No Evidence of Association of ATP8B4 F436L missense Variant in a Large Systemic Sclerosis Cohort

Elena Lopez-Isac¹, Lara Bossini-Castillo², Ana B Palma², Shervin Assassi³, Carmen Pilar Simeón⁴, Norberto Ortego Centeno⁵, Esther Vicente-Rabaneda⁶, Carlos Tolosa⁷, Manuel Rubio-Rivas⁸, Jose Andres Roman Ivorra⁹, Lorenzo Beretta¹⁰, Gianluca Moroncini¹¹, Nicolas Hunzelmann¹², Joerg HW Distler¹³, Gabriela Riekemasten¹⁴, Jeska K. de Vries-Bouwstra¹⁵, Alexandre E. Voskuyl¹⁶, Timothy R.D.J. Radstake¹⁷, Ariane L. Herrick¹⁸, Christopher Denton¹⁹, Carmen Fonseca²⁰, Maureen D Mayes³ and Javier Martín¹, ¹Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, Granada, Spain, ²Cellular Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra (CSIC), Granada, Spain, ³Department of Internal Medicine - Rheumatology, University of Texas-McGovern Medical School, Houston, TX, ⁴Internal Medicine, Hospital Universitari Vall d'Hebron, Barcelona, Spain, ⁵Internal Medicine, Hospital Clínico San Cecilio, Granada, Spain, ⁶Rheumatology, H.U. La Princesa, Madrid, Spain, ⁷Department of Internal Medicine, Corporación Sanitaria Universitaria Parc Taulí, Barcelona, Spain, ⁸Department of Internal Medicine, Hospital Universitario de Bellvitge, Barcelona, Spain, ⁹Department of Rheumatology, Hospital Universitario y Politecnico La Fe, Valencia, Spain, ¹⁰Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy, ¹¹Dipartimento di Scienze mediche e Chirurgiche, Università politecnica delle Marche and Ospedali Riuniti, Ancona, Italy, ¹²Department of Dermatology, University of Cologne, Cologne, Germany, ¹³Internal Medicine 3, University of Erlangen, Erlangen, Germany, ¹⁴Department of Rheumatology, University of Lübeck, Luebeck, Germany, ¹⁵Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands, ¹⁶Department of Rheumatology, VU University medical center, Amsterdam, Netherlands, ¹⁷Laboratory of Translational Immunology, UMC Utrecht, Utrecht, Netherlands, ¹⁸Centre for Musculoskeletal Research, University of Manchester, MAHSC, Salford Royal Hospital, Manchester, United Kingdom, ¹⁹Division of Medicine, Centre for Rheumatology and Connective Tissue Disease, University College London, London, United Kingdom, ²⁰Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Genetic Biomarkers and systemic sclerosis

Session Information

Date: Monday, November 14, 2016

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's – Pathogenesis, Animal Models and Genetics - Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Systemic sclerosis (SSc) is a complex autoimmune disease with heterogeneous clinical manifestations. Over the past seven years our knowledge of the SSc genetic component has greatly increased, mainly thanks to large genetic studies including genome wide association studies (GWASs). However, there is still a large proportion of the SSc heritability that remains unexplained. One of the hypotheses proposed to explain the missing heritability for complex diseases involves rare and low-frequency variants, which are not usually analyzed in GWASs. Next-generation sequencing (NGS) technologies, like whole exome sequencing (WES), have provided a useful strategy for the study of non-common variants. In this regard, Gao et al. performed WES on SSc and reported a novel gene, ATP8B4, as a risk factor for the disease. Their results pointed out F436L (rs55687265) missense variant as the potential causal variant for the association signal. The aim of the present study was to further evaluate the reported signal of association in a large SSc cohort.

Methods: The complete set of individuals enrolled for this study comprised a total of 7,426 SSc patients and 13,087 healthy controls of European ancestry. F436L (rs55687265) rare variant was genotyped using TaqMan SNP genotyping technology. First, association tests were performed in each of the six different case-control cohorts. An inverse variance meta-analysis under a fixed effect model was performed to combine the results in the different cohorts.

Results: A trend towards association was observed for one of the case-control set (P_value = 0.071, OR = 1.58) (Table 1). However, we did not observe any suggestive or significant association signal for the remaining cohorts. Interestingly, we also observed opposite-direction allelic effects across the different populations for the same allele. The meta-analysis combining all the sample sets showed no significant association with the disease (P_meta = 0.484, OR = 1.07). Although we did not find statistically significant associations, a possible role of this locus in SSc susceptibility cannot be ruled out, since we did not assess whether other ATP8B4variants were associated with SSc susceptibility.

Conclusion: This study could not replicate the association of ATP8B4 rs55687265 with SSc. Our results highlight the importance of validation of WES results with other sequencing methods as well as replication of the new associations in independent studies in order to identify true disease-causing mutations.

Disclosure: E. Lopez-Isac, None; L. Bossini-Castillo, None; A. B. Palma, None; S. Assassi, None; C. P. Simeón, None; N. Ortego Centeno, None; E. Vicente-Rabaneda, None; C. Tolosa, None; M. Rubio-Rivas, None; J. A. Roman Ivorra, None; L. Beretta, None; G. Moroncini, None; N. Hunzelmann, None; J. H. Distler, None; G. Riekemasten, None; J. K. de Vries-Bouwstra, None; A. E. Voskuyl, None; T. R. D. J. Radstake, None; A. L. Herrick, None; C. Denton, GSK, Celgene, Actelion, Bayer, Sanofi, Roche-Genentech, Inventiva, 5,CSL Behring, GSK, Actelion, Roche-Genentech, Inventiva, 2; C. Fonseca, None; M. D. Mayes, None; J. Martín, None.

To cite this abstract in AMA style:

Lopez-Isac E, Bossini-Castillo L, Palma AB, Assassi S, Simeón CP, Ortego Centeno N, Vicente-Rabaneda E, Tolosa C, Rubio-Rivas M, Roman Ivorra JA, Beretta L, Moroncini G, Hunzelmann N, Distler JH, Riekemasten G, de Vries-Bouwstra JK, Voskuyl AE, Radstake TRDJ, Herrick AL, Denton C, Fonseca C, Mayes MD, Martín J. No Evidence of Association of ATP8B4 F436L missense Variant in a Large Systemic Sclerosis Cohort [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/no-evidence-of-association-of-atp8b4-f436l-missense-variant-in-a-large-systemic-sclerosis-cohort/. Accessed .

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