¹Division of Endocrinology, Diabetes and Medical Genetics, Medical University of South Carolina, Charleston, SC 29403, USA

²Laboratory of Statistical Genetics, Rockefeller University, New York, NY 10021-6399, USA

³Lipid Research Clinic, Rikshospitalet, Pilestredet 32, N 0027 Oslo, Norway

⁴Department of Internal Medicine, Helsinki University Central Hospital, 00290 Helsinki, Finland

⁵University Medical Center Nijmegen, 6500 HB Nijmegen, The Netherlands

⁶Department of Human Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA

⁷Sanyo Electric Group Health Insurance Association, Kaneshita-cho, 2-11-10 Moriguchi, Osaka, Japan 570-0079

⁸Molecular Disease Branch, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892-1666, USA

⁹Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520-21, Japan

¹⁰Third Department of Medicine, Nagoya City University, Nagoya 467-861 Japan

¹¹Faculty of Medicine, Chemical Pathology, University of Natal, Congella 4013, South Africa

¹²Division of Gasteroenterology, University of Medicine and Dentistry New Jersey, Newark, NJ 07013, USA

Correspondence to: Shailendra B Patel, Division of Endocrinology, Diabetes and Medical Genetics, STR 541, MUSC, 114 Doughty Street, Charleston, SC 29403, USA. Tel: +1 843 876 5227; Fax: +1 843 876 5133; Email: patelsb@musc.edu

Sitosterolaemia (also known as phytosterolaemia, MIM 210250) is a rare recessive autosomal inherited disorder, characterised by the presence of tendon and tuberous xanthomas, accelerated atherosclerosis and premature coronary artery disease. The defective gene is hypothesised to play an important role in regulating dietary sterol absorption and biliary secretion, thus defining a molecular mechanism whereby this physiological process is carried out. The disease locus was localised previously to chromosome 2p21, in a 15 cM interval between microsatellite markers D2S1788 and D2S1352 (based upon 10 families, maximum lodscore 4.49). In this study, we have extended these studies to include 30 families assembled from around the world. A maximum multipoint lodscore of 11.49 was obtained for marker D2S2998. Homozygosity and haplotype sharing was identified in probands from non-consanguineous marriages from a number of families, strongly supporting the existence of a founder effect among various populations. Additionally, based upon both genealogies, as well as genotyping, two Amish/Mennonite families, that were previously thought not to be related, appear to indicate a founder effect in this population as well. Using both homozygosity mapping, as well as informative recombination events, the sitosterolaemia gene is located at a region defined by markers D2S2294 and Afm210xe9, a distance of less than 2 cM. European Journal of Human Genetics (2001) 9, 375-384.

genetics; homozygosity mapping; linkage; cholesterol; atherosclerosis; diet