The genetic variations among individuals are one of the notable factors determining disease severity and drug response. Nowadays, COVID-19 pandemic has been adversely affecting many aspects of human life. We used the Tehran Cardio-Metabolic Genetic Study (TCGS) data that is an ongoing genetic study including the whole-genome sequencing of 1200 individuals and chip genotyping of more than 15,000 participants. Here, the effect of ACE2 variations by focusing on the receptor-binding site of SARS-CoV-2 and ACE2 cleavage by TMPRSS2 protease were investigated through simulations study. After analyzing TCGS data, 570 genetic variations on the ACE2 gene, including single nucleotide polymorphisms (SNP) and insertion/deletion (INDEL) were detected. Interestingly, two observed missense variants, K26R and S331F, which only the first one was previously reported, can reduce the receptor affinity for the viral Spike protein. Moreover, our bioinformatics simulation of 3D structures and docking of proteins explains important details of ACE2-Spike and ACE2-TMPRSS2 interactions, especially the critical role of Arg652 of ACE2 for protease function of TMPRSS2 was uncovered. As our results show that the genetic variation of ACE2 can at least influence the affinity of this receptor to its partners, we need to consider the genetic variations on ACE2 as well as other genes in the pathways that contribute to the pathogenesis of COVID-19 for designing efficient drugs and vaccines.

Due to the central role in insulin secretion, the potassium inwardly-rectifying channel subfamily J member 11 (KCNJ11) gene is one of the essential genes for type 2 diabetes (T2D) predisposition. However, the relevance of this gene to T2D development is not consistent among diverse populations. In the current study, we aim to capture the possible association of common KCNJ11 variants across Iranian adults, followed by a meta-analysis. We found that the tested variants of KCNJ11 have not contributed to T2D incidence in Iranian adults, consistent with similar insulin secretion levels among individuals with different genotypes. The integration of our results with 72 eligible published case–control studies (41,372 cases and 47,570 controls) as a meta-analysis demonstrated rs5219 and rs5215 are significantly associated with the increased T2D susceptibility under different genetic models. Nevertheless, the stratified analysis according to ethnicity showed rs5219 is involved in the T2D risk among disparate populations, including American, East Asian, European, and Greater Middle Eastern, but not South Asian. Additionally, the meta-regression analysis demonstrated that the sample size of both case and control groups was significantly associated with the magnitude of pooled genetic effect size. The present study can expand our knowledge about the KCNJ11 common variant's contributions to T2D incidence, which is valuable for designing SNP-based panels for potential clinical applications in precision medicine. It also highlights the importance of similar sample sizes for avoiding high heterogeneity and conducting a more precise meta-analysis.

Background: Alterations in levels of 25‐hydroxyvitamin D have been associated with the risk of thyroid disease. This study uses Mendelian randomization (MR) to infer the possible causal association of 25‐hydroxyvitamin D with hypothyroidism. Methods: We performed two‐sample MR using the summary statistics data from genome‐wide association studies (GWAS) from populations with European ancestry to infer the causality of genetically controlled levels of 25‐hydroxyvitamin D on the risk of hypothyroidism, Hashimoto′s thyroiditis, and biochemical parameters of thyroid diseases. The inverse‐variance‐weighted (IVW) method was used as the primary method to calculate the combined effect of all SNPs. Other methods were adopted to evaluate the stability and reliability of the results. Comprehensive sensitivity analyses were conducted to ensure that none of the MR analysis′s primary assumptions were violated. Results: The results of the IVW analysis revealed a significant causal association between higher levels of 25‐hydroxyvitamin D and lower risk of hypothyroidism (beta = −0.197, 95% CI [−0.301, −0.093]; SE = 0.053, P _beta = 2.256 × 10 ⁻⁴ ) as well as increased levels of free T4 (beta = 0.204, 95% CI [0.094, 0.305]; SE = 0.056, P _beta = 3.0506 × 10 ⁻⁴ ). On the other hand, no significant causality was determined for higher levels of 25‐hydroxyvitamin D in association with Hashimoto′s thyroiditis (beta = −0.047, 95% CI [−0.245, 0.151], p = 0.641) and TSH levels (IVW method: beta = ‐0.030, SE = 0.034, 95% CI [‐0.097, 0.038]; P = 0.392). Conclusion: The results of this two‐sample MR study provide evidence supporting the potential of 25‐hydroxyvitamin D supplementation in reducing the risk of hypothyroidism.