Lipoprotein(a) is an atherogenic low-density lipoprotein like particle and circulating levels are largely determined by genetics. Patients with familial hypercholesterolemia, an autosomal dominant genetic disorder characterized by elevated low-density lipoprotein cholesterol and increased risk of coronary artery disease also have been observed to have elevated levels of lipoprotein(a); however, it remains unclear why. This study sough to answer whether the occurrence of elevated lipoprotein(a) among individuals with familial hypercholesterolemia is due to a biological phenomenon or ascertainment bias. In this cohort study of the UK Biobank, which represents a population sample not biased to cardiovascular ascertainment, lipoprotein(a) levels were not statistically different between individuals with and without a familial hypercholesterolemia-associated variant (n = 221 vs. 37,486). We also performed a phenome-wide association study between LPA genotypes and ~19,000 phenotypes to demonstrate that elevated lipoprotein(a) is associated with increased low-density lipoprotein cholesterol, a family history of cardiovascular disease, premature coronary artery disease, and a diagnosis of familial hypercholesterolemia. These results suggest that familial hypercholesterolemia does not cause elevated lipoprotein(a), but that elevated lipoprotein(a) increases the likelihood that an individual with genetic familial hypercholesterolemia will be clinically recognized.
Influence of plasma lipoprotein genetics on infectious disease outcomes
Lipoproteins are commonly known as "good" and "bad" cholesterol. The function of lipoproteins is to transport lipids in the blood. But lipoproteins can also bind and remove bacterial toxins from the blood during an infection and reduce the severity of disease. Therefore, it is not surprising that patients with low levels of lipoproteins have an increased risk of developing infections responsible for life-threatening hospitalization and death.
Genetics influence the levels of lipoproteins in the blood, but it is unknown how these genes influence risk of infection. This study will use a large clinical database to investigate how genes that effect lipoproteins influence infectious disease risk. We predict that patients with genetic variations that enhance the ability of lipoproteins to remove bacterial toxins will have reduced risk of developing severe infections. In contrast, patients with genetic variations that impair the ability of lipoproteins to remove bacterial toxins will have increased risk of developing severe infections.
This study will take 1-2 years to complete and has important public health implications. Our work will provide new information on the role of lipoprotein genetics in health and disease. By demonstrating genetic contributions to infection risk, this work has the potential to highlight the use of currently available drugs for the new purpose of treating severe infections. Furthermore, this study could help identify patients that are increased risk of developing future infections or most likely to benefit from personalized treatments given their genetics.
|Lead investigator:||Mr Mark Trinder|
|Lead institution:||University of British Columbia|
2 related Returns
|Return ID||App ID||Description||Archive Date|
|2381||42857||Association of Monogenic vs Polygenic Hypercholesterolemia With Risk of Atherosclerotic Cardiovascular Disease||3 Sep 2020|
|2142||42857||Causal Inference for Genetically Determined Levels of High-Density Lipoprotein Cholesterol and Risk of Infectious Disease||16 Mar 2020|
|3249||Ascertainment Bias in the Association Between Elevated Lipoprotein(a) and Familial Hypercholesterolemia||Trinder et al||2014||Journal of the American College of Cardiology (2020)|