© 1995 American Heart Association, Inc.
Articles |
A Common Variant in the Gene for Lipoprotein Lipase (Asp9
Asn)
Functional Implications and Prevalence in Normal and Hyperlipidemic Subjects
From the Division of Cardiovascular Genetics, Department of Medicine, UCL Medical School, Rayne Institute, London, UK (F.M., S.E.H., P.J.T.); the Department of Medical Biochemistry and Biophysics, University of Umea, Umea, Sweden (Y.T., G.O.); the Lipid Research Group, Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands (P.W.A.R., T.B., B.F.G., J.J.P.K.); the Department of Medicine, Charing Cross Hospital, London, UK (M.S.); the Atherosclerosis Research Unit, King Gustaf V Research Institute, Stockholm, Sweden (A.A.-C., A.H.); the Department of Chemical Pathology and Human Metabolism, Royal Free Hospital School of Medicine, London, UK (D.V., A.F.W.); and the MRC Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine, The Medical College of St Bart's Hospital, London, UK (G.J.M.).
Correspondence to Dr Philippa Talmud, Department of Medicine, Division of Cardiovascular Genetics, University College London Medical School, The Rayne Institute, University St, London, WC1E 6JJ England.
Abstract Subjects with combined hyperlipidemia (CHL) were
screened for mutations 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 identified in 2 individuals. Because this
substitution destroys a recognition site for Taq I, pooling
of DNA samples, amplification, and digest with Taq I allowed
the rapid screening of 1563 healthy individuals and patients of Dutch,
Swedish, English, and Scottish origin. In the general populations of
all four countries, healthy carriers of the mutation were 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
atherosclerosis; the frequency was consistently higher in each patient
group compared with its matched control group. In 773 healthy men from
two general practices in the United Kingdom, 25 carriers and 2
homozygotes for the mutation were identified. In these 27, plasma
triglyceride 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 activity data were
available for some carriers and for 7 of 9 individuals from the
patient groups, and 6 of 6 individuals from the control groups had LPL
activity that was lower than the respective group mean. In vitro
mutagenesis and transient expression in COS cells showed that compared
with the LPL-Asp9 construct, LPL-Asn9 activity and mass were reduced by
20% to 30% in the culture media. Overall however, LPL-Asn9 had only
slightly reduced specific activity (by 18%). Thus, although the
precise mechanism of the effect is unclear, the data strongly suggest
that the LPL-Asn9 variant is associated with and may play a direct role
in predisposing carriers to develop hypertriglyceridemia.
Key Words: familial combined hyperlipidemia • genetic predisposition • lipoprotein lipase
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