Loci on Chromosomes 14 and 2, Distinct from ABCG5/ABCG8, Regulate Plasma Plant Sterol Levels in a C57BL/6J x CASA/Rk Intercross

• Published in: Proceedings of the National Academy of Sciences - PNAS 2002-12, Vol.99 (25), p.16215-16219
• Main Authors: Sehayek, Ephraim, Duncan, Elizabeth M., Lutjohann, Dieter, von Bergmann, Klaus, Ono, Jennie G., Batta, Ashok K., Salen, Gerald, Breslow, Jan L.
• Format: Article
• Language: English
• Subjects: Alleles; Animals; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Biomarkers; Cholesterol - analogs & derivatives; Cholesterol - blood; Cholesterol - pharmacokinetics; Cholesterols; Chromosome Mapping; Chromosomes; Crosses, Genetic; Dietary Fats - pharmacokinetics; Epistasis, Genetic; Female; Genes; Genetic loci; Genotype; Lipoproteins - genetics; Lipoproteins - metabolism; Lod score; Male; Medical research; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Phytosterols; Plasma; Plasma interactions; Sitosterols; Sitosterols - blood; Sitosterols - pharmacokinetics; Species Specificity; Sterols
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.212640599

Plasma plant sterol levels differ among humans due to genetic and dietary factors. A disease characterized by high plasma plant sterol levels, β-sitosterolemia, was recently found to be due to mutations at the ABCG5/ABCG8 locus. To detect variants at this and other loci, a genetic cross was carried out between two laboratory mouse strains. Parental C57BL/6J had almost twice the campesterol and sitosterol levels compared with parental CASA/Rk mice, and F1mice had levels halfway between the parentals. An intercross between F1swas performed and plasma plant sterol levels measured in 102 male and 99 female F2mice. Plasma plant sterols in F2sdisplayed a unimodal distribution, suggesting the effects of several rather a single major gene. In the F2mice, a full genome scan revealed significant linkages on chromosomes 14 and 2. With regard to chromosome 14, analysis showed a single peak for linkage at 17 cM with a logarithm of odds (LOD) score of 9.9, designated plasma plant sterol 14 (Plast14). With regard to chromosome 2, analysis showed two significant peaks for linkage at 18 and 65 cMs with LOD scores of 4.1 and 3.65, respectively, designated Plast2a and Plast2b, respectively. Four interactions between loci, predominantly of an additive nature, were also demonstrated, the most significant between Plast14 and Plast2b (LOD 16.44). No significant linkage or gene interaction was detected for the ABCG5/ABCG8 locus on chromosome 17. Therefore, other genes besides ABCG5/ABCG8 influence plasma plant sterol levels and now become candidates to explain differences in plasma plant sterol levels between humans.