Although previous studies have suggested a relationship between telomere shortening and systemic sclerosis (SSc), the association between these two traits remains poorly understood. The objective of this study was to assess the causal relationship between telomere length in leukocytes (LTL) and SSc using the two-sample Mendelian randomization approach, with the genome-wide association study data for both LTL and SSc. The results of inverse-variance weighted regression (OR = 0.716 [95% CI 0.528–0.970], p = 0.031) and the Mendelian randomization pleiotropy residual sum and outlier method (OR = 0.716 [95% CI 0.563–0.911], p = 0.035) indicate an association between telomere length and SSc. Specifically, longer genetically predicted LTL is associated with a reduced risk of SSc. Sensitivity tests highlight the significant roles of the variants rs10936599 and rs2736100 annotated to the TERC and TERT genes, respectively. Our findings suggest an influence of telomere length in leukocytes on the development of SSc.

Objective: The common gain-of-function variant rs35705950, located in the promoter of MUC5B gene, has been strongly associated with interstitial lung diseases (ILDs) of different aetiology, such as idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated ILD (RA-ILD). In this study, we aimed to investigate the association of this variant and its nearby single nucleotide polymorphisms (SNPs) in the largest cohort of systemic sclerosis-associated ILD (SSc-ILD) to date. Methods: Samples were collected from blood/saliva, followed by DNA extraction and genotyping using SNP arrays. Data for rs35705950 and additional 903 variants within 100 Kb were obtained using genomic imputation. Subsequently, we tested their association in a meta-analysis to increase the consistency of the results, including 10 European ancestry cohorts comprising 2363 patients with SSc-ILD, 3526 SSc patients without ILD and 15 076 controls. Results: Meta-analysis showed no significant association between rs35705950 and SSc-ILD, either comparing patients with SSc with and without ILD (p value: 0.588, OR: 1.05, 95% CI: 0.87 to 1.27) nor patients with SSc-ILD with controls (p value: 0.061, OR: 1.16, 95% CI: 0.99 to 1.36). Moreover, none of the additional 903 variants tested in the genomic region reached statistical significance. Conclusion: Despite analysing the largest and most statistically powered SSc-ILD cohort to date, we found no evidence of association between the MUC5B promoter variant rs35705950 and its surrounding SNPs with SSc-ILD. These results suggest that the pathogenic mechanisms underlying SSc-ILD may only partially overlap with those of other similar ILDs, such as IPF or RA-ILD. This highlights the need for further studies regarding their genetic architecture.

Erdheim–Chester Disease (ECD) is a rare histiocytosis characterized by a wide spectrum of clinical manifestations. Although somatic mutations have been involved in ECD, its etiology remains poorly understood. This study aimed to identify novel molecular mechanisms involved in ECD through the first integrated methylome and transcriptome analysis. Peripheral blood samples were collected from 137 ECD patients and 410 controls. Genome-wide DNA methylation and transcriptome analyses were performed, followed by functional in silico studies using different online bioinformatics tools. Subsequently, methylome and transcriptome data were integrated, and a drug repurposing approach was undertaken. Our results revealed 2511 differentially methylated positions and 1484 differentially expressed genes associated with ECD. The integrative analysis identified 46 alterations in DNA methylation patterns that regulate the expression levels of 29 altered genes in ECD patients, highlighting key genes involved in immune response and tumorigenesis. Remarkably, our results identified B cells and NF-kB signaling pathway as novel contributors of ECD pathogenesis. Finally, the drug repurposing analysis identified potential therapeutic options for ECD patients. In conclusion, this study represents an important advance in understanding the molecular basis of ECD, proposing novel cell types and pathways involved in ECD pathogenesis and suggesting new avenues for clinical management.

Objectives: Coronavirus disease 2019 (COVID-19) and SSc share multiple similarities in their clinical manifestations, alterations in immune response and therapeutic options. These resemblances have also been identified in other immune-mediated inflammatory diseases where a common genetic component has been found. Thus, we decided to evaluate for the first time this shared genetic architecture with SSc. Methods: For this study, we retrieved genomic data from two European-ancestry cohorts: 2 597 856 individuals from The COVID-19 Host Genetics Initiative consortium, and 26 679 individuals from the largest genomic scan in SSc. We performed a cross-trait meta-analyses including >9.3 million single nucleotide polymorphisms. Finally, we conducted functional annotation to prioritize potential causal genes and performed drug repurposing analysis. Results: Our results revealed a total of 19 non-HLA pleiotropic loci, including 2 novel associations for both conditions (BMP1 and PPARG) and 12 emerging as new shared loci. Functional annotation of these regions underscored their potential regulatory role and identified potential causal genes, many of which are implicated in fibrotic and inflammatory pathways. Remarkably, we observed an antagonistic pleiotropy model of the IFN signalling between COVID-19 and SSc, including the well-known TYK2 P1104A missense variant, showing a protective effect for SSc while being a risk factor for COVID-19, along with two additional novel pleiotropic associations (IRF8 and SENP7). Finally, our findings provide new therapeutic options that could potentially benefit both conditions. Conclusion: Our study confirms the genetic resemblance between susceptibility to and severity of COVID-19 and SSc, revealing a novel common genetic contribution affecting fibrotic and immune pathways.

We aimed to analyze the role of the common genetic variants located in the PIN1 locus, a relevant prolyl isomerase required to control the proliferation of spermatogonial stem cells and the integrity of the blood–testis barrier, in the genetic risk of developing male infertility due to a severe spermatogenic failure (SPGF). Genotyping was performed using TaqMan genotyping assays for three PIN1 taggers (rs2287839, rs2233678 and rs62105751). The study cohort included 715 males diagnosed with SPGF and classified as suffering from non-obstructive azoospermia (NOA, n = 505) or severe oligospermia (SO, n = 210), and 1058 controls from the Iberian Peninsula. The allelic frequency differences between cases and controls were analyzed by the means of logistic regression models. A subtype specific genetic association with the subset of NOA patients classified as suffering from the Sertoli cell-only (SCO) syndrome was observed with the minor alleles showing strong risk effects for this subset (OR_addrs2287839 = 1.85 (1.17–2.93), OR_addrs2233678 = 1.62 (1.11–2.36), OR_addrs62105751 = 1.43 (1.06–1.93)). The causal variants were predicted to affect the binding of key transcription factors and to produce an altered PIN1 gene expression and isoform balance. In conclusion, common non-coding single-nucleotide polymorphisms located in PIN1 increase the genetic risk to develop SCO.

Objective: Raynaud’s phenomenon (RP) is the first noticeable symptom of systemic sclerosis (SSc), appearing even years before other signs. Vascular and immune pathways, hallmarks in SSc pathogenesis, are implicated in primary RP. Hence, we aimed to define the shared genetic architecture between these conditions to explore pathogenic mechanisms and whether pleiotropic loci could help identify primary RP patients at increased genetic risk of developing SSc. Methods: We analysed genome-wide association study (GWAS) summary statistics for primary RP (4 986 cases and 850 981 controls) and SSc (10 654 cases and 18 043 controls). We performed a cross-trait meta-analysis (∼8.6M single nucleotide polymorphisms) to identify variants associated with both diseases. Functional annotation was used to prioritise potential causal genes. We also constructed a polygenic risk score (PRS) to assess clinical implications. Results: Beyond the well-known HLA associations, we identified five additional pleiotropic loci, including MEOX2 as a novel association for both traits with opposing effects, ADRA2A representing a novel genetic factor for SSc, and IL12A, NFKB1 and TNIP1 as novel loci for primary RP. Functional annotation highlighted vascular and inflammatory pathways. Finally, the PRS model shows modest discrimination (area under the curve = 0.57). However, it allows the identification of primary RP individuals at high genetic risk of developing SSc (75th percentile, relative risk =1.29 [95% CI 1.02, 1.62]; P-value= 3.58 × 10−2). Conclusion: This study reveals a genetic link between primary RP and SSc, identifying five novel pleiotropic loci and supporting the potential of genetic profiling for early risk assessment and personalised monitoring strategies.