BOSTON — A genomewide scan of sibling pairs from families with a genetic susceptibility to developing venous thromboembolism has identified mutations in four genes on chromosome 7 as likely genetic markers for familial thrombophilia.
Single nucleotide polymorphisms (SNPs) in the four genes were linked to familial thrombophilia syndromes. The genes, which don't overlap with genes previously linked to venous thromboembolism (VTE), may account for a large proportion of missing VTE risk factors, Dr. Marieke de Visser said at a meeting of the International Society on Thrombosis and Haemostasis.
The findings could “greatly expand our repertoire of VTE candidate genes,” commented Dr. Edwin Bovill, chairman of the department of pathology and laboratory medicine at the University of Vermont in Burlington.
VTE is a multicausal disease in which both environmental and genetic factors are known to be involved, said Dr. de Visser of the department of thrombosis and hemostasis at Leiden (the Netherlands) University Medical Center.
“So-called familial thrombophilia is thought to be an oligogenetic disease in which at least two genetic risk factors are present,” she said. About 30% of families with familial thrombophilia have known genetic risk factors, suggesting that a significant proportion of risk factors has yet to be identified. “The idea that genetic risk factors are missing is further supported by the observation that many hemostasis-related proteins both correlate with thrombosis risk and show high hereditability.”
Investigators from the Genetics in Familial Thrombosis (GIFT) collaborative collected data on families seen at 29 Dutch anticoagulation clinics. They recruited 211 families consisting of 213 sibships, with 287 sibling pairs that included 460 siblings (87% of sibships consisted of two siblings, 19% had three siblings, and 3% had four siblings). Affected family members had confirmed VTE at or before the age of 45 years. The authors looked at data on both an index sample (two generations, 211 participants) and a nonindex sample (249 participants).
In both the index and nonindex samples, the mean age at first VTE was about 33.5 years, and 46% had more than one event. In about two-thirds of each group, the first VTE was a deep vein thromboembolism (DVT) in the leg or arm. Pulmonary embolism (PE) was the first presentation in about 20% of patients, DVT and PE occurred in about 9%, and thrombophlebitis occurred in about 9%. In nearly half of the families, at least one parent also had a VTE.
The index group had a high prevalence of genetic risk factors, including factor V Leiden in 36.5%, ABO blood group non-O (82.9%), protein S deficiency type III (10.5%), and protein S deficiency type I (7.6%).
The researchers narrowed their search down to SNPs in four candidate genes on chromosome 7: RAC1, COL28A1, NXPH1, and, most robustly, THSD7A. These candidate genes may account for many of the missing genetic factors associated with VTE risk, Dr. de Visser said.
The study was supported by grants from the Netherlands Heart Foundation and the Netherlands Organization for Scientific Research. Dr. de Visser said that neither she nor her coauthors had relevant conflicts of interest.