An unknown genetic defect increases venous thrombosis risk, through interaction with protein C deficiency.
We used two-locus segregation analysis to test whether an unknown genetic defect interacts with protein C deficiency to increase susceptibility to venous thromboembolic disease in a single large pedigree. Sixty-seven pedigree members carry a His107Pro mutation in the protein C gene, which reduces protein C levels to a mean of 46% of normal. Twenty-one carriers of the mutation and five other pedigree members had verified thromboembolic disease. We inferred the presence in this pedigree of a thrombosis-susceptibility gene interacting with protein C deficiency, by rejecting the hypothesis that the cases of thromboembolic disease resulted from protein C deficiency alone and by not rejecting Mendelian transmission of the interacting gene. When coinherited with protein C deficiency, the interacting gene conferred a probability of a thrombotic episode of approximately 79% for men and approximately 99% for women, before age 60 years.
University of Utah, Department of Human Genetics, Salt Lake City, UT 84112-5330, USA. sandy@sapporo.genetics.utah.edu
S J
SJ
Hasstedt
E G
EG
Bovill
P W
PW
Callas
G L
GL
Long
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D002648:Child; D005260:Female; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017354:Point Mutation; D011486:Protein C / Q000235:genetics*; D020151:Protein C Deficiency / Q000453:epidemiology / Q000235:genetics*; D012307:Risk Factors; D012727:Sex Characteristics; D020246:Venous Thrombosis / Q000453:epidemiology / Q000235:genetics*; D014707:Vermont / Q000453:epidemiology
D011486:Protein C