Transancestral study findings may lead to improved lupus diagnosis and treatment and solve ethnic disparities.
Systemic lupus erythematosus (SLE) has a strong genetic contribution to risk, concluded authors from more than 70 universities who collaborated in identifying 24 new genetic markers that predispose persons to SLE. Both ancestry-dependent and ancestry-independent contributions to SLE risk were found.
Discovering the genomic regions that contribute to an accelerating pattern of SLE risk led the researchers to propose the “cumulative hit hypothesis”-the genetic risk manifests as a nonlinear function of the cumulative risk allele load, a pattern potentially shared across autoimmune and non-autoimmune diseases.
An immune system normally can absorb the effect of some of the risky genes, they stated, but as the number of genes increases, the immune system becomes overwhelmed and a disorder such as SLE results.
SLE has marked gender and ethnic disparities, the international researchers noted. They conducted a large transancestral association study of SLE using Immunochip genotype data from 27,574 persons of European, African, and Hispanic Amerindian ancestry. They identified 83 distinct non-HLA regions, including 24 novel SLE regions, refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect.
The study findings were published recently in Nature Communications.
The ancestral distribution of the genes may explain the ethnic disparities in SLE, the researchers suggested.
“These new observations will help direct future research to better diagnose and treat the disease while also providing insights into why lupus disproportionately affects certain ethnicities at higher rates and more severely,” said Rosalind Ramsey-Goldman, MD, DrPH, the Solovy/Arthritis Research Society Research Professor of Medicine in the Division of Rheumatology at Northwestern University.
“There is a genetic predisposition to developing lupus and this study will help scientists decipher the heterogeneous manifestations of the disease, which is hard to diagnose and treat,” she added. “The hope is that these discoveries lead to better diagnostic tools, such as biomarkers, and assist in the development of targeted therapies.”
Large-scale population screening may not be financially practical, said the authors, but accelerating the diagnosis of suspected lupus by testing narrowly for genetic markers such as those revealed in the current study may be realistic.
The research, led by scientists at the Wake Forest School of Medicine, was supported by the Alliance for Lupus Research, the Arthritis Research UK Special Strategic Award, National Institutes of Health (NIH) grant AR049084; the International Consortium on the Genetics of Systemic Lupus Erythematosus AI083194, CA141700 and AR058621; Excellence Project, Ministry of Andalusia AR043814, AR-06562, AR060366, MD007909, AI107176, AR-057172, RC2 AR058959, U19 A1082714, R01 AR063124, P30 GM110766, R01 AR056360, P60 AR053308, MUSC part is from UL1RR029882 and 5P60AR062755; Oklahoma Samples U19AI082714, U01AI101934, P30GM103510, U54GM104938 and P30AR053483; Northwestern P60 AR066464 and 1U54TR001018; This study was supported by the U.S. National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH K01 AR067280, P60 AR062755, N01AR22265; APPLE Investigators R01AR43727; NIH AR 043727 and 069572; NIAMS/NIH P50-AR055503. The study was also supported by the RILITE foundation and Genentech.
Langefeld CD, Ainsworth HC, Cunninghame Graham DS, et al. “Transancestral mapping and genetic load in systemic lupus erythematosus.” Nat Commun. 2017 Jul 17;8:16021. doi: 10.1038/ncomms16021.