Single nucleotide polymorphism in the low-density lipoprotein receptor is associated with a threefold risk of strokeA case-control and prospective study

More than 600 different, but rare, mutations in the low-density lipoprotein (LDL) receptor have been identified as the cause of familial hypercholesterolaemia. In contrast, only a single common amino acid-changing polymorphism (A370T) has been reported in this gene. The association of this polymorphism with variations in lipid levels is at present unclear.We obtained genotypes for 9238 individuals from The Copenhagen City Heart Study, of which 465 had stroke and 1019 had ischaemic heart disease.In this cohort from the Danish general population, 90.2% (n = 8,332), 9.5% (n = 875), and 0.3% (n = 31) were 370A homozygotes, A370T heterozygotes, and 370T homozygotes, respectively. The incidences of stroke in 370A homozygotes, A370T heterozygotes, and 370T homozygotes were 28, 26, and 100 per 10,000 person-years, respectively (370T homozygotes vs. 370A homozygotes: log-rank, P = 0.002). The relative risk and odds ratio for stroke in 370T homozygotes vs. 370A homozygotes were 3.6 (95% confidence interval, 1.5-8.8) and 3.6 (95% confidence interval, 1.3-9.8) in prospective and cross-sectional studies, respectively. Furthermore, average age at onset of stroke in 370T homozygotes tended to be lower than in heterozygotes and 370A homozygotes combined (59 vs. 66 years, P = 0.08). In contrast, neither levels of cholesterol, LDL cholesterol, apolipoprotein B, or triglycerides, nor risk of ischaemic heart disease was associated with genotype.This is the first prospective study to suggest an association between a polymorphism in the LDL receptor and stroke. Because this association is independent of lipid levels, our results point toward a hitherto unknown function of this receptor in the brain.