A Frequent Mutation in the Lipoprotein Lipase Gene (D9N) Deteriorates the Biochemical and Clinical Phenotype of Familial Hypercholesterolemia

Abstract

Abstract-The D9N substitution is a common mutation in the lipoprotein lipase (LPL) gene. This mutation has been associated with reduced levels of HDL cholesterol and elevated triglycerides (TG) in a wide variety of patients. We investigated the influence of this D9N mutation on lipid and lipoprotein levels and risk for cardiovascular disease (CVD) in patients with familial hypercholesterolemia (FH). A total of 2091 FH heterozygotes, all of Dutch extraction, were screened for the D9N mutation using standard polymerase chain reaction techniques, followed by specific enzyme digestion. A total of 94 FH subjects carrried the D9N mutation at a carrier frequency of 4.5%. Carriers of other common LPL mutations, such as the N291S and the S447X were excluded. Clinical data on 80 FH individuals carrying the D9N were available and were compared with a FH control group matched for age, sex, and body mass index (nϭ203). Analysis revealed significantly higher TG (Pϭ0.01) and lower HDL-cholesterol levels (Pϭ0.002). Dyslipidemia was more pronounced in D9N carriers with higher body mass index. Moreover, FH patients carrying this common LPL mutation were at higher risk for CVD, (odds ratioϭ2. LPL has also been proposed as a key protein in the retention of lipoproteins in the arterial wall by enabling their adherence to extracellular matrix. 4 Moreover, local secretion of LPL by macrophages and its postulated function as a monocyte adhesion protein may favor foam cell formation, a key initial step in atherogenesis. 5,6 Both homozygous and heterozygous LPL deficiency have been demonstrated to predispose to premature CAD and increased progression of coronary atherosclerosis. [7][8][9] In addition, low LPL activity has been associated with markers of decreased vascular compliance such as elevated systolic blood pressure, decreased nitric oxide production, and decreased forearm bloodflow. 10,11 One amino acid substitution in the LPL protein, D9N, underlies heterozygosity for LPL deficiency in approximately 2% to 5% of Caucasians and is therefore a very common variant in the general population. 12,13 This D9N mutation leads to increased TG and decreased HDL cholesterol levels and promotes the progression of angiographically assessed coronary atherosclerosis. 9,12,13 A recent meta-analysis reported that this variant carried a summary odds ratio of 1.59, representing a 59% increase in CAD risk. 1 A number of studies into this D9N mutation, however, have indicated that full expression of the associated atherogenic lipoprotein profile requires the presence of additional environmental or genetic factors. 13,14

Lipoprotein lipase

“…However, a hyperchylomicronemic patient who was heterozygous for Tyr262His and Asp9Asn has been reported (43). Asp9Asn has been linked frequently to hypertriglyceridemia, low HDL, small dense LDL, FCHL and increased risk of CAD, especially if combined with other risk factors (21,(44)(45)(46). According to a meta-analysis by Wittrup, Tybjaerg-Hansen, and Nordestgaard (33), Asp9Asn leads to a 20% increase in TGs, 0.8 mmol/l (3.2 mg/dl) decrease in HDL, and 1.4-fold increased risk of ischemic heart disease, borderline significant.…”

Diagnosis and screening for familial hypercholesterolaemia: finding the patients, finding the genes

“…The mutations causing the enzyme de¢ciency generally do not confer an increased risk of CHD, but when occurring in the presence of FH, there are reports of increased cardiovascular risk, although in another report LDL levels were quite low. 92,93 The e¡ect of other genetic factors such as cholesteryl ester transfer protein (CETP), 94,95 microsomal triglyceride transfer protein (MTP), 96 hepatic lipase, fatty acid-binding protein, 97 methylene tetrahydrofolate reductase (MTHFR), 98 ATP-binding cassette A1 (ABCA1), 99 renin--angiotensin 100 and paraoxonase 101,102 have been described, but it would seem that it is rare for them to exert a major in£uence on the FH phenotype. Gender does seem to have a major in£uence on the FH phenotype, 77 with women demonstrating clinical features of CHD later than men, but earlier than women without FH.…”

Étude d'association entre des polymorphismes de la lipase liprotéique et des facteurs de risque de maladies cardiovasculaires au sein d'une cohorte de travailleurs forestiers du Saguenay-Lac-Saint-Jean /

“…D9N a une fréquence d'hétérozygote dans la population caucasienne de 2 à 4% . Elle a fréquemment été associée à l'hypertriglycéridémie, à un niveau bas de C-HDL, à la présence de LDL petites et denses, à de l'hyperlipidémie familiale combinée (FCHL) et à une augmentation des risques de maladies cardiovasculaires (Hokanson et al, 1999;Wittekoek et al, 1999;van Bockxmeer et al, 2001). …”