Genome-wide association study for systemic lupus erythematosus in an egyptian population

Ashraf A Elghzaly; Celi Sun; Loren L Looger; Misa Hirose; Mohamed Salama; Noha M Khalil; Mervat Essam Behiry; Mohamed Tharwat Hegazy; Mohamed Ahmed Hussein; Mohamad Nabil Salem; Ehab Eltoraby; Ziyad Tawhid; Mona Alwasefy; Walaa Allam; Iman El-Shiekh; Menattallah Elserafy; Anwar Abdelnaser; Sara Hashish; Nourhan Shebl; Abeer Abdelmonem Shahba; Amira Elgirby; Amina Hassab; Khalida Refay; Hanan Mohamed El-Touchy; Ali Youssef; Fatma Shabacy; Abdelkader Ahmed Hashim; Asmaa Abdelzaher; Emad Alshebini; Dalia Fayez; Samah A El-Bakry; Mona H Elzohri; Eman Nagiub Abdelsalam; Sherif F El-Khamisy; Saleh Ibrahim; Gaafar Ragab; Swapan K Nath

doi:10.3389/fgene.2022.948505

Genome-wide association study for systemic lupus erythematosus in an egyptian population

Front Genet. 2022 Oct 17:13:948505. doi: 10.3389/fgene.2022.948505. eCollection 2022.

Authors

Ashraf A Elghzaly¹, Celi Sun², Loren L Looger³, Misa Hirose⁴, Mohamed Salama⁵, Noha M Khalil⁶, Mervat Essam Behiry⁶, Mohamed Tharwat Hegazy⁶, Mohamed Ahmed Hussein⁶, Mohamad Nabil Salem⁷, Ehab Eltoraby⁸, Ziyad Tawhid¹, Mona Alwasefy¹, Walaa Allam⁹, Iman El-Shiekh⁹, Menattallah Elserafy⁹, Anwar Abdelnaser⁵, Sara Hashish⁵, Nourhan Shebl⁵, Abeer Abdelmonem Shahba¹⁰, Amira Elgirby¹¹, Amina Hassab¹², Khalida Refay¹³, Hanan Mohamed El-Touchy¹³, Ali Youssef¹⁴, Fatma Shabacy¹⁴, Abdelkader Ahmed Hashim¹⁵, Asmaa Abdelzaher¹⁶, Emad Alshebini¹⁷, Dalia Fayez¹⁸, Samah A El-Bakry¹⁸, Mona H Elzohri¹⁹, Eman Nagiub Abdelsalam²⁰, Sherif F El-Khamisy^{21

22

9}, Saleh Ibrahim⁴, Gaafar Ragab⁶, Swapan K Nath²

Affiliations

¹ Department of Clinical Pathology, Faculty of Medicine, Mansoura University, El-Mansoura, Egypt.
² Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States.
³ Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, United States.
⁴ Division of Genetics, Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
⁵ Institute of Global Health and Human Ecology, The American University in Cairo, New Cairo, Egypt.
⁶ Rheumatology and Clinical Immunology Unit, Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt.
⁷ Department of Internal Medicine, Faculty of Medicine, Beni-Suef University, Beni Suef, Egypt.
⁸ Department of Internal Medicine, Faculty of Medicine, Mansoura University, El-Mansoura, Egypt.
⁹ Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza, Egypt.
¹⁰ Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt.
¹¹ Department of Internal Medicine, Faculty of Medicine, Alexandria University, Bab Sharqi, Egypt.
¹² Department of Clinical Pathology, Faculty of Medicine, Alexandria University, Bab Sharqi, Egypt.
¹³ Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt.
¹⁴ Department of Rheumatology and Immunology, Faculty of Medicine, Benha University Hospital, Benha, Egypt.
¹⁵ Department of Internal Medicine, Faculty of Medicine, South Valley University, Qena, Egypt.
¹⁶ Department of Clinical Pathology, Faculty of Medicine, South Valley University, Qena, Egypt.
¹⁷ Department of Internal Medicine, Faculty of Medicine, Menoufia University, Al Minufiyah, Egypt.
¹⁸ Rheumatology and Clinical Immunology Unit, Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
¹⁹ Department of Internal Medicine, Faculty of Medicine, Assiut University, Asyut, Egypt.
²⁰ Department of Clinical Pathology, Faculty of Medicine, Assiut University, Asyut, Egypt.
²¹ The Healthy Lifespan Institute, University of Sheffield, Sheffield, United Kingdom.
²² The Institute of Cancer Therapeutics, University of Bradford, Bradford, United Kingdom.

Abstract

Systemic lupus erythematosus (SLE) susceptibility has a strong genetic component. Genome-wide association studies (GWAS) across trans-ancestral populations show both common and distinct genetic variants of susceptibility across European and Asian ancestries, while many other ethnic populations remain underexplored. We conducted the first SLE GWAS on Egyptians-an admixed North African/Middle Eastern population-using 537 patients and 883 controls. To identify novel susceptibility loci and replicate previously known loci, we performed imputation-based association analysis with 6,382,276 SNPs while accounting for individual admixture. We validated the association analysis using adaptive permutation tests (n = 10⁹). We identified a novel genome-wide significant locus near IRS1/miR-5702 (P_corrected = 1.98 × 10^-8) and eight novel suggestive loci (P_corrected < 1.0 × 10^-5). We also replicated (P_perm < 0.01) 97 previously known loci with at least one associated nearby SNP, with ITGAM, DEF6-PPARD and IRF5 the top three replicated loci. SNPs correlated (r ² > 0.8) with lead SNPs from four suggestive loci (ARMC9, DIAPH3, IFLDT1, and ENTPD3) were associated with differential gene expression (3.5 × 10^-95 < p < 1.0 × 10^-2) across diverse tissues. These loci are involved in cellular proliferation and invasion-pathways prominent in lupus and nephritis. Our study highlights the utility of GWAS in an admixed Egyptian population for delineating new genetic associations and for understanding SLE pathogenesis.

Keywords: Egypt; GWAS; admixture; imputation; lupus.

Copyright © 2022 Elghzaly, Sun, Looger, Hirose, Salama, Khalil, Behiry, Hegazy, Hussein, Salem, Eltoraby, Tawhid, Alwasefy, Allam, El-Shiekh, Elserafy, Abdelnaser, Hashish, Shebl, Shahba, Elgirby, Hassab, Refay, El-Touchy, Youssef, Shabacy, Hashim, Abdelzaher, Alshebini, Fayez, El-Bakry, Elzohri, Abdelsalam, El-Khamisy, Ibrahim, Ragab and Nath.