Two novel quantitative trait loci on mouse chromosomes 6 and 4 independently and synergistically regulate plasma apoB levels

Carol Ko, Tsai Ling Lee, Philip W. Lau, Jing Li, Brandi T. Davis, Emanuel Voyiaziakis, David B. Allison, Streamson C. Chua, Jr., Li Shin Huang

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

An elevated plasma apolipoprotein B (apoB) level is a strong predictor of atherosclerosis and coronary heart disease. Epidemiologic and family linkage studies have suggested a genetic basis for the wide variations of plasma apoB levels in the general population. Using a human apoB transgenic (HuBTg) mouse model, we have previously shown that hepatic apoB-100 secretion is a major determinant of the high and low plasma human apoB levels in HuBTg mice of the C57BL/6 (B6) and 129/Sv (129) strains, respectively. In the present article, we present the identification of two novel quantitative trait loci (QTL) as major regulators of plasma human apoB levels in the F2 and N2 (backcrossed) offspring (n = 572) derived from crosses between the B6 and 129 mouse strains. These loci were designated ApoB regulator genes (Abrg), because the gene products are likely to be involved in the regulation of plasma apoB levels either directly or indirectly. The first locus, designated Abrg1, was mapped to chromosome 6 in 8-week-old male and female mice with a combined logarithm of odds ratio (LOD) score of 14 at the D6Mit55 marker (∼45.9 cM). Abrg1 contributed approximately 35% of the genetic variance. The second locus, designated Abrg2, was mapped to chromosome 4 with an LOD score of 8.6 in 8-week-old male mice but an LOD score of only 2.0 in 8-week-old female mice at the D4Mit27 marker (∼35 cM). Abrg2 contributed approximately 26% of the genetic variance. Epistasis between Abrg1 and Abrg2 was detected and accounted for approximately 12% of the genetic variance. The combination of these two QTL has major effects (>70%) on the regulation of plasma human apoB levels in the tested population. In summary, we have identified two novel loci that have a major role in the regulation of plasma apoB levels and are likely to regulate the secretory pathway of apoB. The human orthologs for the Abrg loci are strong candidates for human disorders characterized by altered plasma apoB levels, such as FCHL and familial hypobetalipoproteinemia.

Original languageEnglish (US)
Pages (from-to)844-855
Number of pages12
JournalJournal of Lipid Research
Volume42
Issue number5
StatePublished - 2001
Externally publishedYes

Fingerprint

Chromosomes, Human, Pair 4
Chromosomes, Human, Pair 6
Quantitative Trait Loci
Apolipoproteins B
Chromosomes
Plasmas
Plasma (human)
Genes
Odds Ratio
Regulator Genes
Transgenic Mice
Hypobetalipoproteinemias
Apolipoprotein B-100
129 Strain Mouse
Secretory Pathway
Population
Coronary Disease
Atherosclerosis

Keywords

  • ApoB secretion
  • Familial combined hyperlipidemia
  • Genetics
  • Hypobetalipoproteinemia
  • Inbred mouse strains
  • Mapping

ASJC Scopus subject areas

  • Endocrinology

Cite this

Ko, C., Lee, T. L., Lau, P. W., Li, J., Davis, B. T., Voyiaziakis, E., ... Huang, L. S. (2001). Two novel quantitative trait loci on mouse chromosomes 6 and 4 independently and synergistically regulate plasma apoB levels. Journal of Lipid Research, 42(5), 844-855.

Two novel quantitative trait loci on mouse chromosomes 6 and 4 independently and synergistically regulate plasma apoB levels. / Ko, Carol; Lee, Tsai Ling; Lau, Philip W.; Li, Jing; Davis, Brandi T.; Voyiaziakis, Emanuel; Allison, David B.; Chua, Jr., Streamson C.; Huang, Li Shin.

In: Journal of Lipid Research, Vol. 42, No. 5, 2001, p. 844-855.

Research output: Contribution to journalArticle

Ko, C, Lee, TL, Lau, PW, Li, J, Davis, BT, Voyiaziakis, E, Allison, DB, Chua, Jr., SC & Huang, LS 2001, 'Two novel quantitative trait loci on mouse chromosomes 6 and 4 independently and synergistically regulate plasma apoB levels', Journal of Lipid Research, vol. 42, no. 5, pp. 844-855.
Ko, Carol ; Lee, Tsai Ling ; Lau, Philip W. ; Li, Jing ; Davis, Brandi T. ; Voyiaziakis, Emanuel ; Allison, David B. ; Chua, Jr., Streamson C. ; Huang, Li Shin. / Two novel quantitative trait loci on mouse chromosomes 6 and 4 independently and synergistically regulate plasma apoB levels. In: Journal of Lipid Research. 2001 ; Vol. 42, No. 5. pp. 844-855.
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abstract = "An elevated plasma apolipoprotein B (apoB) level is a strong predictor of atherosclerosis and coronary heart disease. Epidemiologic and family linkage studies have suggested a genetic basis for the wide variations of plasma apoB levels in the general population. Using a human apoB transgenic (HuBTg) mouse model, we have previously shown that hepatic apoB-100 secretion is a major determinant of the high and low plasma human apoB levels in HuBTg mice of the C57BL/6 (B6) and 129/Sv (129) strains, respectively. In the present article, we present the identification of two novel quantitative trait loci (QTL) as major regulators of plasma human apoB levels in the F2 and N2 (backcrossed) offspring (n = 572) derived from crosses between the B6 and 129 mouse strains. These loci were designated ApoB regulator genes (Abrg), because the gene products are likely to be involved in the regulation of plasma apoB levels either directly or indirectly. The first locus, designated Abrg1, was mapped to chromosome 6 in 8-week-old male and female mice with a combined logarithm of odds ratio (LOD) score of 14 at the D6Mit55 marker (∼45.9 cM). Abrg1 contributed approximately 35{\%} of the genetic variance. The second locus, designated Abrg2, was mapped to chromosome 4 with an LOD score of 8.6 in 8-week-old male mice but an LOD score of only 2.0 in 8-week-old female mice at the D4Mit27 marker (∼35 cM). Abrg2 contributed approximately 26{\%} of the genetic variance. Epistasis between Abrg1 and Abrg2 was detected and accounted for approximately 12{\%} of the genetic variance. The combination of these two QTL has major effects (>70{\%}) on the regulation of plasma human apoB levels in the tested population. In summary, we have identified two novel loci that have a major role in the regulation of plasma apoB levels and are likely to regulate the secretory pathway of apoB. The human orthologs for the Abrg loci are strong candidates for human disorders characterized by altered plasma apoB levels, such as FCHL and familial hypobetalipoproteinemia.",
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AU - Voyiaziakis, Emanuel

AU - Allison, David B.

AU - Chua, Jr., Streamson C.

AU - Huang, Li Shin

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