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Journal of Lipid Research, Vol. 47, 2799-2807, December 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Patient-Oriented Research

Heritability and genetic loci of fatty liver in familial combined hyperlipidemia

Martijn C. G. J. Brouwers^1,*, Rita M. Cantor^,, Naoko Kono, Jeong lim Yoon, Carla J. H. van der Kallen^*, Monique A. L. Bilderbeek-Beckers^**, Marleen M. J. van Greevenbroek^*, Aldons J. Lusis^, and Tjerk W. A. de Bruin^*,2

^* Department of Medicine and Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht, Maastricht, The Netherlands
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
^** Department of Radiology, VieCuri Medical Center Noord Limburg, Venlo, The Netherlands
Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA

Published, JLR Papers in Press, September 13, 2006.

² Present address of T. W. A. de Bruin: GlaxoSmithKline, Translational Medicine and Genetics, Research Triangle Park, NC 27713.

¹ To whom correspondence should be addressed. e-mail: martijn.brouwers{at}intmed.unimaas.nl

ABSTRACT

VLDL overproduction, a process that is driven by an excess amount of hepatic fat, is a well-documented feature of familial combined hyperlipidemia (FCHL). The aims of this study were to investigate whether fatty liver, measured with ultrasound and as plasma alanine aminotransferase (ALT) levels, develops against a genetic background in FCHL and to identify chromosomal loci that are linked to these traits. In total, 157 FCHL family members and 20 spouses participated in this study. Radiological evidence of fatty liver was more prevalent not only in FCHL probands (40%) but also in their relatives (35%) compared with spouses (15%) (P < 0.05). Heritability calculations revealed that 20–36% of the variability in ALT levels could be attributed to genetic factors. Nonparametric quantitative trait locus (QTL) analysis revealed three significant (P < 0.001) loci with either the ultrasound or the ALT trait in the male sample: 1q42.3, 7p12-21, and 22p13-q11; none was found in the female sample or the entire group. Of these QTLs, the 7p region was consistent over time, because reanalysis with ALT levels that were determined during a visit 5 years earlier yielded similar results. This study shows that fatty liver is a heritable aspect of FCHL. Replication of particularly the 7p region is awaited.

Supplementary key words steatosis • nonalcoholic fatty liver disease • quantitative trait locus • linkage analysis • alanine aminotransferase

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