Published online before print February 27, 2003, doi: 10.1161/01.RES.0000064174.69165.66
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Submitted on August 21, 2002
Revised on February 14, 2003
Accepted on February 14, 2003
Locus on Chromosome 6p Linked to Elevated HDL Cholesterol Serum Levels and to Protection Against Premature Atherosclerosis in a Kindred With Familial Hypercholesterolemia
Samuel Canizales-Quinteros ;
From Unidad de Biología Molecular y Medicina Genómica (S.C.-Q., L.R., M.R.-T., S.R.-J., A.H.-V., V.F.-O., M.T.T.-L.), Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México e Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán; Departamento de Sistemas Biológicos (S.C.-Q.), Universidad Autónoma Metropolitana-Xochimilco; Departamento de Endocrinología y Metabolismo de Lípidos (C.A.A.-S., E.R.-R., A.L.-E., M.A.-G., F.G.-P., J.R.), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán; and Departamento de Biología Celular, Instituto de Fisiología Celular (A.Z.-D., J.L.V.-G.), and Dirección General de Servicios de Cómputo Académico (G.V.-H.), Universidad Nacional Autónoma de México, México City, Mexico; and the Howard Hughes Medical Institute (G.I.B.) and Departments of Biochemistry and Molecular Biology (G.I.B.) and Medicine and Human Genetics (N.J.C., G.I.B.), the University of Chicago, Chicago, Ill.
* To whom correspondence should be addressed. E-mail: tusie{at}servidor.unam.mx.
Heterozygous familial hypercholesterolemia (FH) is a highly atherogenic genetic disorder leading to premature coronary heart disease (CHD), usually before 60 years of age. We studied an extended multigenerational kindred with FH linked to chromosome 1p32 in which atherosclerotic complications were either delayed or prevented in individuals with elevated HDL cholesterol (HDL-C) levels or hyperalphalipoproteinemia (HA). Premature CHD was observed in FH individuals without HA. The study of this family established that the HA trait in the family also followed an autosomal dominant mode of inheritance with a pattern of segregation independent from FH. We identified a locus on chromosome 6 linked to elevated HDL-C levels (HA) in this family. Haplotype analysis refined the localization to a 7.32-cM interval (73 to 80 cM from pter) flanked by markers D6S1280 and D6S1275. Parametric 2-point and multipoint analyses yielded maximum lod scores of 3.05 and 3.17, respectively. This finding was confirmed with a nonparametric multipoint score of 3.78 (P=0.0009). We propose that this locus, linked to elevated HDL-C levels, confers protection against premature CHD within an FH context.
Key words: LDL cholesterol • HDL cholesterol • genetics • familial hypercholesterolemia • hyperalphalipoproteinemia
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