ASSIGNMENT OF TANGIER-DISEASE TO CHROMOSOME 9Q31 BY A GRAPHICAL LINKAGE EXCLUSION STRATEGY

A low level of high density lipoprotein (HDL) cholesterol is a strong predictor of ischaemic heart disease (IHD) and myocardial infarction(1 -3). One cause of low HDL-cholesterol is Tangier disease (TD), an auto somal codominant inherited condition first described in 1961 in two si blings on Tangier Island in the United States of America(4). Apart fro m low HDL-cholesterol levels and an increased incidence of atheroscler osis(5), TD is characterized by reduced total cholesterol, raised trig lycerides, peripheral neuropathy and accumulation of cholesteryl ester s in macrophages, which causes enlargement of the liver, spleen and to nsils(4,6). In contrast to two other monogenic HDL deficiencies in whi ch defects in the plasma proteins apoA-I and LCAT interfere primarily with the formation of HDL (refs 7-10), TD shows a defect in cell signa lling and the mobilization of cellular lipids(11-14). The genetic defe ct in TD is unknown, and identification of the Tangier gene will contr ibute to the understanding of this intracellular pathway and of HDL me tabolism and its link with IHD. We report here the localization of the genetic defect in TD to chromosome 9q31, using a genome-wide graphica l linkage exclusion strategy in one pedigree, complemented by classica l rod score calculations at this region in a total of three pedigrees (combined lod 10.05 at D9S1784). We also provide evidence that TD may be due to a loss-of-function defect.