A new locus for autosomal recessive hypercholesterolemia maps to human chromosome 15q25-q26

Abstract

High serum cholesterol is an established risk factor for cardiovascular disease and is the prime target for therapeutic intervention in large groups of patients. The development of modern treatments for this major risk factor was propelled by the early realization that forms of severe hypercholesterolemia could be caused by dominantly inherited defects in the LDL receptor or in the APOB gene. Further understanding of the mechanisms contributing to early atherosclerosis will allow for new targets for therapy. We therefore identified and investigated the genetics of families from Sardinia that have recessive inheritance of precocious hypercholesterolemia. We used five families in an analysis of linkage of the autosomal recessive hypercholesterolemia locus, termed "ARH1," to chromosome 15q25-q26. A genomewide search mapped the disease-causing gene with a LOD score of 3.3 and excluded major contributions to the phenotype of other genes. A candidate gene present in the mapped chromosome region-the ligand-activated liver-transcription-factor gene ARP1 (apolipoprotein regulatory-protein gene)-has been excluded after DNA sequencing. The close-bred nature of the Sardinian population offers unique opportunities for isolation of this hypercholesterolemia-causing gene.

Figure 1

Structure of the five Sardinian pedigrees with hypercholesterolemia. Circles denote females; squares, males; blackened symbols, affected individuals. Double lines indicate consanguineous matings. Numbers below each symbol indicate age at the time of this study or age at death; numbers inside symbols indicate the number of siblings with an identical phenotype. Stars above symbols denote individuals included in the linkage analysis.

Figure 2

Suggested haplotypes of chromosome 15q24-15qter in families with ARH. The common region shared in affected individuals within each family is boxed. Displayed haplotypes were calculated by use of the GENEHUNTER program.

Figure 3

Multipoint linkage analysis of ARH, displaying chromosome 15 results. Markers are indicated below the X-axis. The ARP1 gene is located at 15q25-15q26.

Figure 4

Multipoint-linkage-analysis data for all chromosomes except the sex chromosomes. LOD scores >−2 are hidden and indicate that the chromosome region is excluded for linkage. Chromosome X was excluded by single-point analysis, with use of LINKAGE software, version 5.1.