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Articles by A. J. Lusis
Total Records ( 2 ) for A. J. Lusis
  S. S Wang , L. J Martin , E. E Schadt , H Meng , X Wang , W Zhao , L Ingram Drake , M Nebohacova , M Mehrabian , T. A Drake and A. J. Lusis
 

Background— Disruption of the elastic lamina, as an early indicator of aneurysm formation, and vascular calcification frequently occur together in atherosclerotic lesions of humans.

Methods and Results— We now report evidence of shared genetic basis for disruption of the elastic lamina (medial disruption) and medial calcification in an F2 mouse intercross between C57BL/6J and C3H/HeJ on a hyperlipidemic apolipoprotein E (ApoE–/–) null background. We identified 3 quantitative trait loci (QTLs) on chromosomes 6, 13, and 18, which are common to both traits, and 2 additional QTLs for medial calcification on chromosomes 3 and 7. Medial disruption, including severe disruptions leading to aneurysm formation, and medial calcification were highly correlated and occurred concomitantly in the cross. The chromosome 18 locus showed a striking male sex-specificity for both traits. To identify candidate genes, we integrated data from microarray analysis, genetic segregation, and clinical traits. The chromosome 7 locus contains the Abcc6 gene, known to mediate myocardial calcification. Using transgenic complementation, we show that Abcc6 also contributes to aortic medial calcification.

Conclusions— Our data indicate that calcification, though possibly contributory, does not always lead to medial disruption and that in addition to aneurysm formation, medial disruption may be the precursor to calcification.

  P. S Gargalovic , A Erbilgin , O Kohannim , J Pagnon , X Wang , L Castellani , R LeBoeuf , M. L Peterson , B. T Spear and A. J. Lusis
 

Background— We previously mapped a quantitative trait locus on chromosome 15 in mice contributing to high-density lipoprotein cholesterol and triglyceride levels and now report the identification of the underlying gene.

Methods and Results— We first fine-mapped the locus by studying a series of congenic strains derived from the parental strains BALB/cJ and MRL/MpJ. Analysis of gene expression and sequencing followed by transgenic complementation led to the identification of zinc fingers and homeoboxes 2 (Zhx2), a transcription factor previously implicated in the developmental regulation of -fetoprotein. Reduced expression of the protein in BALB/cJ mice resulted in altered hepatic transcript levels for several genes involved in lipoprotein metabolism. Most notably, the Zhx2 mutation resulted in a failure to suppress expression of lipoprotein lipase, a gene normally silenced in the adult liver, and this was normalized in BALB/cJ mice carrying the Zhx2 transgene.

Conclusions— We identified the gene underlying the chromosome 15 quantitative trait locus, and our results show that Zhx2 functions as a novel developmental regulator of key genes influencing lipoprotein metabolism.

 
 
 
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