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. 2013 Oct 3;3(10):1819-25.
doi: 10.1534/g3.113.007567.

Identification of a Novel Polymorphism in X-linked sterol-4-alpha-carboxylate 3-dehydrogenase (Nsdhl) Associated With Reduced High-Density Lipoprotein Cholesterol Levels in I/LnJ Mice

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Free PMC article

Identification of a Novel Polymorphism in X-linked sterol-4-alpha-carboxylate 3-dehydrogenase (Nsdhl) Associated With Reduced High-Density Lipoprotein Cholesterol Levels in I/LnJ Mice

David J Bautz et al. G3 (Bethesda). .
Free PMC article

Abstract

Loci controlling plasma lipid concentrations were identified by performing a quantitative trait locus analysis on genotypes from 233 mice from a F2 cross between KK/HlJ and I/LnJ, two strains known to differ in their high-density lipoprotein (HDL) cholesterol levels. When fed a standard diet, HDL cholesterol concentration was affected by two significant loci, the Apoa2 locus on Chromosome (Chr) 1 and a novel locus on Chr X, along with one suggestive locus on Chr 6. Non-HDL concentration also was affected by loci on Chr 1 and X along with a suggestive locus on Chr 3. Additional loci that may be sex-specific were identified for HDL cholesterol on Chr 2, 3, and 4 and for non-HDL cholesterol on Chr 5, 7, and 14. Further investigation into the potential causative gene on Chr X for reduced HDL cholesterol levels revealed a novel, I/LnJ-specific nonsynonymous polymorphism in Nsdhl, which codes for sterol-4-alpha-carboxylate 3-dehydrogenase in the cholesterol synthesis pathway. Although many lipid quantitative trait locus have been reported previously, these data suggest there are additional genes left to be identified that control lipid levels and that can provide new pharmaceutical targets.

Keywords: HDL cholesterol; Nsdhl; QTL; genomics.

Figures

Figure 1
Figure 1
Genome-wide scan for HDL and non-HDL plasma level in 233 F2 progeny after 12−14 weeks on standard chow. Plasma HDL (A, C) and non-HDL (B, D) cholesterol values were log2-transformed before analysis. QTL analysis also was performed in males (n = 127, solid line) and females (n = 106, dashed line) separately (C, D). Chromosomes 1 through X are represented numerically along the x-axis with LOD scores plotted along the y-axis. Significant (P < 0.05) and suggestive (P < 0.63) levels were determined by 1000 permutations for the autosomes and 16,803 permutations for chromosome X.
Figure 2
Figure 2
Plasma lipid values based on sex and the genotype at marker rs13483831 (Chr X). (A) HDL cholesterol. (B) Non-HDL cholesterol. K/K denotes mice homozygous for the KK/HlJ allele, K/I denotes females heterozygous for the KK/HlJ and I/LnJ alleles, and I/I denotes mice homozygous for the I/LnJ allele. Error bars indicate SEM. **P < 0.0001.
Figure 3
Figure 3
Plasma lipid values based on sex and the genotypes at markers rs13476229 (Chr 1) and rs13483831 (Chr X). (A, B) males; (C, D) females. (A, C) HDL cholesterol. (B, D) Non-HDL cholesterol. K/K denotes mice homozygous for the KK/HlJ allele, K/I denotes females heterozygous for the KK/HlJ and I/LnJ alleles, and I/I denotes mice homozygous for the I/LnJ allele. Dashed lines represent the average values when only considering the genotype at marker rs13476229. Error bars indicate SEM. P < 0.05, P < 0.01, *P < 0.001, **P < 0.0001.
Figure 4
Figure 4
Nsdhl sequence analysis. (A) Sequencing chromatograms for Nsdhl from KK/HlJ and I/LnJ mice showing A->G polymorphism. (B) Nsdhl sequence alignment from various species with the novel polymorphism indicated in red.

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References

    1. Bornholdt D., Konig A., Happle R., Leveleki L., Bittar M., et al. , 2005. Mutational spectrum of NSDHL in CHILD syndrome. J. Med. Genet. 42: e17. - PMC - PubMed
    1. Broman K. W., Wu H., Sen S., Churchill G. A., 2003. R/qtl: QTL mapping in experimental crosses. Bioinformatics 19: 889–890 - PubMed
    1. Broman K. W., Sen S., Owens S. E., Manichaikul A., Southard-Smith E. M., et al. , 2006. The X chromosome in quantitative trait locus mapping. Genetics 174: 2151–2158 - PMC - PubMed
    1. Churchill G. A., Doerge R. W., 1994. Empirical threshold values for quantitative trait mapping. Genetics 138: 963–971 - PMC - PubMed
    1. Cox A., Ackert-Bicknell C., Dumont B. L., Ding Y., Tzenova Bell J., et al. , 2009. A new standard genetic map for the mouse. Genetics 182: 1335–1344 - PMC - PubMed

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