Estimating causal effects of atherogenic lipid-related traits on COVID-19 susceptibility and severity using a two-sample Mendelian randomization approach

Abstract

Background As the number of COVID-19 deaths continues to rise worldwide, the identification of risk factors for the disease is an urgent issue, and it remains controversial whether atherogenic lipid-related traits including serum apolipoprotein B, low-density lipoprotein (LDL)-cholesterol, and triglyceride levels, are risk factors. The aim of this study was to estimate causal effects of lipid-related traits on COVID-19 risk in the European population using a two-sample Mendelian randomization (MR) approach. Methods We used summary statistics from a genome-wide association study (GWAS) that included 441,016 participants from the UK Biobank as the exposure dataset of lipid-related traits and from COVID-19 Host Genetics Initiative GWAS meta-analyses of European ancestry as the outcome dataset for COVID-19 susceptibility (32,494 cases and 1,316,207 controls), hospitalization (8316 cases and 1,549,095 controls), and severity (4792 cases and 1,054,664 controls). We performed two-sample MR analyses using the inverse variance weighted (IVW) method. As sensitivity analyses, the MR-Egger regression, weighted median, and weighted mode methods were conducted as were leave-one-out sensitivity analysis, the MR-PRESSO global test, PhenoScanner searches, and IVW multivariable MR analyses. A P value below 0.0055 with Bonferroni correction was considered statistically significant. Results This MR study suggested that serum apolipoprotein B or LDL-cholesterol levels were not significantly associated with COVID-19 risk. On the other hand, we inferred that higher serum triglyceride levels were suggestively associated with higher risks of COVID-19 susceptibility (odds ratio [OR] per standard deviation increase in lifelong triglyceride levels, 1.065; 95% confidence interval [CI], 1.001–1.13; P = 0.045) and hospitalization (OR, 1.174; 95% CI, 1.04–1.33; P = 0.012), and were significantly associated with COVID-19 severity (OR, 1.274; 95% CI, 1.08–1.50; P = 0.004). Sensitivity and bidirectional MR analyses suggested that horizontal pleiotropy and reverse causation were unlikely. Conclusions Our MR study indicates a causal effect of higher serum triglyceride levels on a greater risk of COVID-19 severity in the European population using the latest and largest GWAS datasets to date. However, as the underlying mechanisms remain unclear and our study might be still biased due to possible horizontal pleiotropy, further studies are warranted to validate our findings and investigate underlying mechanisms.

COVID-19-associated hypertriglyceridemia and impact of treatment

“…Moreover, a study used Mendelian randomization in European population from United Kingdom Biobank to examine the lipid-related traits causal effects on the risk of COVID-19, suggested that higher TG serum level was linked to greater COVID-19 susceptibility (odds ratio (OR) per standard deviation increase in lifelong TG levels, 1.065; 95% CI, 1.001-1.13, p = 0.045), COVID-19 severity (OR, 1.274; 95% CI, 1.08-1.50, p = 0.004), and hospitalization (OR, 1.174; 95% CI, 1.04-1.33, p = 0.012). However, the mechanism that explains the association of hypertriglyceridemia with worsening COVID-19 course is unclear (14). The proposed mechanism for the occurrence of hypertriglyceridemia seems multifaceted (15,16).…”

Beneficial effects of prehospital use of statins in a large United States cohort of hospitalized coronavirus disease 2019 patients

“…Continued statin use decreases chronic LDL and VLDL-mediated low-grade inflammation seen in obesity, metabolic syndrome, diabetes, heart disease, renal disease, and stroke 27 . Mendelian randomization studies have shown a causal relationship between higher triglyceride levels and increased susceptibility to and severity of COVID-19, suggesting statins could be protective in COVID-19 patients through their lipid-lowering effects 28 . Interestingly, our study revealed lower levels of LDL, VLDL, CRP and hs-CRP, and lower mortality and morbidity outcomes in preexisting statin users compared with nonusers.…”

The correlations among racial/ethnic groups, hypertriglyceridemia, thrombosis, and mortality in hospitalized patients with COVID-19

“…An earlier study conducted in Milwaukee, WI, during the initial one month of the COVID-19 pandemic (March 1st to March 31st, 2020) reported that people who were enrolled in Medicaid had a higher likelihood of hospital admission [ 48 ]. Other reports also described significant healthcare inequity for Black/African American and Hispanic/Latino communities, which include a disparity in healthcare or insurance access [ 49 ]. Similarly, patients with poorer socioeconomic status were less frequently seek healthcare or only during emergency, which could lead to worsened outcomes during hospitalization [ 50 , 51 ].…”

“…Our previous study conducted during earlier period of the pandemic showed that hypertriglyceridemia during hospitalization in patients with COVID-19 was correlated with mortality [ 12 ], consistent with the findings of the current study. Additionally, based on a genome-wide association study (GWAS), a consistent result was found that genetic variants that associate with hypertriglyceridemia were associated with COVID-19 severity in both inpatients and outpatients [ 49 ]. Likewise, investigation in the genetic variants related to Hemophagocytic lymph histiocytosis, such as the perforin gene, in Asian and non-White Hispanic patients are needed to assess the increased prevalence of hypertriglyceridemia.…”