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 (Pvalue = 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 (Pmeta = 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.
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 October 27, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/no-evidence-of-association-of-atp8b4-f436l-missense-variant-in-a-large-systemic-sclerosis-cohort/