Common polymorphisms in the CYP7A1 gene do not contribute to variation in rates of bile acid synthesis and plasma LDL cholesterol concentration

Abrahamsson, Anna; Krapivner, Sergey; Gustafsson, Ulf; Muhrbeck, Olle; Eggertsen, Gösta; Johansson, Inger; Persson, Irene; Angelin, Bo; Ingelman-Sundberg, Magnus; Björkhem, Ingemar; Einarsson, Curt; Hooft, Ferdinand M. van’t

doi:10.1016/j.atherosclerosis.2005.01.032

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Volume 182, Issue 1 , Pages 37-45, September 2005

Common polymorphisms in the CYP7A1 gene do not contribute to variation in rates of bile acid synthesis and plasma LDL cholesterol concentration

Anna Abrahamsson
- Department of Medicine, Division of Gastroenterology and Hepatology, Karolinska Institute at Huddinge University Hospital, SE-14186 Stockholm, Sweden
- These authors made equal contributions to the study.
Sergey Krapivner
- The Atherosclerosis Research Unit, King Gustaf V Research Institute, Department of Medicine, Karolinska Institute at Karolinska Hospital, SE-17176 Stockholm, Sweden
- These authors made equal contributions to the study.
Ulf Gustafsson
- Department of Surgery, Karolinska Institute at Danderyd Hospital, SE-18288 Danderyd, Sweden
Olle Muhrbeck
- Department of Surgery, Karolinska Institute at Danderyd Hospital, SE-18288 Danderyd, Sweden
Gösta Eggertsen
- Department of Clinical Chemistry, Karolinska Institute at Huddinge University Hospital, SE-14186 Stockholm, Sweden
Inger Johansson
- Department of Environmental Medicine, Division of Molecular Toxicology, Karolinska Institute, SE-17177 Stockholm, Sweden
Irene Persson
- Department of Environmental Medicine, Division of Molecular Toxicology, Karolinska Institute, SE-17177 Stockholm, Sweden
Bo Angelin
- Center for Metabolism and Endocrinology, Karolinska Institute at Huddinge University Hospital, SE-14186 Stockholm, Sweden
Magnus Ingelman-Sundberg
- Department of Environmental Medicine, Division of Molecular Toxicology, Karolinska Institute, SE-17177 Stockholm, Sweden
Ingemar Björkhem
- Department of Clinical Chemistry, Karolinska Institute at Huddinge University Hospital, SE-14186 Stockholm, Sweden
Curt Einarsson
- Department of Medicine, Division of Gastroenterology and Hepatology, Karolinska Institute at Huddinge University Hospital, SE-14186 Stockholm, Sweden
Ferdinand M. van’t Hooft
- The Atherosclerosis Research Unit, King Gustaf V Research Institute, Department of Medicine, Karolinska Institute at Karolinska Hospital, SE-17176 Stockholm, Sweden
- Corresponding author. Tel.: +46 8 51773201; fax: +46 8 311298.

Received 4 November 2004; received in revised form 18 January 2005; accepted 26 January 2005.

Abstract

Transcriptional regulation of the cholesterol 7α-hydroxylase (CYP7AI) gene is of critical importance for bile acid and cholesterol metabolism. We evaluated the physiological significance of two common polymorphisms (−203C/A and −469T/C) in the promoter region of the CYP7AI gene. No evidence was found for physiological differences between either the −203C and −203A alleles or the −469T and −469C alleles in transient transfection studies using native 834bp promoter constructs. Moreover, no association was observed between the CYP7AI promoter polymorphisms and the hepatic cholesterol 7α-hydroxylase activity and parameters of bile acid synthesis rates, as analyzed in subjects with gallstone disease. In addition, no relationships were found between the promoter polymorphisms and plasma LDL cholesterol concentration in association studies conducted in three different groups of middle-aged Swedish men. Finally, near complete allelic association was found between the two promoter polymorphisms and the IVS6+363G/A polymorphism at the 3′ end of the CYP7AI gene (|D′|=0.98), indicating strong linkage disequilibrium across the whole CYP7AI gene.

It is concluded that common polymorphisms of the CYP7A1 gene do not contribute to variation in cholesterol 7α-hydroxylase activity, rates of bile acid synthesis and plasma LDL cholesterol concentration in humans.

Keywords: DNA, Lipoproteins, Restriction fragment length polymorphism, Low density lipoprotein