Relationship Between Genetic Risk and Age of Diagnosis in Systemic Lupus Erythematosus

Daniela Dominguez; Sylvia Kamphuis; Joseph Beyene; Joan Wither; John B Harley; Irene Blanco; Catarina Vila-Inda; Hermine Brunner; Marissa Klein-Gitleman; Deborah McCurdy; Dawn M Wahezi; Thomas Lehman; Marija Jelusic; Christine A Peschken; Janet E Pope; Dafna D Gladman; John G Hanly; Ann E Clarke; Sasha Bernatsky; Christian Pineau; C Douglas Smith; Susan Barr; Gilles Boire; Eric Rich; Earl D Silverman; Canadian Network for Improved Outcomes in SLE (CaNIOS) and APPLE Investigators

doi:10.3899/jrheum.200002

Relationship Between Genetic Risk and Age of Diagnosis in Systemic Lupus Erythematosus

J Rheumatol. 2021 Jun;48(6):852-858. doi: 10.3899/jrheum.200002. Epub 2020 Oct 15.

Authors

Daniela Dominguez¹, Sylvia Kamphuis², Joseph Beyene³, Joan Wither⁴, John B Harley⁵, Irene Blanco⁶, Catarina Vila-Inda⁶, Hermine Brunner⁷, Marissa Klein-Gitleman⁸, Deborah McCurdy⁹, Dawn M Wahezi¹⁰, Thomas Lehman¹¹, Marija Jelusic¹², Christine A Peschken¹³, Janet E Pope¹⁴, Dafna D Gladman¹⁵, John G Hanly¹⁶, Ann E Clarke¹⁷, Sasha Bernatsky¹⁸, Christian Pineau¹⁹, C Douglas Smith²⁰, Susan Barr²¹, Gilles Boire²², Eric Rich²³, Earl D Silverman; Canadian Network for Improved Outcomes in SLE (CaNIOS) and APPLE Investigators

Affiliations

¹ D. Dominguez, MSc, Division of Rheumatology, Hospital for Sick Children, Hospital for Sick Children, Research Institute, University of Toronto, Toronto, Ontario, Canada.
² S. Kamphuis, MD, PhD, Division of Rheumatology Department of Pediatrics, Sophia Children's Hospital, Erasmus Medical Center, Rotterdam, the Netherlands.
³ J. Beyene, PhD, Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton.
⁴ J. Wither, MD, PhD, Division of Genetics and Development, Krembil Research Institute, Arthritis Centre of Excellence, Division of Rheumatology, Toronto Western Hospital, University Health Network, Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada.
⁵ J.B. Harley, MD, PhD, Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati, and US Department of Veterans Affairs Medical Center, Cincinnati, Ohio.
⁶ I. Blanco, MD, C. Vila-Inda, MD, Albert Einstein College of Medicine, Division of Rheumatology, Bronx, New York.
⁷ H. Brunner, MD, MSc, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
⁸ M. Klein-Gitleman, MD, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
⁹ D. McCurdy, MD, Division of Pediaitric Rheumatology, University of California Los Angeles, Los Angeles, California.
¹⁰ D.M. Wahezi, MD, Children's Hospital at Montefiore, Division of Pediatric Rheumatology, Albert Einstein College of Medicine, the Bronx, New York.
¹¹ T. Lehman, MD, Division of Pediatric Rheumatology, Hospital for Special Surgery, New York, New York, USA.
¹² M. Jelusic, MD, Department of Pediatric Rheumatology, University of Zagreb School of Medicine, Zagreb, Croatia.
¹³ C.A. Peschken, MD, MSc, Departments of Medicine and Community Health Sciences, University of Manitoba, Winnipeg, Manitoba.
¹⁴ J.E. Pope, MD, MPH, Professor of Medicine, Department of Medicine, University of Western Ontario, London, Ontario.
¹⁵ D.D. Gladman, MD, Department of Medicine, University of Toronto, Toronto, Ontario.
¹⁶ J.G. Hanly, MD, Division of Rheumatology, Department of Medicine and Department of Pathology, Queen Elizabeth II Health Sciences Center and Dalhousie University, Halifax, Nova Scotia.
¹⁷ A.E. Clarke, MD, Cumming School of Medicine, University of Calgary, Calgary, Alberta.
¹⁸ S. Bernatsky, MD, PhD, Department of Medicine, McGill University, Montreal, Quebec.
¹⁹ C. Pineau, MD, Department of Medicine, McGill University Hospital, Montreal, Quebec.
²⁰ C.D. Smith, MD, Department of Medicine, Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario.
²¹ S. Barr, MD, Division of Rheumatology, Department of Medicine, University of Calgary, Calgary, Alberta.
²² G. Boire, MD, Division of Rheumatology, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec.
²³ E. Rich, MD, Division of Rheumatology, Centre Hospitalier de l'Université de Montreal, Department of Medicine, University of Montreal School of Medicine, Montreal, Quebec.

PMID: 33060314
DOI: 10.3899/jrheum.200002

Abstract

Objective: Specific risk alleles for childhood-onset systemic lupus erythematosus SLE (cSLE) vs adult-onset SLE (aSLE) patients have not been identified. The aims of this study were to determine if there is an association (1) between non-HLA-related genetic risk score (GRS) and age of SLE diagnosis, and (2) between HLA-related GRS and age of SLE diagnosis.

Methods: Genomic DNA was obtained from 2001 multiethnic patients and genotyped using the Immunochip. Following quality control, genetic risk counting (GRCS), weighted (GRWS), standardized counting (GRSCS), and standardized weighted (GRSWS) scores were calculated based on independent single-nucleotide polymorphisms from validated SLE loci. Scores were analyzed in a regression model and adjusted by sex and ancestral population.

Results: The analyzed cohort consisted of 1540 patients: 1351 females and 189 males (675 cSLE and 865 aSLE). There were significant negative associations between all non-HLA GRS and age of SLE diagnosis: P = 0.011 and r² = 0.175 for GRWS; P = 0.008 and r² = 0.178 for GRSCS; P = 0.002 and r² = 0.176 for GRSWS (higher GRS correlated with lower age of diagnosis.) All HLA GRS showed significant positive associations with age of diagnosis: P = 0.049 and r² = 0.176 for GRCS; P = 0.022 and r² = 0.176 for GRWS; P = 0.022 and r² = 0.176 for GRSCS; P = 0.011 and r² = 0.177 for GRSWS (higher GRS correlated with higher age of diagnosis).

Conclusion: Our data suggest that there is a linear relationship between genetic risk and age of SLE diagnosis and that HLA and non-HLA GRS are associated with age of diagnosis in opposite directions.

Keywords: SLE; SNP; age of onset; genetic risk score.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Age of Onset
Child
Female
Genetic Predisposition to Disease
Genotype
Humans
Lupus Erythematosus, Systemic* / diagnosis
Lupus Erythematosus, Systemic* / genetics
Male
Polymorphism, Single Nucleotide
Risk Factors