COMMON C-TO-T SUBSTITUTION AT POSITION--480 OF THE HEPATIC LIPASE PROMOTER ASSOCIATED WITH A LOWERED LIPASE ACTIVITY IN CORONARY-ARTERY DISEASE PATIENTS

We studied the molecular basis of low hepatic lipase (HL) activity in normolipidemic male patients with angiographically documented coronary artery disease (CAD). In 18 subjects with a lowered HL activity (<225 mU/mL), all nine exons of the HT,gene and part of the promoter region (nucleotides -524 to +7) were sequenced. No structural mutations in t he coding part of the HL gene were found, but 50% of the subjects show ed a C-to-T substitution at nucleotide -480. Screening for the base su bstitution in 782 patients yielded an allele frequency of 0.213 (297 h eterozygotes, 18 homozygotes). In a group of 316 nonsymptomatic contro l subjects, the allele frequency was 0.189, which is significantly les s than in the CAD patients (P=.035). In the CAD patients, the C-to-T s ubstitution was associated with a lowered lipase activity (heterozygot es -15%, homozygotes -20%). The patients were divided into quartiles o n the basis of HL activity. Sixty percent (allele frequency 0.32) of t he patients in the lowest quartile (HL activity <306 mU/mL) had the ge ne variant against 27% (allele frequency 0.14) in the highest quartile (HL activity >466 mU/mL). In the noncarriers, but not in the carriers , HL activity was related with plasma insulin, being increased at high er insulin concentration. Homozygous carriers had a significantly high er HDL cholesterol level than noncarriers (1.13+/-0.28 mmol/L versus 0 .92+/-0.22 mmol/L, P<.02). Our results show that a C-to-T substitution at -480 of the HL promoter is associated with a lowered HL activity. The base substitution, or a;closely linked gene variation, may contrib ute to the variation in HL activity and affect plasma lipoprotein meta bolism.