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Journal of Lipid Research, Vol. 45, 1660-1665, September 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Polymorphisms in the ABCG5 and ABCG8 genes associate with cholesterol absorption and insulin sensitivity

Helena Gylling^1,*, Maarit Hallikainen^*, Jussi Pihlajamäki, Jyrki Ågren, Markku Laakso, Radhakrishnan A. Rajaratnam^**, Rainer Rauramaa and Tatu A. Miettinen^**

^* Departments of Clinical Nutrition, University of Kuopio, and Kuopio University Hospital, Kuopio, Finland
Medicine, University of Kuopio, and Kuopio University Hospital, Kuopio, Finland
Physiology, University of Kuopio, and Kuopio University Hospital, Kuopio, Finland
Kuopio Research Institute of Exercise Medicine, Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland
^** Division of Internal Medicine, Department of Medicine, University of Helsinki, Helsinki, Finland

¹ To whom correspondence should be addressed. e-mail: helena.gylling{at}uku.fi

The roles of polymorphisms of the sitosterolemia genes ABCG5 and ABCG8 in the regulation of cholesterol metabolism and insulin sensitivity were studied in mildly hypercholesterolemic noncoronary subjects (n = 263, 144 men and 119 women) divided into tertiles by baseline serum cholestanol-to-cholesterol ratio (118.3 and 147.7 10² x mmol/mol cholesterol), a surrogate marker of cholesterol absorption efficiency. The lowest cholestanol tertile was associated with high body mass index (BMI), plasma glucose, serum insulin and triglycerides, and cholesterol synthesis markers (cholestenol, desmosterol, lathosterol) and low HDL cholesterol and cholesterol absorption markers (campesterol, sitosterol) (P <0.01 for all). The 19H allele of the ABCG8 gene accumulated in the lowest cholestanol tertile (P < 0.001) and was associated with low total and LDL cholesterol and absorption markers and with high synthesis markers (P < 0.05 for all). The 604E allele of the ABCG5 gene in men was associated with high BMI, plasma insulin, low serum sitosterol, and high serum cholestenol levels (P < 0.05 for all). In a subgroup of 71 men, the 604E allele was associated with insulin resistance measured with the hyperinsulinemic euglycemic clamp.

In conclusion, low cholesterol absorption efficiency was associated with characteristics of the metabolic syndrome. Low serum cholesterol and cholesterol absorption were linked to the D19H polymorphism of the ABCG8 gene, and characteristics of the insulin resistance syndrome in men were linked with the Q604E polymorphism of the ABCG5 gene.

Supplementary key words cholesterol synthesis • phytosterols • lathosterol

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