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Evidence for genetic overlap between adult onset Still’s disease and hereditary periodic fever syndromes

  • Genes and Disease
  • Published:
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Abstract

Objective

Adult onset Still’s disease (AOSD) is a severe, autoimmune disease that can be challenging to treat with conventional therapeutics and biologicals in a considerable number of cases. Therefore, there is a high need to understand its pathogenesis better. As major clinical symptoms overlap between AOSD and hereditary periodic fever syndromes (HPFS), we analysed four known HPFS genes in AOSD.

Methods

We performed Sanger sequencing and quantitative analysis of all coding regions of MEFV, TNFRSF1A, MVK and NLRP3 in 40 AOSD patients. All rare coding variants (n = 6) were evaluated for several aspects to classify them as benign to pathogenic variants. Statistical analysis was performed to analyse whether variants classified as (likely) pathogenic were associated with AOSD.

Results

We identified three rare variants in MEFV, one previously not described. Association to the three likely pathogenic MEFV variants was significant (p c = 2.34E− 03), and two of the three carriers had a severe course of disease. We observed strong evidence for significant association to mutations in TNFRSF1A (p c = 2.40E− 04), as 5% of patients (2/40) carried a (likely) pathogenic variant in this gene. Both of them received a biological for treatment.

Conclusion

Our results indicate TNFRSF1A as a relevant gene in AOSD, especially in patients with a more challenging course of disease, while causal variants remain to be identified in the majority of patients.

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Abbreviations

ACMG:

American College of Medical Genetics

ANA:

Antinuclear antibodies

AOSD:

Adult onset Still’s disease

BDGP:

Berkeley Drosophila genome project

CAPS:

Cryopyrin-associated periodic syndromes

CINCA:

Chronic infantile neurological, cutaneous, articular syndrome

DMARD:

Disease-modifying anti-rheumatic drugs

EVS:

Exome variant server

ExAC:

Exome aggregation consortium

FMF:

Familial Mediterranean fever

GERP++:

Genomic evolutionary rate profiling

GPT:

Glutamate-pyruvate-transaminase

HPFS:

Hereditary periodic fever syndromes

HSF:

Human splicing finder

IL:

Interleukin

LRT:

Likelihood ratio test

MAF:

Minor allele frequency

MEFV :

Familial Mediterranean Fever gene

MKD:

Mevalonate kinase deficiency

MLPA:

Multiplex ligation-dependent probe amplification

MVK :

Mevalonate kinase gene

MWS:

Muckle–Wells syndrome

NFE:

Non-Finnish Europeans

NLRP3 :

NLR Family Pyrin Domain Containing 3

RT-PCR:

Reverse transcriptase polymerase chain reaction

SIFT:

Scale-invariant feature transform

TNF:

Tumour necrosis factor

TNFRSF1A :

Tumour necrosis factor receptor superfamily member 1A

TRAPS:

Tumour necrosis factor receptor-associated periodic syndrome

VUS:

Variant of uncertain significance

γ-GT:

γ-Glutamyltransferase

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Acknowledgements

We are grateful to all patients and family members for participating in our study. The present work was performed in fulfillment of the requirements for obtaining the degree “Dr. med.” at the Friedrich-Alexander-University Erlangen-Nürnberg (FAU).

Author information

Authors and Affiliations

  1. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 10, 91052, Erlangen, Germany

    R. Sighart, S. Löhr, A. Reis & U. Hüffmeier

  2. Department of Internal Medicine 3 and Institute of Clinical Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    J. Rech & A. Hueber

  3. Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany

    N. Blank

  4. Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    H. Sticht

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  1. R. Sighart
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Contributions

J.R., A.H. and U.H. designed the study. J.R., A.H. and N.B. recruited patients and collected clinical data. Genetic, statistical and bioinformatics analyses were performed by R.S., S.L. and H.S. All authors were involved in the interpretation of data. R.S. and U.H. wrote the manuscript that was read and approved by all authors.

Corresponding author

Correspondence to U. Hüffmeier.

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Ethical approval

The study was conducted according to the Helsinki agreement and approved by the research ethics board of the FAU Erlangen Nürnberg under the protocol number 52_14 B in 2014 and changes were approved in 2015.

Funding

This study was partly funded by the Interdisciplinary Centre for Clinical Research (MD-Thesis Scholarship [RS] and laboratory rotation [UH]) of the Clinical Centre Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany.

Conflict of interest

NB received speaking fees (< 5000 €) from SOBI and Novartis. All other authors have declared no conflicts of interest.

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Sighart, R., Rech, J., Hueber, A. et al. Evidence for genetic overlap between adult onset Still’s disease and hereditary periodic fever syndromes. Rheumatol Int 38, 111–120 (2018). https://doi.org/10.1007/s00296-017-3885-0

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