A frequent mutation in the lipoprotein lipase gene (D9N) deteriorates the biochemical and clinical phenotype of familial hypercholesterolemia

The D9N substitution is a common mutation in the lipoprotein lipase (LPL) g ene, This mutation has been associated with reduced levels of HDL cholester ol and elevated triglycerides (TG) in a wide variety of patients. We invest igated the influence of this D9N mutation on lipid and lipoprotein levels a nd risk for cardiovascular disease (CVD) in patients with familial hypercho lesterolemia (FH). A total of 2091 FH heterozygotes, all of Dutch extractio n, were screened for the D9N mutation using standard polymerase chain react ion techniques, followed by specific enzyme digestion. A total of 94 FH sub jects carried 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 (n = 203). Analysis revealed significantly higher TG (P = 0.01) and lower HDL-cholesterol levels (P = 0.002). 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 ratio = 2.8; 95% CI, 1.43 to 5.32; P = 0.002), The common D9N LPL mutation leads to increased T G and decreased HDL plasma levels in patients with FH. These effects are mo st apparent in those FH heterozygotes with an increased body mass index. Fu rthermore, this mutation, present in 4.5% of Dutch FH heterozygotes, leads to increased risk for CVD.