Identification of potential susceptibility genes in patients with primary Sjögren’s syndrome-associated pulmonary arterial hypertension through whole exome sequencing
Arthritis Research & Therapy volume 25, Article number: 175 (2023)
Pulmonary arterial hypertension (PAH) is a rare complication of primary Sjögren’s syndrome (pSS). Several genes have proven to be associated with pSS and PAH. However, there is no study specifically addressing the genetic susceptibility in pSS combined with PAH.
Thirty-four unrelated patients with pSS-PAH were recruited from April 2019 to July 2021 at Peking Union Medical College Hospital. Demographic and clinical data were recorded in detail, and peripheral blood samples were collected for whole-exome sequencing (WES). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to predict the functional effect of mutant genes. Genetic variants identified by WES were confirmed by polymerase chain reaction (PCR)-Sanger sequencing.
We totally identified 141 pathogenic variant loci of 129 genes in these 34 pSS-PAH patients, using WES analysis. Patients with a family history of rheumatic diseases are more likely to carry FLG mutations or carry gene variations related to the biosynthesis of the amino acids pathway (p < 0.05). According to Sanger sequencing confirmation and pathogenicity validation, we totally identified five candidate pathogenic variants including FLG c.12064A > T, BCR c.3275_3278dupCCGG, GIGYF2 c.3463C > A, ITK c.1741C > T, and SLC26A4 c.919-2A > G.
Our findings provide preliminary data of exome sequencing to identify susceptibility loci for pSS-PAH and enriched our understanding of the genetic etiology for pSS-PAH. The candidate pathogenic genes may be the potential genetic markers for early warning of this disease.
Primary Sjögren’s syndrome (pSS) is an autoimmune connective tissue disease (CTD) characterized by exocrine gland dysfunction, resulting predominately in dryness of the mouth and eyes . Pulmonary arterial hypertension (PAH) is a major cause of death in CTD patients, with a 5-year survival of 62.9% in China . CTD-associated PAH (CTD-PAH) is classified as group I pulmonary hypertension, which also includes idiopathic PAH (IPAH), heritable PAH (HPAH), PAH due to drugs or toxins, PAH associated with human immunodeficiency virus infection, portal hypertension, congenital heart diseases and schistosomiasis . The most common underlying diseases in Chinese patients with CTD-PAH were systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and pSS . PAH is a rare and severe complication of pSS with poor prognosis  and the pathogenesis of pSS-associated PAH (pSS-PAH) is unclear yet.
Mutations in the gene bone morphogenic protein receptor type 2 (BMPR2) were reported as the most common genetic cause of PAH and have proven to be associated with long-term outcomes in IPAH, HPAH, and anorexigen-associated PAH . More recently, more IPAH susceptibility genes, including the gene encoding human bone morphogenetic protein 9 (BMP9) and prostacyclin synthase (PTGIS), were identified by employing whole exome sequencing (WES) and functional assessments [6, 7]. Several studies using targeted gene sequencing panels were also conducted in CTD-PAH patients [8, 9]. In addition, genetic studies in pSS have identified mutations in HLA, IRF5, STAT4, GTF2I, and CCL11 (eotaxin) [10,11,12] genes. However, the susceptibility locus for pSS-PAH remains unknown.
The aim of this study was to explore the genetic susceptibility of pSS-PAH and to establish a preliminary understanding on the association between genotypes and clinical phenotypes.
A total of 34 pSS-PAH patients were recruited based on a clinical registry in Peking Union Medical College Hospital (PUMCH) between April 2019 and July 2021, a national referral center for CTD-PAH patients. All subjects satisfied the 2002 American–European Consensus Group classification criteria  and the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for pSS . Diagnoses of PAH were based on right heart catheterization (RHC), defined as a mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg at rest, a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, and a pulmonary vascular resistance of ≥ 3 Wood units (WU) . The exclusion criteria included the presence of any other CTD, left heart disease, interstitial lung disease, and chronic thromboembolic disease confirmed by ventilation perfusion scintigraphy (V/Q) or computed tomographic pulmonary angiography (CTPA). Written informed consent was obtained from all subjects. This study was approved by the Institutional Review Board of PUMCH (JS-2038).
Data and sample collection
The demographic characteristics, medical history, physical examination findings, laboratory profiles, echocardiography results, RHC data, and treatment information were recorded. The evaluation of pSS was achieved through pSS disease damage index (SSDDI) . Peripheral blood samples were collected from all subjects. DNA was extracted from the peripheral blood by standard procedure based on sodium dodecyl sulfate-proteinase K-phenol/chloroform extraction .
Genomic DNA from 34 patients underwent WES. Purified DNA was fragmented, end-repaired, A-tailed, and underwent adaptors ligation and DNA fragments enrichment. Next-generation sequencing was carried out on HiSeq 4000 System (Illumina). Sequencing analysis was performed in all patients using an in-house developed analytical pipeline . The sequencing reads were mapped to the GRCh37/hg19 human reference sequence using the Burrows-Wheeler Aligner (BWA)-MEM alignment algorithm. The BAM files were manipulated by Picard. HaplotypeCaller was used to call potential variant sites. The annotation and filtration of gene variants, including de novo variants, compound heterozygotes, and recessive inherited variants, were generated based on Gemini (version 0.19.1). The functional assessments, including functional prediction algorithms, conservation scores, and ensemble scores, were computed using GERP + + , CADD , SIFT , and Polyphen-2 . PCR-Sanger sequencing was performed to validate the candidate disease-related variants detected by WES based on Applied Biosystems 3730xl DNA Analyzer (Thermo Fisher Scientific, Waltham, MA, USA). The PCR program was followed: 95 °C for 3 min; 94 °C for 30 s, 58 °C for 30 s, 72 °C for 40 s (38 cycles); 72 °C for 8 min. The sequencing results were aligned to reference sequences through CodonCode Aligner (version 126.96.36.199; CodonCode, Centerville, MA, USA).
Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted for all the candidate variants detected by WES. The online software and human genome databases, including 1000 Genomes Project Phase 3 (Han Chinese in Beijing China), Mutation Taster, Polyphen-2, ACMG, and Mendelian Clinically Applicable Pathogenicity (M-CAP) Score, were applied to identify mutation frequencies and predict the functional effects of the variants.
Categorical variables were presented as number (percentage), and continuous variables were presented as median (interquartile range, IQR). Comparisons of categorical data were made by chi-square test. Comparisons of continuous data were made by the Wilcoxon rank-sum test. A two-side p < 0.05 was considered as statistically significant. All statistical analyses were performed using SPSS V26.0 for statistics and R V4.2.0 for visualization.
Clinical characteristics of pSS-PAH patients
The demographic and clinical manifestations of the patients are shown in Table 1. The patients were mainly female (97.06%), with a median age at onset of symptoms attributable to pSS of 33.50 years (range, 29.25–40.00 years) and a median age at onset of symptoms attributable to PAH of 34.00 years (range, 30.50–41.50 years). The profiles of autoantibodies included the presence of anti-SSA in 31 (91.18%) and anti-SSB in 11 (32.25%) cases. The majority of patients were consistent with the WHO functional class II (82.35%). Seven (20.59%) patients had a family history of rheumatic diseases.
Identification of variants from whole exome sequencing
A total of 141 pathogenic variant loci of 129 genes were identified by WES (Fig. 1, Additional file 1). In 34 patients, each patient carries 1 to 11 candidate pathologic variants. Variations of the following genes were identified in more than 1 patients: BCR (41.18%, n = 14), FLG (11.76%, n = 4), CRB1 (8.82%, n = 3), GIGYF2 (8.82%, n = 3), ILDR1 (8.82%, n = 3), ITK (8.82%, n = 3), LIPH (8.82%, n = 3), PRKRA (8.82%, n = 3), DYSF (5.88%, n = 2), ERCC2 (5.88%, n = 2), FMN2 (5.88%, n = 2), GJB4 (5.88%, n = 2), LAMC3 (5.88%, n = 2), MLH1 (5.88%, n = 2), MUTYH (5.88%, n = 2), NPHP4 (5.88%, n = 2), SERPINB7 (5.88%, n = 2), SLC26A4 (5.88%, n = 2), SOHLH1 (5.88%, n = 2), and TNNI3 (5.88%, n = 2). Missense, frameshift, stop-gain, splicing, and intronic were the major five types of variants found in this cohort, accounting for 38.46%, 25.44%, 18.93%, 12.43%, and 4.73% of the total mutations, respectively. Missense variation was the main variant type in CRB1, DYSF, ERCC2, GIGYF2, GJB4, ITK, LIPH, MLH1, MUTYH, NPHP4, SERPINB7, and TNNI3. Frameshift variation was the main variant type in BCR, FMN2, and LAMC3. Stop-gain variation was the main variant type in FLG, ILDR1, LAMC3, MUTYH, PRKRA, and SERPINB7. Splice variation was the main variant type in SLC26A4 and SOHLH1.
Function enrichment of susceptibility genes
The pathway analysis yielded 22 GO terms with a p-value < 0.01 and 7 KEGG terms with a p-value < 0.05 (Fig. 2). The GO terms with the greatest number of genes were “cytosol” (41.09%, 53 out of 129 genes), “extracellular exosome” (22.48%, 29 out of 129 genes), “membrane” (20.93%, 27 out of 129 genes), “ATP binding” (16.28%, 21 out of 129 genes), “calcium ion binding” (10.08%, 13 out of 129 genes), “apical plasma membrane” (7.75%, 10 out of 129 genes), “visual perception” (6.20%, 8 out of 129 genes). The KEGG terms with the greatest number of genes were “metabolic pathways” (20.16%, 26 out of 129 genes), “purine metabolism” (3.88%, 5 out of 129 genes), “thyroid hormone synthesis” (3.88%, 5 out of 129 genes), and “carbon metabolism” (3.88%, 5 out of 129 genes).
Correlation between genotype and phenotype
Correlation analysis between genotypes and observed phenotypes in the patients with pSS-PAH (Fig. 3) found that patients carrying FLG mutations (r = 0.491, p < 0.01) and those with gene variations involved in the purine pathway (r = 0.405, p < 0.01) were prone to having family history of rheumatic diseases. BCR variations (r = 0.429, p < 0.01) and gene variations involved in the extracellular exosome pathway (r = 0.404, p < 0.01) were associated with higher SSDDI scores. Patients carrying PRKRA variations (r = 0.412, p < 0.01) were prone to have a higher WHO cardiac function class.
Validation of susceptibility genes and pathogenicity prediction
Genes identified in more than one patient or identified in patient(s) with family history were confirmed in the Sanger sequencing. A total of 28 susceptibility variant loci from 24 genes were confirmed (Fig. 4, Additional file 2). The following pathogenic variants were identified in more than one patient: FLG c.12064A > T (n = 4), BCR c.3275_3278dupCCGG (n = 3), GIGYF2 c.3463C > A (n = 3), ITK c.1741C > T (n = 2), and SLC26A4 c.919-2A > G (n = 2). These variants, except for SLC26A4, were all located in exons and resulted in amino acid substitutions or truncation (Table 2). In addition, MutationTaster programs predicted c.12064A > T in FLG, c.3275_3278dupCCGG in BCR, c.1741C > T in ITK, and c.919-2A > G in SLC26A4 were disease-causing mutations. According to the ACMG criteria, these four variants were moderate pathogenic variants.
This is the first WES study aiming to find genetic variants associated with pSS-PAH. In the present study, we identified pathogenic variants in FLG, BCR, ITK, and SLC26A4, and one likely pathogenic variant in GIGYF2 through WES and subsequent Sanger sequencing confirmation. Furthermore, patients with variants in FLG are more likely to have a family history of rheumatic diseases.
The subjects enrolled in our study were incident or prevalent pSS-PAH patients with regular medical follow-up in our center. PAH is a rare and severe complication of pSS, characterized by hypertrophy and remodeling of the right ventricle [4, 28]. With the development of genetic technology such as whole-genome and whole-exome sequencing, several key genes were identified in patients with familial PAH and IPAH, especially BMPR2. Further analysis from cohorts of patients with CTD-PAH, mainly with SSc-PAH, has identified additional susceptibility genes including TBX4, ABCC8, KCNA5, and GDF2/BMP9 [9, 29]. To the best of our knowledge, the genetic features have not been reported in pSS-PAH patients worldwide. This pilot study is the first to explore genetic susceptibility of this severe complication of Sjögren’s syndrome. Our study demonstrated that several novel genes, but not susceptible genes in IPAH and other CTD-PAH, may determine the genetic susceptibility of developing pSS-PAH.
Patients with interleukin-2-inducible T-cell kinase (ITK) deficiency is prone to lymphoproliferative diseases, including Hodgkin and non-Hodgkin lymphoma, EBV lymphoproliferative disease, and hemophagocytic lymphohistiocytosis . A recent study in a family with two pSS patients (sisters) identified ITK c.1741C > T in both probands and one unaffected sister, but not in another unaffected sister. Further bioinformatic analyses confirmed ITK is an immune-related gene playing a role in regulating T cell differentiation and development and T-cell receptor proximal signaling . Though it was elucidated that the aberrant ITK is associated with pulmonary inflammation through T cell regulation and oxidative-stress mechanisms , this gene has not been elucidated in the pathogenesis of PAH. Our study confirmed disease-causing variant, ITK c.1741C > T, in the exon 16 of the ITK gene occurred not only in patients with pSS, but also in patients with pSS-PAH. Additional studies are required to explore the potential role of ITK for pulmonary vascular involvement in pSS. In addition, ITK inhibitor ibrutinib may be a potential treatment for pSS-PAH .
Solute carrier family 26 member 4 (SLC26A4), which maps to chromosome 7 at q22.3, encodes a membrane protein (pendrin) responsible for the anion (especially chloride) exchange between the cytosol and extracellular space in the inner ear and thyroid gland. Moreover, its genetic and epigenetic abnormalities have been identified in cancers such as prostate cancer , thyroid cancer , and acute myoid leukemia . Another study illustrated that the mutant SLC26A4 results in the excessive accumulation of chloride in the cytoplasm and thus induces cell apoptosis by inhibiting PI3K/Akt/mTOR pathway phosphorylation . PI3K/Akt/mTOR pathway has a strong link with the occurrence of PAH . In the present study, we observed that a pathogenic variant of the SLC26A4 gene may be involved with the risk of developing pSS-PAH. Replication in other CTD-PAH cohorts will be important to estimate the contribution of SLC26A4.
We also reported disease-causing variants in the gene BCR activator of RhoGEF and GTPase (BCR) and the gene encoding filaggrin (FLG), and a probably damaging variant in the Grb10 interacting GYF protein 2 (GIGYF2) gene. Furthermore, it was demonstrated that variations in the gene BCR were significantly associated with organ damage accrual in patients with pSS-PAH. We also detected a significant phenotype-genotype correlation between the gene FLG and the family history of rheumatic and musculoskeletal diseases among these pSS-PAH patients. The BCR gene, located on chromosome 22, is most known as the breakpoint for chromosomes 22 and 9 reciprocal translocation, which produces the Philadelphia chromosome and is common in patients with chronic myelogenous leukemia . Although the fusion gene has been extensively studied in the pathogenesis of leukemia, the function of BCR and whether it is a potential trigger to other tumors and diseases are not clear yet. FLG variants are the most replicated and strongest genetic risk factors for eczema and eczema-associated asthma . Furthermore, FLG variants participate in susceptibility to psoriasis, as well as other autoimmune and skin disorders [41, 42]. GIGYF2 variants are of interest for their important role in familial Parkinson’s disease [25, 43]. In addition, GIGYF2 protein was identified as an adapter protein that binds activated IGF-I and insulin receptors . Thus, our study suggests for the first time the roles of BCR, FLG, and GIGYF2 in the pathogenesis of pSS-PAH.
The study on susceptibility genes of multifactorial diseases, like pSS-PAH, remains challenging. Although our sample size was relatively small and we lack the data of the control group, this is the first WES study which clarifies the genotype–phenotype correlations in patients with pSS-PAH. Further studies are necessary to recruit healthy controls, pSS patients without PAH and IPAH patients, and large cohort of patients with pSS-PAH to conduct site-based association analysis for common variants and gene-based burden analysis for rare variants. Furthermore, more experiments are needed to illuminate the expression and related functions of these candidate genes.
Using WES on rare diseases cohort, our work firstly identified novel susceptibility genes associated with pSS-PAH. These variants in FLG, BCR, GIGYF2, ITK, and SLC26A4 may serve as potential biomarkers in Chinese pSS-PAH patients.
Availability of data and materials
The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.
Pulmonary arterial hypertension
Primary Sjögren’s syndrome
Kyoto Encyclopedia of Genes and Genomes
Polymerase chain reaction
Connective tissue disease
Systemic lupus erythematosus
Bone morphogenic protein receptor type 2
Bone morphogenetic protein 9
Peking Union Medical College Hospital
American College of Rheumatology
European League Against Rheumatism
Right heart catheterization
Mean pulmonary arterial pressure
Pulmonary artery wedge pressure
Ventilation perfusion scintigraphy
Computed tomographic pulmonary angiography
PSS disease damage index
World Health Organization
Interleukin-2-inducible T-cell kinase
Solute carrier family 26 member 4
Grb10 interacting GYF protein 2
Fox RI. Sjögren’s syndrome. Lancet. 2005;366(9482):321–31.
Zhao J, Wang Q, Liu Y, Tian Z, Guo X, Wang H, et al. Clinical characteristics and survival of pulmonary arterial hypertension associated with three major connective tissue diseases: A cohort study in China. Int J Cardiol. 2017;236:432–7.
Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D34-41.
Wang J, Li M, Wang Q, Zhang X, Qian J, Zhao J, et al. Pulmonary arterial hypertension associated with primary Sjögren’s syndrome: a multicentre cohort study from China. Eur Respir J. 2020;56(5):1902157.
Evans JD, Girerd B, Montani D, Wang XJ, Galiè N, Austin ED, et al. BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. Lancet Respir Med. 2016;4(2):129–37.
Wang XJ, Lian TY, Jiang X, Liu SF, Li SQ, Jiang R, et al. Germline BMP9 mutation causes idiopathic pulmonary arterial hypertension. Eur Respir J. 2019;53(3):1801609.
Wang XJ, Xu XQ, Sun K, Liu KQ, Li SQ, Jiang X, et al. Association of Rare PTGIS Variants With Susceptibility and Pulmonary Vascular Response in Patients With Idiopathic Pulmonary Arterial Hypertension. JAMA Cardiol. 2020;5(6):677–84.
Huang C, Yang J, Li MT, Wang Q, Zhao JL, Yang XX, et al. CBLN2 rs2217560 was Associated with Pulmonary Arterial Hypertension in Systemic Lupus Erythematosus. Chin Med J (Engl). 2018;131(24):3020–1.
Hernandez-Gonzalez I, Tenorio-Castano J, Ochoa-Parra N, Gallego N, Pérez-Olivares C, Lago-Docampo M, et al. Novel Genetic and Molecular Pathways in Pulmonary Arterial Hypertension Associated with Connective Tissue Disease. Cells. 2021;10(6):1488.
Imgenberg-Kreuz J, Rasmussen A, Sivils K, Nordmark G. Genetics and epigenetics in primary Sjogren's syndrome. Rheumatology (Oxford). 2019.
Li Y, Zhang K, Chen H, Sun F, Xu J, Wu Z, et al. A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjögren’s syndrome at 7q11.23. Nature Genetics. 2013;45:1361.
Reksten TR, Johnsen SJ, Jonsson MV, Omdal R, Brun JG, Theander E, et al. Genetic associations to germinal centre formation in primary Sjogren’s syndrome. Ann Rheum Dis. 2014;73(6):1253–8.
Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al. Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;61(6):554–8.
Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, et al. 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjögren’s Syndrome: A Consensus and Data-Driven Methodology Involving Three International Patient Cohorts. Arthritis Rheumatol. 2017;69(1):35–45.
Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67–119.
Vitali C, Palombi G, Baldini C, Benucci M, Bombardieri S, Covelli M, et al. Sjögren’s Syndrome Disease Damage Index and disease activity index: scoring systems for the assessment of disease damage and disease activity in Sjögren’s syndrome, derived from an analysis of a cohort of Italian patients. Arthritis Rheum. 2007;56(7):2223–31.
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16(3):1215.
Fan X, Zhao S, Yu C, Wu D, Yan Z, Fan L, et al. Exome sequencing reveals genetic architecture in patients with isolated or syndromic short stature. J Genet Genomics. 2021;48(5):396–402.
Davydov EV, Goode DL, Sirota M, Cooper GM, Sidow A, Batzoglou S. Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput Biol. 2010;6(12):e1001025.
Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46(3):310–5.
Vaser R, Adusumalli S, Leng SN, Sikic M, Ng PC. SIFT missense predictions for genomes. Nat Protoc. 2016;11(1):1–9.
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248–9.
Nemoto-Hasebe I, Akiyama M, Nomura T, Sandilands A, McLean WHI, Shimizu H. FLG mutation p.Lys4021X in the C-terminal imperfect filaggrin repeat in Japanese patients with atopic eczema. Br J Dermatol. 2009;161(6):1387–90.
Hu Z, Xiong Z, Xu X, Li F, Lu L, Li W, et al. Loss-of-function mutations in filaggrin gene associate with psoriasis vulgaris in Chinese population. Hum Genet. 2012;131(7):1269–74.
Ghani M, Lang AE, Zinman L, Nacmias B, Sorbi S, Bessi V, et al. Mutation analysis of patients with neurodegenerative disorders using NeuroX array. Neurobiol Aging. 2015;36(1):545.e9-14.
ClinVar. NM_005546.4(ITK):c.1741C>T (p.Arg581Trp) AND Lymphoproliferative syndrome 1. https://www.ncbi.nlm.nih.gov/clinvar/134372508/.
ClinVar. NM_005546.4(ITK):c.1741C>T (p.Arg581Trp) AND Autoinflammatory syndrome. https://www.ncbi.nlm.nih.gov/clinvar/134695889/.
Hassoun PM. Pulmonary Arterial Hypertension. N Engl J Med. 2021;385(25):2361–76.
Koumakis E, Wipff J, Dieudé P, Ruiz B, Bouaziz M, Revillod L, et al. TGFβ receptor gene variants in systemic sclerosis-related pulmonary arterial hypertension: results from a multicentre EUSTAR study of European Caucasian patients. Ann Rheum Dis. 2012;71(11):1900–3.
Ghosh S, Drexler I, Bhatia S, Adler H, Gennery AR, Borkhardt A. Interleukin-2-Inducible T-Cell Kinase Deficiency-New Patients, New Insight? Front Immunol. 2018;9:979.
Wang Y, Chen S, Chen J, Xie X, Gao S, Zhang C, et al. Germline genetic patterns underlying familial rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren’s syndrome highlight T cell-initiated autoimmunity. Ann Rheum Dis. 2020;79(2):268–75.
Nadeem A, Al-Harbi NO, Ahmad SF, Al-Harbi MM, Alhamed AS, Alfardan AS, et al. Blockade of interleukin-2-inducible T-cell kinase signaling attenuates acute lung injury in mice through adjustment of pulmonary Th17/Treg immune responses and reduction of oxidative stress. Int Immunopharmacol. 2020;83:106369.
Sagiv-Barfi I, Kohrt HE, Czerwinski DK, Ng PP, Chang BY, Levy R. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc Natl Acad Sci U S A. 2015;112(9):E966–72.
Luo C, Liu Z, Gan Y, Gao X, Zu X, Zhang Y, et al. SLC26A4 correlates with homologous recombination deficiency and patient prognosis in prostate cancer. J Transl Med. 2022;20(1):313.
Xing M, Tokumaru Y, Wu G, Westra WB, Ladenson PW, Sidransky D. Hypermethylation of the Pendred syndrome gene SLC26A4 is an early event in thyroid tumorigenesis. Cancer Res. 2003;63(9):2312–5.
Kroeger H, Jelinek J, Estécio MR, He R, Kondo K, Chung W, et al. Aberrant CpG island methylation in acute myeloid leukemia is accentuated at relapse. Blood. 2008;112(4):1366–73.
Dai X, Li J, Hu X, Ye J, Cai W. SLC26A4 Mutation Promotes Cell Apoptosis by Inducing Pendrin Transfer, Reducing Cl(-) Transport, and Inhibiting PI3K/Akt/mTOR Pathway. Biomed Res Int. 2022;2022:6496799.
Babicheva A, Makino A, Yuan JX. mTOR Signaling in Pulmonary Vascular Disease: Pathogenic Role and Therapeutic Target. Int J Mol Sci. 2021;22(4):2144.
Osman AEG, Deininger MW. Chronic Myeloid Leukemia: Modern therapies, current challenges and future directions. Blood Rev. 2021;49:100825.
Marenholz I, Kerscher T, Bauerfeind A, Esparza-Gordillo J, Nickel R, Keil T, et al. An interaction between filaggrin mutations and early food sensitization improves the prediction of childhood asthma. J Allergy Clin Immunol. 2009;123(4):911–6.
Oudot T, Lesueur F, Guedj M, de Cid R, McGinn S, Heath S, et al. An association study of 22 candidate genes in psoriasis families reveals shared genetic factors with other autoimmune and skin disorders. J Invest Dermatol. 2009;129(11):2637–45.
Ross KA. Coherent somatic mutation in autoimmune disease. PLoS One. 2014;9(7):e101093.
Lautier C, Goldwurm S, Dürr A, Giovannone B, Tsiaras WG, Pezzoli G, et al. Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease. Am J Hum Genet. 2008;82(4):822–33.
Higashi S, Iseki E, Minegishi M, Togo T, Kabuta T, Wada K. GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation. J Neurochem. 2010;115(2):423–37.
We thank all the patients for their participation. We thank Dr. Huan Mi from the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences for her work in data analysis, and Dr. Jieying Wang and Dr. Ziwei Liu from the Peking Union Medical College and Chinese Academy of Medical Sciences for their work in sample collecting.
This study was supported by the National College Students’ innovation training program (202010023025), CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1–005), the National High Level Hospital Clinical Research Funding (2022-PUMCH-B-013).
Ethics approval and consent to participate
All patients included in the cohort provided written informed consent prior to inclusion. This study was approved by the Institutional Review Board of PUMCH (JS-2038).
Consent for publication
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Susceptibility genes of primary Sjögren’s syndrome-associated pulmonary arterial hypertension identified by whole genome sequencing.
Variants found in FLG, BCR, GIGYF2, ITK, and SLC26A4 verified by Sanger sequencing.
About this article
Cite this article
Li, M., Shi, Y., Zhao, J. et al. Identification of potential susceptibility genes in patients with primary Sjögren’s syndrome-associated pulmonary arterial hypertension through whole exome sequencing. Arthritis Res Ther 25, 175 (2023). https://doi.org/10.1186/s13075-023-03171-y