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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1089.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Genetic Localization to Chromosome 1p32 of the Third Locus for Familial Hypercholesterolemia in a Utah Kindred

Steven C. Hunt; Paul N. Hopkins; Katrina Bulka; Michael T. McDermott; Thomas L. Thorne; Bryan B. Wardell; Benjamin R. Bowen; Dennis G. Ballinger; Mark H. Skolnick; Mark E. Samuels

From Cardiovascular Genetics (S.C.H., P.N.H.), Department of Medicine, University of Utah, Salt Lake City; Myriad Genetics Inc, (K.B., M.T.M., T.L.T., B.B.W., D.G.B., M.H.S., M.E.S.), Salt Lake City, Utah; and Novartis Institute for Biomedical Research (B.R.B.), Summit, NJ.

Correspondence to Steven C. Hunt, PhD, University of Utah, Cardiovascular Genetics, 410 Chipeta Way, Room 167, Salt Lake City, UT 84108. E-mail steve{at}ucvg.med.utah.edu

Abstract—Clinical familial hypercholesterolemia has been shown to result from mutations in 2 genes, the low density lipoprotein (LDL) receptor on chromosome 19 and apolipoprotein B on chromosome 2. However, we have recently described a Utah pedigree in which linkage to both genes was clearly excluded. A multipoint linkage analysis of 583 markers genotyped on 31 (18 affected) members of this pedigree was undertaken to localize a genetic region that may harbor a third gene that could result in clinical familial hypercholesterolemia. A multipoint log of the odds score of 6.8 was obtained for markers on 1p32. Haplotype carriers and affected status are completely concordant (18/18 persons). The phenotype is also expressed in young children (ages 4 and 9). Specific recombinant individuals in the pedigree restrict the region of linkage to an 17 cM interval between polymorphic markers D1S2130 and D1S1596. This region appears to overlap the region found linked to severe hypercholesterolemia in French and Spanish families. The identification of the gene in this region may provide important pathophysiological insights into new mechanisms that may lead to highly elevated LDL cholesterol and other associated dyslipidemic phenotypes.

Key Words: familial hypercholesterolemia • genetics • LDL cholesterol • linkage analysis

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