{
  "abstract": "Introduction Raynaud’s phenomenon (RP) is often the first manifestation of systemic sclerosis (SSc), affecting 90% of SSc patients compared to only 5% of the general population. In addition, vascular and immune pathways, hallmarks in SSc pathogenesis, are also implicated in primary RP. Hence, we aimed to define the shared genetic architecture between these conditions to uncover underlying pathogenic mechanisms and identify primary RP individuals at high risk of developing SSc.Material and Methods To identify genetic variants associated with both diseases, we performed a cross-trait meta-analysis including ~8.6 million variants and 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 then conducted functional annotation of the associated variants to prioritize potential causal genes. Additionally, we calculated polygenic risk score (PRS) to assess the predictive utility of the identified variants.Results We observed a significant genetic correlation between SSc and primary RP (rg = 0.315 ± 0.105, p-value = 0.003), highlighting their shared genetic component. In addition, we identified five non-HLA pleiotropic loci, including MEOX2 as a novel association for both traits ( figure 1). Notably, MEOX2-associated variants showed a protective effect for primary RP but increased risk for SSc. We hypothesized that reduced MEOX2 expression could improve microvascular perfusion in primary RP, while exacerbating SSc via enhanced NF-κB signaling. Moreover, functional annotation revealed new candidate genes in vascular and inflammatory pathways, such as IL12A, NFKB1, TNIP1 for primary RP and ADRA2A for SSc. Finally, PRS comparison showed a significant difference between primary RP and SSc with secondary RP (mean PRS primary RP: -3.51E-3 vs mean PRS SSc with secondary RP: 7.01E-5; p-value = 7.52E-3), indicating that the PRS could distinguish between primary RP and SSc patients. Classification in the highest-risk PRS group was significantly associated with SSc comorbidity (p-value = 3.58E-2), corresponding to an increased relative risk of 1.29 [95% CI: 1.02 - 1.62] for developing SSc among primary RP individuals.Conclusions This study uncovers a genetic link between primary RP and SSc, identifying MEOX2 as a potential key contributor to their pathogenesis. Additionally, our results support the potential utility for early risk stratification of the genetic markers identified in the cross-trait meta-analysis and represent an initial step toward integrating genetic information into future personalized approaches for monitoring patients with primary RP.Abstract OC.41 Figure 1Manhattan plot for the cross-trait meta-analysis of primary RP and SSc. Chromosomes are displayed on the x-axis, while statistical significance is represented on the y-axis in -log10(p-value) format. The red line denotes the genome-wide significance threshold (p = 5 x 10’), and the blue dashed line marks the suggestive significance threshold (p = 5 x 10’5). Variants shown in gray are significant but do not meet the predefined criteria (nominal significance in each trait and a lower p-value in the meta-analysis compared to each individual trait). Loci that meet these criteria are labeled",
  "authors": [
    {
      "affiliations": [
        "Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain"
      ],
      "name": "Carlos Rangel-Peláez"
    },
    {
      "affiliations": [
        "Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain"
      ],
      "name": "Inmaculada Rodriguez-Martin"
    },
    {
      "affiliations": [
        "Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain"
      ],
      "name": "Carlos Rosa-Baez"
    },
    {
      "affiliations": [
        "Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain"
      ],
      "name": "Martin Kerick"
    },
    {
      "affiliations": [
        "Systemic Autoimmune Diseases Unit, Department of Internal Medicine, Hospital Universitari Vall d Hebron, Barcelona, Spain"
      ],
      "name": "Alfredo Gullen-Del-Castillo"
    },
    {
      "affiliations": [
        "Systemic Autoimmune Diseases Unit, Department of Internal Medicine, Hospital Universitari Vall d Hebron, Barcelona, Spain"
      ],
      "name": "Carmen Pilar Simeón-Aznar"
    },
    {
      "affiliations": [
        "Systemic Autoimmune Disease Unit, Hospital Clínico San Cecilio, Instituto de Investigación Biosanitaria Ibs. Granada, Granada, Spain"
      ],
      "name": "José Luis Callejas"
    },
    {
      "affiliations": [
        "Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Oliver Distler"
    },
    {
      "affiliations": [
        "International SSc Group, International, * Other"
      ],
      "name": "International SSc Group"
    },
    {
      "affiliations": [
        "PRECISESADS Clinical Consortium, International, * Other"
      ],
      "name": "PRECISESADS Clinical Consortium"
    },
    {
      "affiliations": [
        "Royal Adelaide Hospital and the University of Adelaide, Adelaide, Australia"
      ],
      "name": "Susanna Proudman"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Melbourne, Fitzroy, Australia",
        "The University of Sydney School of Public Health, Sydney, Australia"
      ],
      "name": "Mandana Nikpour"
    },
    {
      "affiliations": [
        "Australian Scleroderma Interest Group (ASIG), Australia, Australia"
      ],
      "name": "Australian SSc Interest Group (ASIG)"
    },
    {
      "affiliations": [
        "Department of Dermatology and Venereology, University Hospital Cologne, Cologne, Germany"
      ],
      "name": "Nicolas Hunzelmann"
    },
    {
      "affiliations": [
        "Department of Clinical and Molecular Science, Marche Polytechnic University, Ancona, Italy",
        "Department of Internal Medicine, Marche University Hospital, Ancona, Italy"
      ],
      "name": "Gianluca Moroncini"
    },
    {
      "affiliations": [
        "The Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands"
      ],
      "name": "Jeska de Vries-Bouwstra"
    },
    {
      "affiliations": [
        "The University of Manchester, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK"
      ],
      "name": "Ariane Herrick"
    },
    {
      "affiliations": [
        "Department of Rheumatology, Université Paris Cité UFR de Médecine, Paris, France"
      ],
      "name": "Yannick Allanore"
    },
    {
      "affiliations": [
        "Centre for Genomics and Oncological Research, Pfizer, University of Granada/Andalusian Regional Government, Granada, Spain"
      ],
      "name": "Marta Eugenia Alarcón-Riquelme"
    },
    {
      "affiliations": [
        "Scleroderma Unit, Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policl, Milan, Italy"
      ],
      "name": "Lorenzo Beretta"
    },
    {
      "affiliations": [
        "UT Health Houston, Division of Rheumatology, McGovern Medical School, Houston, USA"
      ],
      "name": "Maureen Mayes"
    },
    {
      "affiliations": [
        "Centre for Rheumatology, Royal Free Hospital, UCL, London, UK"
      ],
      "name": "Christopher Denton"
    },
    {
      "affiliations": [
        "UT Health Houston, Division of Rheumatology, McGovern Medical School, Houston, USA"
      ],
      "name": "Shervin Assassi"
    },
    {
      "affiliations": [
        "Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain"
      ],
      "name": "Javier Martín"
    },
    {
      "affiliations": [
        "Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain"
      ],
      "name": "Marialbert Acosta-Herrera"
    },
    {
      "affiliations": [
        "Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain"
      ],
      "name": "Lourdes Ortiz-Fernández"
    }
  ],
  "title": "OC.41 Cross-trait genetic analysis reveals MEOX2 as a novel susceptibility locus shared between primary Raynaud’s phenomenon and systemic sclerosis",
  "uid": "9ff8c331-fefe-5604-8150-55007b16c735"
}