Lipoprotein lipase and apolipoprotein E polymorphisms : relationship to hypertriglyceridemia associated with pregnancy
Creators: name: McGladdery, Sandra Helen
Publisher: name: University of British Columbia
Year: 2009

description: Normal pregnancy is associated with a mild increase in plasma total cholesterol (TC) and a 3 to 4-fold increase in plasma triglycerides (TG). Plasma TG concentration is determined by the balance between the rate of production of TG-rich lipoproteins and the rate of removal of these lipoproteins from the circulation by lipolytic enzymes such as lipoprotein lipase (LPL) and hepatic lipase (HL) and its subsequent uptake by the liver through apo E receptor. Complete deficiency of LPL is manifested as chylomicronemia, a rare autosomal co-dominant disorder. While heterozygous individuals rarely present with chylomicronemia they may have a milder form of hypertriglyceridemia. Variations in the apo E gene have also been associated with increases in plasma TG in addition to changes in plasma TC, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Because of the overproduction of TG-rich VLDL, normal pregnancy challenges the lipolytic capacity of LPL and the ability to clear remnants via the apo E receptor. Cases of chylomicronemia and pancreatitis occurring during pregnancy have been reported in previously healthy women. During the course of pregnancy, LPL and apo E polymorphisms may cause TG levels to increase. It is hypothesized that pregnant women carrying some of these polymorphisms will develop more severe hypertriglyceridemia during the course of pregnancy. The objective of this thesis is to investigate the impact of three known LPL polymorphisms (Asp9Asn, Asn291 Ser, Ser447X) and the apo E genotype (4/4, 4/3, 3/3, 3/2, 2/4, 2/2) on lipid levels during pregnancy. Two hundred and fifty healthy women in the 3rd trimester of pregnancy were recruited. Fasting plasma TG, TC, HDL-C, LDL-C, insulin, glucose and fractional esterification rate of HDL (FER[sub HDL]) were measured. Analysis of the LPL and apo E genes' polymorphisms were performed, in addition to sequencing of the LPL gene in 5 women with the highest TG levels. The frequencies of the LPL (D9N, 0.9%; N291S, 4.6%; S447X, 18%) and the apo E (E2, 7.6%; E3, 81.4 %, E4, 11.0%) polymorphisms were similar to previously published results in non-pregnant women. Carriers of S447X had significantly lower TG levels (p=0.003), and carriers of the N291S had significantly lower HDL-C levels (p&lt;0.02) and higher FER[sub HDL] (p=0.007) than the non-carriers. The small number of D9N carriers did not permit statistical analysis of the data. Possession of the E2 allele was associated with significantly lower levels of TC, LDL-C and FERHDL (p&lt;0.05) compared to E3/E3, and carriers of the apo E4 allele had increased plasma insulin levels compared to E3/E3. Sequencing of the LPL gene lead to the discovery of a new intron mutation in one of the women, which may be, at least in part, responsible for her increased TG levels. These findings support the notion that LPL and apo E polymorphisms play an important role in TG metabolism. We demonstrated that this observation extends to the pregnant state. The effect of these polymorphisms during pregnancy on lipid levels and its relationship to future risk of coronary artery disease in these women remains unclear and requires further study.