A COMMON MUTATION IN THE LIPOPROTEIN-LIPASE GENE PROMOTER, -93T G, ISASSOCIATED WITH LOWER PLASMA TRIGLYCERIDE LEVELS AND INCREASED PROMOTER ACTIVITY IN-VITRO/

Single-strand conformational polymorphism analysis of the lipoprotein lipase promoter identified a T-->G transition at position -93. The fre quency in healthy white men was 3.4% (n=1575). There was an 83% alleli c association between -93T-->G and Asp(9)-->Asn (D9N); all N9 mutation s occurred on a -93G allele, but not all -93G mutations occurred on an N9 allele. It was thus possible to assess the effect on plasma trigly ceride (Tg) levels of the rare -93G mutation in the presence of the wi ld-type D9. Carriers of the -93G, with genotype TG/DD, had significant ly lower Tg levels than TT/DD individuals (1.36 versus 1.78 mmol/L, P= .01); carriers of both mutations (TG/DN) had the highest Tg levels (1. 93 mmol/L). When the group was stratified above and below the sample m ean for body mass index (BMI), carriers of the -93G on a D9 allele (TG /DD) were ''protected'' against the Tg-raising effect of obesity, as a ssessed by BMI. In Afro-Caribbeans (n=91), the carrier frequency of -9 3G was 18-fold higher (63%), with weaker (17%) allelic association bet ween -93G and N9. In vitro, the -93G promoter had 24% higher activity than the -93T in a rat smooth muscle cell line and 18% higher activity in a human adrenal cell line. A protein identified by band-shift assa ys bound to the -93G but not to the -93T allele, which may explain the lower Tg levels in -93G carriers.