The role of brain function related metabolic health in cardiovascular diseases using Mendelian randomization

Abstract

After a steep decline in the cardiovascular disease (CVD) mortality rate in recent decades, a deflection point followed by a flattening has occurred since 2011 in the United States, indicating that combating CVD has begun a new era with more challenges, featuring increasing difficulty in identifying new targets for intervention. In this situation, identifying additional targets from new or over-looked perspectives, such as from the overlap of brain function with physical health, might provide some novel insights. Depression is co-morbid with CVD, with randomized controlled trials showing potential cardiovascular benefit of anti- depressants for CVD patients with depression. In addition, the observed overlap between CVD and cognitive decline indicates the possibility of common causes or risk factors. Current evidence concerning the role of brain function related metabolites, such as tryptophan metabolism (which plays a role in depression) and apolipoprotein E (apoE) (which is important in cognitive decline), in CVD and its risk factors is mainly based on traditional observational studies or animal experiments, which are limited as sources of evidence for public health interventions.

I addressed the gap by investigating the role of brain function related metabolites in CVD, using instrumental variable analyses with genetic instruments, i.e., Mendelian randomization, based on available summary statistics from large genome-wide association studies, such as the CARDIoGRAMplusC4D consortium, and individual level data from the UK Biobank. Specifically, I investigated the effects of tryptophan and its main catabolites (serotonin and kynurenine) on ischemic heart disease (IHD) and its risk factors; the effects of key enzymes in the tryptophan-kynurenine pathway, i.e., indoleamine 2,3-dioxygenase 1 (IDO1) and kynurenine--oxoglutarate transaminase 3 (KAT3) on IHD, ischemic stroke, their risk factors, and cancers; the effects of opioid use, which interacts with serotonin, on IHD and its major risk factors, and chronic obstructive pulmonary disease (COPD); the age and sex specific effects of APOE common genotypes on IHD and its conventional risk factors in the UK Biobank; and the effects of three isoforms of plasma apoE (apoE2, apoE3 and apoE4) on IHD and lipid profile.

I found that the kynurenine might be harmful for IHD. The rate limiting enzyme in the first step of tryptophan-kynurenine pathway, IDO1, could possibly protect against IHD, stroke and diabetes. IDO1 might protect against prostate cancer. Opioid use had a possible harmful role in IHD and COPD. Regarding the effects of apoE genetic variants and proteins, the APOE genotypes affect risk of IHD, with similar patterns for apolipoprotein B and pulse pressure, while the ε2ε2 genotype might be harmful for IHD in younger people. I also found positive associations of apoE2 and apoE4 with IHD, LDL cholesterol and apolipoprotein B.

Taking together, in this thesis I found potential role of metabolites that are relevant to depression or cognitive decline, in IHD, using a robust study design, which provide insights into further investigations for the development of new drug targets for IHD prevention and treatment. Larger genetic studies of a wider range of metabolites are needed so that assessments in more depth can be made.