PURPOSE:Persons with total cholesterol (TC) levels less than 130 mg/dL (less than 3.26 mmol/L) make up less than 1% of a healthy population. Causes of hypocholesterolemia include a diet very low in cholesterol and saturated fat, disease, genetic factors (including low apolipoprotein B-100 [apo B-100] and the apo E allele), and drug therapy. The purpose of this study was to determine the causes of hypocholesterolemia in a healthy Kaiser Foundation Health Plan (KFHP) population. PATIENTS AND METHODS:We conducted a dietary and health survey of 201 healthy hypocholesterolemic adults (range: 2.04 to 3.88 mmol/L [79 to 150 mg/dL]) and 200 matched control subjects with TC levels in the middle quintile of the population (range: 5.0 to 5.61 mmol/L [194 to 217 mg/dL]) who had routine health screening from 1983 through 1985. We did apo E phenotyping studies and lipid and apo A-1 and B-100 measurements in a subgroup of 45 hypocholesterolemic subjects (mean TC level: 3.26 mmol/L [126 mg/dL]) and in a comparison group of 49 unmatched volunteers (mean TC level: 5.04 +/- 0.75 mmol/L [195 +/- 29 mg/dL]). RESULTS:We found no differences in dietary intake or clinically significant medical illness between hypocholesterolemic and control subjects. In the hypocholesterolemic subgroup, we found an increased frequency of the apo E2 allele (epsilon 2) and a decreased frequency of the apo E4 allele (epsilon 4); the frequencies of the epsilon 2, epsilon 3, and epsilon 4 alleles were 33.3%, 63.3%, and 3.3%, respectively. The corresponding apo E allele frequencies in the comparison subgroup were 8.2%, 73.5%, and 18.4%, similar to those previously reported for the general population and significantly different from those found in the hypocholesterolemic subgroup (p < 0.0001). One hypocholesterolemic subject (a 46th patient) had a mutation in the apo B gene that resulted in the synthesis of a truncated species of apo B (apo B-46). CONCLUSION:Our study indicates that hypocholesterolemia in our KFHP urban population is usually not caused by diet or disease. Biochemical factors, including the increased frequency of the apo E-2 phenotype and the decreased frequency of the apo E-4 phenotype, are more important.