Mutation screening and association of human retinoid X receptor variation with lipid levels in familial type 2 diabetes

Authors: Wang H.¹; Chu W.¹; Hemphill C.¹; Hasstedt S.J.²; Elbein S.C.¹

Source: Molecular Genetics and Metabolism, Volume 76, Number 1, May 2002 , pp. 14-22(9)

Publisher: Academic Press

Abstract:

Both type 2 diabetes (T2DM) and familial combined hyperlipidemia have been mapped to human chromosome 1q21–q24. This region includes the retinoid X receptor (RXR), which is a strong candidate for both glucose and lipid metabolism. Retinoid X receptors form heterodimers with a variety of nuclear receptors, including peroxisome-proliferator-activated receptors and(PPAR andPPAR), and are synergistic targets for drugs that alter glucose and lipid metabolism. We hypothesized thatRXR variation could explain the linkage of diabetes and lipid disorders to this region. We screened each of the 10 exons, the flanking intronic sequences, the3 untranslated region, and the 5 flanking region. We identified 14 variants, none of which altered the coding sequence. Of the 10 variants examined in a diabetes case-control study, three showed nominal(p<0.05) associations with T2DM. We subsequently typed four variants in all members of the 63 multiplex families used in our previous linkage analysis. No individual variant showed excess transmission to offspring with T2DM using a transmission disequilibrium test and only a single rare haplotype showed evidence of an association with T2DM. Likewise, neither individual variants nor haplotypes were associated with either fasting or post-challenge glucose in non-diabetic subjects. In contrast, three of the four variants were associated with fasting free fatty acid (FFA) levels (p=0.024–0.00044) and two variants were associated with triglyceride levels(p<0.05). These findings were supported by the association of several haplotypes with FFA and triglyceride levels.RXR haplotypes were also associated with several measures of pancreatic-cell function, consistent with the proposed role of lipid metabolism in insulin secretion. These data suggest that RXR may contribute to disordered lipid metabolism in members of familial T2DM kindreds, but this gene is unlikely to explain the linkage of T2DM with this region.

© 2002 Elsevier Science (USA)

Language: English

Document Type: Research article

Affiliations: 1: Central Arkansas Veterans Healthcare System and Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA 2: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA

Publication date: 2002-05-01

• In this: publication
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• In this Subject: Anatomy & Physiology ,  Biology ,  Biochemistry
• By this author: Wang H. ;  Chu W. ;  Hemphill C. ;  Hasstedt S.J. ;  Elbein S.C.

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