The association of rs17713054 with Neanderthal origin at 3p21.31 locus with the severity of COVID-19 in Iranian patients.

Since the COVID-19 pandemic, the diversity of clinical manifestations in patients has been a tremendous challenge. It seems that genetic variations, as one of the players, contribute to the variety of symptoms. Genome-wide association studies have demonstrated the influence of certain genomic regions on the disease prognosis. Particularly, a haplotype at 3p21.31 locus, inherited from Neanderthals, showed an association with COVID-19 severity. Despite several studies regarding this haplotype, some key variants are not sufficiently addressed. In the present study, we investigated the association of rs17713054 at 3p21.31 with COVID-19 severity. We analyzed the genotype of 251 Iranian COVID-19 patients (151 patients with asymptomatic to mild form as control and 100 patients with severe to critical symptoms without any comorbidities as case group) using the ARMS-PCR method. Results demonstrated that the A allele confers an almost twofold increased risk for COVID-19 severity (P value = 0.008). The AA genotype also raises the risk by more than 11 times following the recessive model (P value = 0.013). In conclusion, the A allele in rs17713054 was a risk allele in Iranian patients and was independently associated with COVID-19 severity. More studies are beneficial to confirm these findings in other populations and to develop strategies for risk assessment, prevention, and personalized medicine.

Clinical manifestation, epidemiology, genetic basis, potential molecular targets, and current treatment of polycystic liver disease.

Polycystic liver disease (PLD) is a rare condition observed in three genetic diseases, including autosomal dominant polycystic liver disease (ADPLD), autosomal dominant polycystic kidney disease (ADPKD), and autosomal recessive polycystic kidney disease (ARPKD). PLD usually does not impair liver function, and advanced PLD becomes symptomatic when the enlarged liver compresses adjacent organs or increases intra-abdominal pressure. Currently, the diagnosis of PLD is mainly based on imaging, and genetic testing is not required except for complex cases. Besides, genetic testing may help predict patients' prognosis, classify patients for genetic intervention, and conduct early treatment. Although the underlying genetic causes and mechanisms are not fully understood, previous studies refer to primary ciliopathy or impaired ciliogenesis as the main culprit. Primarily, PLD occurs due to defective ciliogenesis and ineffective endoplasmic reticulum quality control. Specifically, loss of function mutations of genes that are directly involved in ciliogenesis, such as Pkd1, Pkd2, Pkhd1, and Dzip1l, can lead to both hepatic and renal cystogenesis in ADPKD and ARPKD. In addition, loss of function mutations of genes that are involved in endoplasmic reticulum quality control and protein folding, trafficking, and maturation, such as PRKCSH, Sec63, ALG8, ALG9, GANAB, and SEC61B, can impair the production and function of polycystin1 (PC1) and polycystin 2 (PC2) or facilitate their degradation and indirectly promote isolated hepatic cystogenesis or concurrent hepatic and renal cystogenesis. Recently, it was shown that mutations of LRP5, which impairs canonical Wnt signaling, can lead to hepatic cystogenesis. PLD is currently treated by somatostatin analogs, percutaneous intervention, surgical fenestration, resection, and liver transplantation. In addition, based on the underlying molecular mechanisms and signaling pathways, several investigational treatments have been used in preclinical studies, some of which have shown promising results. This review discusses the clinical manifestation, complications, prevalence, genetic basis, and treatment of PLD and explains the investigational methods of treatment and future research direction, which can be beneficial for researchers and clinicians interested in PLD.

The association of APOE genotype with COVID-19 disease severity.

COVID-19 has caused the recent pandemic of respiratory infection, which threatened global health. The severity of the symptoms varies among affected individuals, from asymptotic or mild signs to severe or critical illness. Genetic predisposition explains the variation in disease severity among patients who suffer from severe symptoms without any known background risk factors. The present study was performed to show the association between APOE genotype and the severity of COVID-19 disease. The APOE genotype of 201 COVID-19 patients (101 patients with asymptomatic to mild form of the disease as the control group and 100 patients with severe to critical illness without any known background risk factors as the case group) were detected via multiplex tetra-primer ARMS-PCR method. Results showed that the e4 allele increased the risk of the COVID-19 infection severity more than five times and the e4/e4 genotype showed a 17-fold increase in the risk of severe disease. In conclusion, since our study design was based on the exclusion of patients with underlying diseases predisposing to severe form of COVID-19 and diseases related to the APOE gene in the study population, our results showed that the e4 genotype is independently associated with the severity of COVID-19 disease. However, further studies are needed to confirm these findings in other nations and to demonstrate the mechanisms behind the role of these alleles in disease severity.