Genetic variation of low-to-medium-affinity Fc-gamma receptors in Guillain-Barré syndrome

Abstract

Introduction: Fc-gamma receptors (FcγRs) are important for the effector functions of immunoglobulin G (IgG) and are therefore expected to play a role in the pathophysiology of Guillain-Barré syndrome (GBS). The FCGR2/3 locus, which encodes low-to-medium-affinity FcγRs, contains extensive genetic variation. We hypothesized that genetic variation in the FCGR2/3 locus influences GBS susceptibility, muscle weakness, outcomes, and the pharmacokinetics of intravenous immunoglobulin (IVIg).

Methods: Copy number variation and single nucleotide polymorphisms in the FCGR2/3 locus were studied using multiplex ligation-dependent probe amplification (MLPA). The study cohort consisted of 467 GBS patients and 919 healthy controls of European descent. Severe weakness was defined as an MRC sum score < 40 at nadir. The increase in serum IgG one or two weeks after start of IVIg treatment was determined.

Results: No significant associations were found between genetic variation in the FCGR2/3 locus and susceptibility to GBS. However, in patients with an antecedent Campylobacter jejuni infection, a higher frequency of three or more FCGR3A copies was observed compared to healthy controls (p = 0.023). FCGR3A copy numbers were also associated with more severe disease (OR = 2.02; 95% CI = 1.00-4.12), even after correcting for age and positive C. jejuni serology. No association was found between FCGR2/3 variants and the ability to walk unaided in time-to-event analyses. In addition, the pharmacokinetics of IVIg were not affected by genetic variation in the FCGR2/3 locus.

Conclusion: Overall, FCGR2/3 polymorphisms are not associated with susceptibility to GBS or response to IVIg treatment. However, associations may exist in specific subgroups, as demonstrated in patients with a preceding C. jejuni infection who more frequently carry a duplication in FCGR3A.

Keywords: Autoantibodies; CNV; Fc-receptors; Immune-mediated neuropathy; Polymorphisms.

Fig. 1

Genomic organization of the FCGR2/3 locus at 1q23.3. A Copy number variation regions (CNRs) are identified at specific breakpoints, with each region encompassing a series of genes marked by matching colors. CNR5 denotes a novel CNR [51]. CNR1 and CNR4 are not separated due to the limitations of our method to distinguish between them. Gene orientations are indicated by arrows. Genes are not drawn to scale. All functional SNPs and haplotypes identified in this study are displayed for their respective genes. NA1, NA2, and SH are haplotypes determined by six SNPs. B Exact location of the breaking points in CNR5 are not known, but are within the highlighted area. C Schematic overview of the theoretical duplication allele of CNR5 leading to a chimeric FCGR3A/3B gene. Abbreviations: CNR copy number variation region, SNP single nucleotide polymorphism, Chr chromosome, ORF open-reading frame, NAHR nonallelic homologous recombination