Atherosclerosis 174 (2004) 357–362 TXNIP gene not associated with familial combined hyperlipidemia in the NHLBI Family Heart Study Hilary Coon a,∗ , Nanda Singh b , Diane Dunn b , John H. Eckfeldt c , Michael A. Province d , Paul N. Hopkins e , Robert Weiss b , Steven C. Hunt e , Mark F. Leppert b a Neurodevelopmental Genetics Project, University of Utah, 421 Wakara Way, Suite 143, Salt Lake City, UT 84108, USA b Department of Human Genetics, University of Utah, Salt Lake City, UT, USA c Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, MN, USA d Division of Biostatistics, Washington University, St. Louis, MO, USA e Cardiovascular Genetics, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA Received 23 September 2003; received in revised form 3 February 2004; accepted 5 February 2004 Available online 1 April 2004 Abstract Familial combined hyperlipidemia (FCHL) is the most common familial dyslipidemia, and is implicated in up to 20% of cases of premature coronary heart disease. Positive linkage to chromosome 1q was found in FCHL families participating in the NHLBI Family Heart Study (FHS), replicating linkage found in other studies. The HcB-19 mouse, which shares phenotypes with FCHL, was shown in other studies to have a nonsense mutation in the thioredoxin interacting protein gene (txnip). txnip is a gene on mouse chromosome 3 in a region syntenic with the 1q human FCHL linkage region. We re-sequenced the human homolog of mouse txnip in the FHS sample and identified nine single nucleotide polymorphisms (SNPs). We did not observe the nonsense mutation found in the HcB-19 mouse, and only three of the SNPs discovered were sufficiently polymorphic for analysis. No association between FCHL and the TXNIP gene was found. Within FCHL cases, presence of variants also did not significantly affect body mass index or levels of lipids, insulin, or glucose. Our results suggest that in this sample, TXNIP does not play a major role in FCHL or related traits, and is unlikely to account for the positive evidence of linkage in this region. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Hyperlipidemia; FCHL; TXNIP; Association; Linkage 1. Introduction Familial combined hyperlipidemia (FCHL) is the most common familial dyslipidemia with a prevalence of 1–2% [1], and is implicated in up to 20% of cases of premature CHD [2]. FCHL criteria require elevation in both serum total cholesterol and triglycerides within the family, with at least two affected first degree relatives [3]. Positive ev- idence for linkage to FCHL on chromosome 1q21–23 has been found in Finnish, US, Chinese, and German subjects [4–6]. Castellani et al. [7] mapped a region on mouse chro- mosome 3, syntenic to human 1q21–23, causing traits that ∗ Corresponding author. Tel.: +1-801-585-3068; fax: +1-801-585-9096. E-mail address: hilary@wilbur.med.utah.edu (H. Coon). mimic FCHL in the HcB-19 mouse strain. Subsequently, Bodnar et al. [8] cloned this gene in the HcB-19 mouse. They found reduced mRNA expression of thioredoxin inter- acting protein (txnip), and located a mutation resulting in a stop codon in the gene encoding txnip. This mutation caused differences in regulation of thioredoxin, resulting in an in- crease in plasma free fatty acids, triglycerides, cholesterol, and ketone bodies in the liver, as described in Bodnar et al. [8]. In the NHLBI Family Heart Study (FHS), there are 72 FCHL families comprising 170 hyperlipidemic subjects for a total of 134 affected sib-sib or sib-half sib pairs. Because the FCHL phenotype previously showed linkage to the chro- mosome 1q region in these same families [5], and because of the reported missense mutation in the mouse model, we chose to examine the TXNIP gene to determine its causal im- pact on clinical FCHL and related quantitative phenotypes. 0021-9150/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2004.02.004