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In SLE genetics, white does not equal black, 1+1 does not equal 2

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Science Immunology  04 Aug 2017:
Vol. 2, Issue 14, eaao3114
DOI: 10.1126/sciimmunol.aao3114

Abstract

A transancestral SLE study examining the relationship between genetic load and disease risk.

Recent genetic association studies for immune-mediated diseases have been carried out using a microarray that probes 195,806 single-nucleotide polymorphisms (SNPs), including the top 2000 independent associations for 11 autoimmune and inflammatory diseases. The article by Langefeld et al. describes a large systemic lupus erythematosus (SLE) genotyping study of three groups, including cases and controls of African American (AA), Hispanic Amerindian (HA), and European (EA) ancestry. Statistical analysis revealed 83 non–human leukocyte antigen (HLA) SLE risk associations, primarily in the EA group. Several risk regions were linked to genes by expression quantitative trait loci (eQTL) analyses and indicate how variations in gene expression levels and predicted altered protein levels might contribute to disease pathogenesis.

Transancestral meta-analysis of HLA alleles supported a compound risk allele heterozygosity model, indicating that having two different HLA risk alleles conferred greater risk of disease than having two copies of the same risk allele. Analyses of HLA class II suggested that risk and protective alleles were influenced by key HLA amino acid sequences. Overall, the SLE HLA was characterized by a complex multigenic effect.

Two limitations of this work were the EA bias in the design of the array and the lower frequencies of AA (20%) and HA (14%) samples available for the study. However, previous studies have been principally limited to samples of EA origin. This work highlights the need for more genetic studies on non-EA individuals because they are more likely to develop SLE and can have more severe disease.

The authors show that SLE risk is a nonlinear function of the risk allele load; propose “cumulative hit hypothesis for autoimmune diseases”; and suggest that, as the number of risk alleles or “genetic load” increases in an individual, the immune system may be more prone to dysfunction. Further endeavors to delineate the affected genes, key pathways, and cell types involved in disease will advance targeted strategies toward individualized treatments for SLE and other autoimmune diseases.

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