Association study of the JAK/STAT signaling pathway with susceptibility to COVID-19 in moroccan patient and in-silico analysis of rare variants

The goal of our study was to explore the association of the polymorphisms in the JAK/STAT pathway among Moroccan COVID-19 patients, using a case-control approach. Next-generation sequencing was employed to investigate the IFNAR1, IFNAR2, JAK1, TYK2, STAT2, and IRF9 genes within the JAK/STAT pathway. We also performed an in silico study to examine the rare variants in this pathway. Statistical analyses were conducted using MedCalc software. Protein 3D structures were determined via the I-TASSER server, with variant structures generated using PyMOL. YASARA View allowed local 3D analysis comparing native and variant structures for pathogenic rare variants. The study encompassed 206 COVID-19 patients, averaging 45.70 ± 12.73 years and a control group (N=118). Among the examined genes, 15 common polymorphisms and 7 rare variants were identified. Adjustment for age and gender revealed a significant association between TYK2 p.Gly363Ser (p=0.036) and COVID-19 infection, where the GA variant exhibited protective effects (0.6361 [0.3405-1.1884], p=0.035). Additionally, STAT2 p.Met594Ile showed an association to COVID-19 risk (p=0.042), with heterozygous GC being linked to infection (p=0.037, OR=2.7135 [0.5684 -12.9532]). Notably, IFNAR1 p.Val168Leu mutated C allele was significantly associated with reduced susceptibility to COVID-19 severity (p=0.028, OR=0.5936 [0.3725 - 0.9461]), under the additive model (p=0.045, OR=0.626 [0.3958 - 0.9899]). Rare variants IFNAR1 p.Trp318Cys, p.Ser476Phe, and IFNAR2 p.Cys271Tyr were predicted deleterious, impacting protein structure via hydrogen bond and hydrophobic interaction alterations. Burden analysis of rare variants revealed a protective cumulative effect against COVID-19 severity for TYK2 (p=0.0013, OR=0.1438 [0.04237 - 0.4803]) under the dominant model. This study underscores the role of genetic factors in COVID-19 susceptibility and advocates further explorations regarding functional impacts of JAK/STAT pathway rare variants.