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

BACKGROUND: 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.

METHODS: We obtained genotypes for 9238 individuals from The Copenhagen City Heart Study, of which 465 had stroke and 1019 had ischaemic heart disease.

RESULTS: 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.

CONCLUSION: 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.