Published Online
on September 22, 2005

A more recent version of this article appeared on October 1, 2005

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Submitted on December 13, 2004
Revised on April 20, 2005
Accepted on May 30, 2005

Polymorphisms in Transforming Growth Factor--Related Genes ALK1 and ENG Are Associated With Sporadic Brain Arteriovenous Malformations

Ludmila Pawlikowska PhD; Mary N. Tran PhD; Achal S. Achrol BS; Connie Ha BS; Esteban Burchard MD; Shweta Choudhry PhD; Jonathan Zaroff MD; Michael T. Lawton MD; Richard Castro MD; Charles E. McCulloch PhD; Douglas Marchuk PhD; Pui-Yan Kwok MD, PhD; William L. Young MD^*; for the UCSF BAVM Study Project

From the Cardiovascular Research Institute (L.P., C.H., P.Y.K.), Departments of Anesthesia and Perioperative Care and Center for Cerebrovascular Research (M.N.T., A.A., W.L.Y.), Departments of Epidemiology and Biostatistics (C.E.M.), Neurological Surgery (M.T.L., W.L.Y.), Neurology (W.L.Y.), and Medicine (E.B., S.C., R.C., J.Z.), University of California, San Francisco; and the Department of Genetics, Duke University Medical Center, Durham, NC (D.A.M.).

^* To whom correspondence should be addressed. E-mail: ccr{at}anesthesia.ucsf.edu.

Background and Purpose--Mutations in endoglin (ENG) and activin-like kinase (ALK1) cause hereditary hemorrhagic telangiectasias, disorders characterized by pulmonary and brain arteriovenous malformations (BAVMs). We investigated whether polymorphisms in these genes are also associated with sporadic BAVM.

Methods--A total of 177 sporadic BAVM patients and 129 controls (all subjects white) were genotyped for 2 variants in ALK1 and 7 variants in ENG.

Results--The ALK1 IVS3-35A>G polymorphism was associated with BAVM: (AnyA [AA+AG] genotype: odds ratio, 2.47; 95% CI, 1.38 to 4.44; P=0.002). Two ENG polymorphisms, ENG -1742A>G and ENG 207G>A, showed a trend toward association with BAVM that did not reach statistical significance.

Conclusions--A common polymorphism in ALK1 is associated with sporadic BAVM, suggesting that genetic variation in genes mutated in familial BAVM syndromes may play a role in sporadic BAVMs.

Key words: case-control studies • genetics • vascular malformations

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