GWAS meta‑analysis of axial spondyloarthritis and Behçet’s disease identifies CXCR6 as a novel MHC‑I‑opathy gene in a Turkish population

Author: Dr. Mohammad Saeed

Dr. Mohammad Saeed is a member of the EULAR MHC-I-opathy group.

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“MHC-I-opathy” is a family of inflammatory disorders with a strong genetic link to HLA-I. These include Axial spondyloarthritis (AxSpA; previously Ankylosing spondylitis (AS) associated with HLA-B27), Behçet’s disease (BD; associated with HLA-B51) and psoriasis. Though the MHC-I genetic associations were discovered about 50 years ago, the pathogenesis of these disorders is not fully understood. To identify immunogenetic pathways for MHC-I-opathies, a cluster-based meta-analysis of AxSpA and BD Genome-wide association studies (GWAS) using OASIS was conducted. Both selected GWAS were from Turkiÿe for homogenous population effect.

OASIS (Objective Assimilation of SNPs Interacting in Synchrony) is a GWAS clustering algorithm, developed by Dr. Mohammad Saeed to identify genes of modest significance. These are often missed in classic analysis that use Manhattan plots to identify significant associations in GWAS. Clustering or binning methods, such as OASIS, increase power by decreasing the number of tests per study.

HLA-I was the only locus that was highly significant (P<1× ­10–8) in both GWAS datasets. OASIS identified 234 independent modestly significant non-HLA loci in the two GWAS datasets (Bonferroni correction: P≤2.14×10⁻4; −log10 P≥3.67). The most signficant genes that this study identified were IL23R (1p31.3), LACC1 (13q14.11) and the novel CXCR6 (3p21.31). These are significantly associated with both AxSpA and BD. All three genes are down-regulated in these MHC-I-opathies. Protein interaction network showed that CXCR6 is part of the interactome of IL23R and LACC1 (P=0.00243). The novel gene, CXCR6, identified here codes for a G-protein coupled receptor expressed in several T-cell subsets and regulate their migration to tissues. A previous biological study showed that CXCR6+ CD8+ T-cells were actively recruited to psoriasis-affected skin. It also showed that TNF-α inhibition, which is part of the therapeutics (such as the biologic medications Eternacept, Adalimumab and Infliximab) for AxSpA and BD, reduced the CXCR6-mediated T-cell recruitment.

In summary, this study identified 15 loci common to both AxSpA and BD that may provide diagnostic and therapeutic targets for MHC-I-opathy. Major candidate genes for MHC-I-opathy identified here are IL23R, LACC1, and CXCR6. By integrating locus-level significance with functional validation in independent expression datasets, we ensured that only statistically robust and biologically relevant associations were highlighted, thereby strengthening the reliability and interpretability of our findings.

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Dr. Mohammad Saeed was invited to present his research on the ‘Genetics of MHC-I-Opathy’ at the British Society for Rheumatology (BSR) (April 24, 2024). The summary of the research was published in the official BSR Journal, Rheumatology.

The presentation was well-received by the august audience of Rheumatologists and Immunologists at the BSR 2024. A lengthy follow-up meeting was held at the University of Leeds and a collaboration for data and analysis exchange was established with Dr. Mohammad Saeed. University of Leeds has been recognized as a center of excellence in Rheumatology by EULAR (European League against Rheumatism) since 2005.

This research received no funding to perform. However, participation at the BSR 2024 Meeting was sponsored by High-Q and KIAZEN Pharmaceuticals, Pakistan. This was considered Advertising campaign for the Sponsors and declared at the BSR Meeting Oral Presentation. 

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Dr. Mohammad Saeed, M.D.
Consultant Rheumatology and Immunogenetics
Fellowships (USA): Rheumatology, Musculoskeletal Ultrasound, Genomics, Immunology

Dr. Mohammad Saeed graduated from Aga Khan University Medical College and has Fellowships in Genomics from Northwestern University, Chicago, and Immunology from the University of Arkansas for Medical Sciences (UAMS). He trained in Internal Medicine and Rheumatology at UAMS and has further specialization in Musculoskeletal Ultrasound from Boston University (USSONAR program). He has been faculty at UAMS and Staff Scientist at Nephropath, USA.

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He is an active researcher working on the genetics of lupus and other autoimmune disorders and has previously contributed substantially to Neurogenetics. He has several publications in international journals and has been a member of professional organizations including the American College of Rheumatology, European Lupus Society (SLEuro) and American Society of Human Genetics. He is a member of the Pakistan Society for Rheumatology and Health Research Advisory Board, Pakistan.

Rheumatology deals with inflammation anywhere in the body (kidneys, lungs, brain, and nerves, or even eyes) as well as disorders of joints and bones. These conditions are often difficult to diagnose due to the variety of symptoms they produce in different organ systems. Dr. Saeed has a special interest in patients who have not had a diagnosis despite visiting several doctors. Other common Rheumatologic diseases Dr. Saeed manages, include Osteoporosis and Osteoarthritis, Rheumatoid arthritis, Gout, Systemic lupus erythematosus, Myositis, Reactive arthritis, Psoriasis, and Vasculitis. These conditions can vary from mild to severe disease but have good treatments available especially if diagnosed early.

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Often patients ask about drug side-effects while others are confused by their Google searches. Here’s my presentation in Pakistan Society for Rheumatology (PSR) 2017 on side-effects of Rheumatology medications. Moreover, the link to American College of Rheumatology (ACR) Patient-care and Treatment site is also provided as a reliable comprehensive source for our patients.

Dr. Saeed’s PSR Presentation on drug side-effects

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Autoimmune Disease management requires specific medications, many of which are not readily available for our patients or are available at high costs. To better serve our patients ImmunoCure has opened a Pharmacy, staffed by highly competent Pharmacists. We aim to provide patients with a wide variety of medications at the lowest possible costs in an organized environment. Since ImmunoCure deals with Rheumatology, Neuroimmunology, Infectious Diseases and General Internal Medicine as well, we offer patients of these specialties similar services. For our patients from afar we provide home delivery as well.

Pakistan Society for Rheumatology (PSR) Conference 2019 was held in Karachi. Dr. Mohammad Saeed gave a plenary talk on “Lupus Nephritis” and reviewed the pathogenesis and treatment of the disease. This presentation is available for download using the link below. The presentation included kidney biopsy findings. the role of antibodies, mechanism of disease induction and propagation and how the various lupus drugs act, as well the latest genetic findings including APOL1 in Collapsing lupus glomerulopathy and PLA2R1 in Membranous glomerulonpehritis (MGN) and its interaction with lupus. These major genetic discoveries are co-authored by Dr. Mohammad Saeed.

ImmunoCure now offers PLA2R antibody test for MGN which may help in obviating the need for kidney biopsy in these patients and may be decisive in choosing a therapeutic regimen.

Dr. Mohammad Saeed Lupus Nephritis PDF

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Dr. Mohammad Saeed was invited to talk on the “Multiple Sclerosis Pathogenesis” at the Aga Khan University (AKU). The event was organized by the Multiple Sclerosis Research and Education Forum at AKU led by Professor Mohammad Wasay (Neurologist). The day-long Multiple Sclerosis (MS) workshop was part of a nation-wide effort to train medical and paramedical staff in MS care. The presentation by Dr. Mohammad Saeed is attached below.

Early diagnosis and treatment is key to preventing neurological damage to patients. At ImmunoCure Laboratory rapid and efficient tests of the highest quality are available for a vast array of autoimmune diseases, including those affecting the nervous system. For demyelinating diseases such as Multiple Sclerosis, Neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSD) ImmunoCure offers Immunoflourescence based testing for Aquaporin-4 (AQP4) antibody and myelin oligodendrocyte glycoprotein (MOG) antibody. AQP4-Ab is present in 80% of NMO while MOG-Ab is present in ~ 30% of NMOSD negative for AQP4-Ab. MOG-Ab is also present in 30-40% of acute disseminated encephalomyelitis (ADEM) and 5% of MS patients (1). These novel tests are helping Neurologists across Pakistan in making accurate and early diagnosis of autoimmune neurological diseases. Early diagnosis followed by rapid treatment, often with the latest biologic medications, has a major impact on reducing complications of these devastating diseases which were formerly thought to be incurable.

1. Peschl et al. (2017). Front Immunol. PMID: 28533781

Dr. Mohammad Saeed Multiple Sclerosis Presentation

Academic Debate: Ocrevus vs Rituximab for Multiple sclerosis Treatment