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Low-density lipoprotein receptor mutations generate synthetic genome-wide associations.

ABSTRACT: Genome-wide association (GWA) studies have discovered multiple common genetic risk variants related to common diseases. It has been proposed that a number of these signals of common polymorphisms are based on synthetic associations that are generated by rare causative variants. We investigated if mutations in the low-density lipoprotein receptor (LDLR) gene causing familial hypercholesterolemia (FH, OMIM #143890) produce such signals. We genotyped 480?254 polymorphisms in 464 FH patients and in 5945 subjects from the general population. A total of 28 polymorphisms located up to 2.4?Mb from the LDLR gene were genome-wide significantly associated with FH (P<10(-8)). We replicated the 10 top signals in 2189 patients with a clinical diagnosis of FH and in 2157 subjects of a second sample of the general population (P<0.000087). Our findings confirm that rare variants are able to cause synthetic genome-wide significant associations, and that they exert this effect at relatively large distances from the causal mutation.

SUBMITTER: Oosterveer DM

PROVIDER: S-EPMC3641383 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Low-density lipoprotein receptor mutations generate synthetic genome-wide associations.

Oosterveer Daniëlla M DM Versmissen Jorie J Defesche Joep C JC Sivapalaratnam Suthesh S Yazdanpanah Mojgan M Mulder Monique M van der Zee Leonie L Uitterlinden André G AG van Duijn Cornelia M CM Hofman Albert A Kastelein John J P JJ Aulchenko Yurii S YS Sijbrands Eric J G EJ

European journal of human genetics : EJHG 20120912 5

Genome-wide association (GWA) studies have discovered multiple common genetic risk variants related to common diseases. It has been proposed that a number of these signals of common polymorphisms are based on synthetic associations that are generated by rare causative variants. We investigated if mutations in the low-density lipoprotein receptor (LDLR) gene causing familial hypercholesterolemia (FH, OMIM #143890) produce such signals. We genotyped 480 254 polymorphisms in 464 FH patients and in ...[more]

PMID: 22968135

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Project description:Liver X receptor (LXR) agonists have the potential to treat atherosclerosis based on their ability to enhance reverse cholesterol transport. However, their side effects, such as induction of liver lipogenesis and triglyceridemia, may limit their pharmaceutical development. In contrast to the nonsteroidal LXR agonist N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317), 3alpha, 6alpha, 24-trihydroxy-24, 24-di(trifluoromethyl)-5beta-cholane (ATI-829), a novel potent synthetic steroidal LXR agonist, was a poor inducer of sterol regulatory element-binding protein 1c expression in hepatoma HepG2 cells, whereas both compounds increased ABCA1 expression in macrophage THP-1 cells. In male low-density lipoprotein receptor-deficient mice, ATI-829 selectively activated LXR target gene expression in mouse intestines and macrophages but not in the liver. A significant increase in liver triglyceride and plasma triglyceriderich small very low-density lipoprotein (VLDL) was observed in T0901317 but not ATI-829-treated mice. Compared with vehicle-treated mice, atherosclerosis development was significantly inhibited in the innominate artery after treatment with either compound. However, in the aortic root, inhibition of atherosclerosis was only observed in the right (right coronary artery-associated sinus) but not the left coronary-related sinus (left coronary artery-associated sinus; LC) of mice treated with either compound. Lesions in the innominate artery were less complex after treatment with either compound and contained mostly macrophage foam cells. In contrast, LC lesions were more complex and had a large collagen-positive fibrous cap and less macrophage foam cell area after treatment with either compound. The T0901317-induced hypertriglyceridemia was accompanied by an increase in small triglyceride-rich VLDL that may influence LXR agonist-mediated antiatherosclerotic effects at certain vascular sites. ATI-829, by selectively activating LXR in certain tissues without inducing hypertriglyceridemia, is a good candidate for drug development.

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Low-density lipoprotein receptor mutations generate synthetic genome-wide associations.

Publications

Low-density lipoprotein receptor mutations generate synthetic genome-wide associations.

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