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

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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.

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