IGHG3 hinge length variation was associated with the risk of critical disease and death in a Spanish COVID-19 cohort

Abstract

IgG3 would play an important role in the immune adaptive response against SARS-CoV-2, and low plasma levels might increase the risk of COVID-19 severity and mortality. The IgG3 hinge sequence has a variable repeat of a 15 amino acid exon with common 4-repeats (M) and 3-repeats (S). This length IGHG3 polymorphism might affect the IgG3 effector functions. The short hinge length would reduce the IgG3 flexibility and impairs the neutralization and phagocytosis compared to larger length-isoforms. We genotyped the IGHG3 length polymorphism in patients with critical COVID-19 (N = 516; 107 death) and 152 moderate-severe but no-critical cases. Carriers of the S allele had an increased risk of critical ICU and mortality (p < 0.001, OR = 2.79, 95% CI = 1.66-4.65). This adverse effect might be explained by a less flexibility and reduced ability to induce phagocytosis or viral neutralization for the short length allele. We concluded that the IgG3 hinge length polymorphism could be a predictor of critical COVID-19 and the risk of death. This study was based on a limited number of patients from a single population, and requires validation in larger cohorts.

Immunoglobulin genes and severity of COVID-19

“…The association of the IGHG3 hinge length polymorphisms with the risk of critical disease and death has been previously reported (López-Martínez et al 2022a , b ). We previously reported a significantly increased frequency of the rs1801274 G (131 Arg ) among COVID-19 deaths (López-Martínez et al 2022a , b ). In this study, the G allele was non-significantly more common among deaths vs. survivors ( p = 0.06).…”

“…We previously reported significant associations of IGHG3 and FCGR2A polymorphisms with the risk of developing critical COVID-19 (López-Martínez et al 2022a , b ). Due to the pivotal role of IgG1 in response against SARS-CoV-2, we hypothesized that common functional variants in the IGHG1 gene—either individually or synergistically with IGHG3 and FCGR2A —might modulate the extent of COVID-19 severity.…”

“…Several studies have demonstrated that increased hinge lengths result in greater IgG3 flexibility that would facilitate its binding to multiple epitopes, resulting in more potent phagocytosis and viral neutralization. IgG3 hinge-length polymorphism has been associated with the severity of infectious diseases, including COVID-19 (López-Martínez et al 2022a , b ). A SNP in the EC2 domain of FCGR2A -CD32a (rs1801274, c.497G>A, p.Arg131His) has been implicated in differential IgG-FcγR binding affinity: the H 131 isoform has a higher binding affinity to IgG1 compared to the R 131 (Bruhns et al 2009 ), potentially resulting in increased capacity of binding to IgG immune complexes among individuals with the His/His genotype.…”

“…DNA was obtained from whole blood leukocytes, and all individuals were genotyped for IGHG1 rs1071803 C/T (Arg97Lys), IGHG3 hinge-length, and FCGR2A rs1801274 A/G polymorphisms, using previously described procedures (López-Martínez et al 2022a , b ; Pandey et al 2019 ).…”

Immune characteristics of kidney transplant recipients with acute respiratory distress syndrome induced by COVID-19 at single-cell resolution

“…In COVID-19 cases, somatic hypermutation (SHM) and class-switch recombination (CSR) events of IGHG3 are more frequent than those of other IgG subclasses [ 26 ]. High frequencies of SHM and CSR can specifically alter the hinge length polymorphism of IGHG3, diminishing the neutralizing ability of antibodies against the virus [ 34 ]. Hence, the elevated abundance of Plasma_IGHG3 in ARDS_KTR group could potentially exacerbate the risk of disease progression and mortality in these patients.…”