
R
R
Louhija
J
J
Penttinen
R
R
Erkkola
R
R
Wang
L
L
Martin
G M
GM
Oshima
J
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics*; D001120:Arginine / Q000235:genetics; D001161:Arteriosclerosis / Q000453:epidemiology / Q000235:genetics*; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics; D003545:Cysteine / Q000235:genetics; D005387:Finland / Q000453:epidemiology; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007231:Infant, Newborn; D007930:Leucine / Q000235:genetics; D008136:Longevity / Q000235:genetics*; D008800:Mexico / Q000453:epidemiology; D008875:Middle Aged; D010649:Phenylalanine / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D014898:Werner Syndrome / Q000453:epidemiology / Q000235:genetics*
D010649:Phenylalanine; D001120:Arginine; D007930:Leucine; D003545:Cysteine