A cholesterol-lowering gene maps to chromosome 13q

A cholesterol-lowering gene has been postulated from familial hypercholeste rolemia (FH) families having heterozygous persons with normal LDL levels an d homozygous individuals with LDL levels similar to those in persons with h eterozygous FH. We studied such a family with FH thar also had members with out FH and with lower-than-normal LDL levels. We performed linkage analyses and identified a locus at 13q, defined by markers D13S156 and D13S158. FAS TLINK and GENE-HUNTER yielded LOD scores >5 and >4, respectively, whereas a n affected-sib-pair analysis gave a peak multipoint LOD score of 4.8, corre sponding to a P value of 1.26 x 10(-6). A multipoint quantitative-trait-loc us (QTL) linkage analysis with maximum-likelihood binomial QTL verified thi s locus as a QTL for LDL levels. To test the relevance of this QTL in an in dependent normal population, we studied MZ and DZ twin subjects. An MZ-DZ c omparison confirmed genetic variance with regard to lipid concentrations. W e then performed an identity-by-descent linkage analysis on the DZ twins, w ith markers at the 13q locus. We found strong:evidence for linkage at this locus with LDL (P<.0002), HDL (P<.004), total cholesterol (P<.0002), and bo dy-mass index (P<.0001). These data provide support for the existence of a new gene influencing lipid concentrations in humans.