High plasma apolipoprotein B (apoB) and LDL cholesterol levels increase cardiovascular disease risk. These highly correlated measures may be partially controlled by common genetic polymorphisms. To identify chromosomal regions that contain genes causing low plasma levels of one or both parameters in Caucasian families ascertained for familial hypobetalipoproteinemia (FHBL), we conducted a wholegenome scan using 443 microsatellite markers typed in nine multigenerational families with at least two members with FHBL. Both variance components and regression-based linkage methods were used to identify regions of interest. Common linkage regions were identified for both measures on chromosomes 10q25.1-10q26.11 [maximum log of the odds (LOD) 5 4.2 for LDL and 3.5 for apoB] and 6q24.3 (maximum LOD 5 1.46 for LDL and 1.84 for apoB). There was also evidence for linkage to apoB on chromosome 13q13.2 (LOD 5 1.97) and to LDL on chromosome 3p14.1 at 94 centimorgan (LOD 5 1.52). Bivariate linkage analysis provided further evidence for loci contributing to both traits (6q24.3, LOD 5 1.43; 10q25.1, LOD 5 1.74). We evaluated single nucleotide polymorphisms (SNPs) in genes within our linkage regions to identify variants associated with apoB or LDL levels. The most significant finding was for rs2277205 in the 5 ¶ untranslated region of acyl-coenzyme A dehydrogenase short/branched chain and LDL (P 5 10 27 ). Three additional SNPs were associated with apoB and/or LDL (P , 0.01). Although only the linkage signal on chromosome 10 reached genome-wide statistical significance, there are likely multiple chromosomal regions with variants that contribute to low levels of apoB and LDL and that may protect against coronary heart disease.-Sherva, R., P. Yue, G. Schonfeld, and R. J. Neuman. High plasma apolipoprotein B (apoB) and LDL cholesterol concentrations are equally and independently associated with an increased long-term relative risk of coronary heart disease (1, 2). Patients in the highest tertile of apoB and LDL have an ?2-fold increase in coronary heart disease risk over those in the lower tertiles after multivariate adjustment. Other studies suggest that increased apoB levels may be associated with an even greater risk of coronary heart disease than high LDL cholesterol concentrations (3, 4).Data from twin studies show that there is a strong heritability for apoB and LDL levels (5, 6), and numerous genome scans have attempted to identify loci linked to lipid levels. A recent summary of the results from various lipid genome scans lists significant or suggestive evidence for linkage on chromosomes 1, 2, 3, 6, and 11 for apoB and on chromosomes 1,3,4,5,6,10,11,13,15,17,19, and X for LDL (7). In addition, linkage scans for loci influencing both traits have identified regions on chromosomes 2, 11, and 18 (7).In this study, we performed genome-wide linkage analysis in a cohort of Caucasian families ascertained for familial hypobetalipoproteinemia (FHBL). FHBL is a disorder in which subjects have extremely low levels of apoB and L...