Genome scan of venous thrombosis in a pedigree with protein C deficiency.
Kindred Vermont II has a high frequency of venous thrombosis, occurring primarily in pedigree members with type I protein C deficiency due to a 3363 inserted (Ins) C mutation in exon 6 of the protein C gene. However, only a subset of 3363 InsC carriers have suffered thrombotic episodes, suggesting that the increased risk of thrombosis results upon the co-occurrence of 3363 InsC with a second, unknown, thrombophilic mutation that segregates independently within the pedigree. To test this hypothesis and to localize the co-occurring gene, we performed a genome scan of venous thrombosis in Kindred Vermont II. Non-parametric linkage statistics identified three potential gene locations, on chromosomes 11q23 (nominal P < 0.0001), 18p11.2-q11.2 (P < 0.0007), and 10p12 (P < 0.0003), supporting the presence of at least one additional thrombophilic mutation in the pedigree. Identification of the unknown mutation(s) promises to reveal a new genetic risk factor for thrombophilia, contribute to our understanding of the blood clotting mechanism, and expand our knowledge of the diversity of oligogenic disease.
Hasstedt
S J
SJ
Department of Human Genetics, University of Utah, Salt Lake City, UT 84112-5330, USA. sandy@genetics.utah.edu
Scott
B T
BT
Callas
P W
PW
Vossen
C Y
CY
Rosendaal
F R
FR
Long
G L
GL
Bovill
E G
EG
D000293:Adolescent; D000328:Adult; D000368:Aged; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D002880:Chromosomes, Human, Pair 11; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D020151:Protein C Deficiency / Q000150:complications / Q000235:genetics*; D019851:Thrombophilia / Q000150:complications / Q000235:genetics*; D020246:Venous Thrombosis / Q000209:etiology / Q000235:genetics*