Two Cases of Familial Mediterranean Fever Involving MEFV Variants: The Importance of Differentiating the Diagnosis from COVID-19.

Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease associated with the MEFV gene. FMF is common in Mediterranean peoples but not highly recognized in Japan. We herein report two cases of Japanese FMF patients who were diagnosed by genetic testing for the MEFV gene during the Coronavirus disease 2019 (COVID-19) pandemic. Both patients presented with symptoms similar to COVID-19, which delayed the definitive diagnosis. Patients with a confirmed diagnosis of FMF may be eligible for physical, emotional, and financial benefits. Therefore, the COVID-19 pandemic highlights the importance of differentiating the diagnosis by genetic testing.

Estimating causal effects of genetically predicted type 2 diabetes on COVID-19 in the East Asian population.

Background: Observational studies suggested that type 2 diabetes mellitus (T2DM) was associated with an increased risk of coronavirus disease 2019 (COVID-19). However, Mendelian randomization (MR) studies in the European population failed to find causal associations, partly because T2DM was pleiotropically associated with body mass index (BMI). We aimed to estimate the causal effects of T2DM on COVID-19 outcomes in the East Asian (EAS) population using a two-sample MR approach. Methods: We obtained summary statistics from a genome-wide association study (GWAS) that included 433,540 EAS participants as the exposure dataset for T2DM risk and from COVID-19 Host Genetics Initiative GWAS meta-analyses (round 7) of EAS ancestry as the outcome dataset for COVID-19 susceptibility (4,459 cases and 36,121 controls), hospitalization (2,882 cases and 31,200 controls), and severity (794 cases and 4,862 controls). As the main MR analysis, we performed the inverse variance weighted (IVW) method. Moreover, we conducted a series of sensitivity analyses, including IVW multivariable MR using summary statistics for BMI from a GWAS with 158,284 Japanese individuals as a covariate. Results: The IVW method showed that the risk of T2DM significantly increased the risk of COVID-19 susceptibility (odds ratio [OR] per log (OR) increase in T2DM, 1.11; 95% confidence interval [CI], 1.02-1.20; P = 0.014) and hospitalization (OR, 1.15; 95% CI, 1.04-1.26; P = 0.005), although the risk of severity was only suggestive. Moreover, IVW multivariable MR analysis indicated that the causal effects of T2DM on COVID-19 outcomes were independent of the effect of BMI. Conclusions: Our MR study indicated for the first time that genetically predicted T2DM is a risk factor for SARS-CoV-2 infection and hospitalized COVID-19 independent of obesity in the EAS population.

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

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.