A COMMON VARIANT IN THE GENE FOR LIPOPROTEIN-LIPASE (ASP9-]ASN) FUNCTIONAL IMPLICATIONS AND PREVALENCE IN NORMAL AND HYPERLIPIDEMIC SUBJECTS

Subjects with combined hyperlipidemia (CHL) were screened for mutation s in the lipoprotein lipase (LPL) gene by single-strand conformational polymorphism, and a previously reported G-->A DNA sequence change in exon 2, causing substitution of Asp by Asn at position 9, was identifi ed in 2 individuals. Because this substitution destroys a recognition site for Tag I, pooling of DNA samples, amplification, and digest with Tag I allowed the rapid screening of 1563 healthy individuals and pat ients of Dutch, Swedish, English, and Scottish origin. In the general populations of all four countries, healthy carriers of the mutation we re detected at a frequency of 1.6% to 4.4% (mean, 3.0%; 95% confidence interval, 2.0% to 4.0%). The frequency of carriers was roughly twice as high (range, 4.0% to 9.8%) in selected patients with CHL or type IV hyperlipoproteinemia or in subjects with angiographically assessed at herosclerosis; the frequency was consistently higher in each patient g roup compared with its matched control group. In 773 healthy men from two general practices in the United Kingdom, 25 carriers and 2 homozyg otes for the mutation were identified. In these 27, plasma triglycerid e but not plasma cholesterol levels were significantly higher than in noncarriers (2.25 versus 1.82 mmol/L, P<.02), and this difference was maintained in three subsequent annual measurements. Postheparin LPL ac tivity data were available for some carriers and for 7 of 9 individual s from the patient groups, and 6 of 6 individuals from the control gro ups had LPL activity that was lower than the respective group mean. In vitro mutagenesis and transient expression in COS cells showed that c ompared with the LPL-Asp9 construct, LPL-Asn9 activity and mass were r educed by 20% to 30% in the culture media. Overall however, LPL-Asn9 h ad only slightly reduced specific activity (by 18%). Thus, although th e precise mechanism of the effect is unclear, the data strongly sugges t that the LPL-Asn9 variant is associated with and may play a direct r ole in predisposing carriers to develop hypertriglyceridemia.