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(Circulation. 1999;100:693-699.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Splice-Site Mutations in Atherosclerosis Candidate Genes

Relating Individual Information to Phenotype

Yskert von Kodolitsch, MD; Reed E. Pyeritz, MD, PhD; Peter K. Rogan, PhD

From the Department of Cardiology (Y.v.K.), University Hospital Eppendorf, Hamburg, Germany; Departments of Human Genetics, Medicine, and Pediatrics (R.E.P.), Allegheny General Hospital, Pittsburgh, Pa; and Section of Molecular Genetics and Molecular Medicine (P.K.R.), Children's Mercy Hospital, Kansas City, Mo.

Correspondence to Peter K. Rogan, PhD, Section of Molecular Genetics and Molecular Medicine, Children's Mercy Hospital and Clinics, 2401 Gillham Road, Kansas City, MO 64108. E-mail progan{at}cmh.edu

Background—Nucleotide variants in several genes for lipid and methionine metabolism influence the risk of premature atherosclerosis. Ten percent of single nucleotide substitutions in these genes involve mRNA splice sites. The effects of some of these changes on splicing and on phenotypic severity are not inherently obvious.

Methods and Results—Using an information theory-based model, we measured the individual information content (R_i, in bits) of splice sites adjacent to 289 mutations (including 31 splice-site mutations) in the atherosclerosis candidate genes APOAII, APOB, APOCII, APOE, CBS, CETP, LCAT, LIPA, LDLR, and LPL. The predictions of information analysis were then corroborated by published mRNA analyses. The R_i values of mutant sites were consistent with either complete (n=17) or partial (n=8) inactivation of these sites. Seven mutations were predicted to activate cryptic splice sites. Predicted inactive mutant sites were associated with either "average" or "severe" dyslipidemia and commensurate reductions in protein levels or activity, whereas mutations expected to exhibit residual splicing had average or "mild" effects on lipid and protein expression.

Conclusions—Information analysis of splice-junction variants in atherosclerosis candidate genes distinguishes inactive from leaky splice sites and identifies activated cryptic sites. Predicted changes in splicing were related to phenotypic severity.

Key Words: atherosclerosis • genetics • lipids • risk factors • RNA

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