Lipoprotein(a) in Alzheimer, Atherosclerotic, Cerebrovascular, Thrombotic, and Valvular Disease
Authors: Susanna C. Larsson, Dipender Gill, Amy M. Mason, Tao Jiang, Magnus Bäck, Adam S. Butterworth, Stephen Burgess
Journal: Circulation (2020)

◼ heart valve diseases ◼ lipoprotein(a) ◼ Mendelian randomization analysis ◼ stroke L ipoprotein(a) (Lp[a]) is a circulating lipoprotein with proatherogenic, proinflammatory, and possibly prothrombotic properties.Circulating Lp(a) levels are largely genetically determined, in particular, by the LPA gene.As such, genetic variants at the LPA locus can serve as instrumental variables for investigating the clinical effects of circulating Lp(a) levels.3][4] Evidence on the causal role of elevated Lp(a) levels for other atherosclerotic and specific valvular diseases is limited, although there are MR data supporting a positive association between genetically predicted Lp(a) levels and peripheral artery disease. 2,3Whether Lp(a) is causally related to thrombotic disease and cerebrovascular disease remains unclear. 2,3,5n this study, we used the UK Biobank cohort to perform an MR investigation into the causal effects of circulating Lp(a) levels on atherosclerotic, cerebrovascular, thrombotic, and valvular diseases.Because a recent MR study provided evidence of an inverse association of Lp(a) levels with Alzheimer disease, 5 we additionally explored whether genetically predicted Lp(a) levels are associated with Alzheimer disease and dementia.This study included 367 586 unrelated European-descent UK Biobank participants.Outcomes were defined based on International Classification of Diseases and Related Health Problems codes, and self-reported data validated by interview with a nurse.Incident cases were recorded until March 31, 2017, and deaths were recorded until February 14, 2018.The UK Biobank was approved by the North West Multicentre Research Ethics Committee, and all participants provided written informed consent.We used a genetic instrument comprising 43 single-nucleotide polymorphisms (at the LPA locus) conditionally associated with Lp(a) levels at genome-wide significance in 27 540 European-descent participants from the CHD Exome+ Consortium (no overlap with UK Biobank). 1 Genetic associations with Lp(a) were taken from the CHD Exome+ Consortium and were additionally validated in UK Biobank.The instrument explained 61.0% of the variance in Lp(a) levels in UK Biobank.Effect sizes of the single-nucleotide polymorphisms-outcome associations were estimated in UK Biobank using logistic regression under an additive model with adjustment for age, sex, and 10 principal components of ancestry.MR estimates were obtained using the inverse variance-weighted method with adjustment for correlations among the single-nucleotide polymorphisms.The associations with the outcomes per genetically predicted 50-mg/dL increase in Lp(a) levels are shown in the Figure .Our results support a strong causal relationship between Lp(a) levels and coronary artery disease.The observed odds ratio was 1.36 (95% CI, 1.32-1.40),which is similar to the previously observed association in the CHD Exome+ Consortium (odds ratio rescaled per 50-mg/dL