Functional and Practical Insights Into the Genetic Basis of Takayasu Arteritis

Abstract

Takayasu arteritis (TAK) is a rare vasculitis characterized by inflammation of large arteries. Although the exact etiology of TAK remains unclear, a genetic predisposition to the disease has been established. Large-scale genetic studies have significantly contributed to the identification of genetic variation associated with immune-mediated diseases. To date, five genome-wide association studies (GWAS) have been performed in TAK, identifying multiple genetic susceptibility loci across the genome. Here, we summarize the major findings from GWAS in TAK and provide an in silico functional evaluation of the associated loci (P < 5 × 10^-8) and variants in high linkage disequilibrium with them (r² > 0.8). By exploring gene expression and chromatin interaction data, we identified candidate causal genes in TAK, some of them with well-known functional implications. The analysis of transcription factor motifs within TAK-associated loci revealed enrichment of the STAT and RUNX families, both characterized by their role in immune functions and inflammatory responses. The enrichment in biological processes in susceptibility loci confirmed the involvement of specific immune-related pathways in TAK. Further, we devised and calculated a cumulative genetic risk score for TAK and confirmed differences in genetic risk for the disease among ancestries. Finally, we provide a practical guide to communicate genetic information for TAK to patients and families.

Figure 1

Timeline summarizing large‐scale genetic studies conducted in Takayasu arteritis. Genotyping arrays, sample sizes, and populations included in each study are indicated.

Figure 2

HOMER motif enrichment of Takayasu arteritis–associated SNPs and variants in high linkage disequilibrium with them (r² > 0.8). A window of 200 bp upstream and downstream of each SNP was applied, and a total of one million random genomic windows were selected as background. The following are transcription factor family abbreviations: BHLH, basic helix‐loop‐helices; BZIP, basic leucine zipper; ETS, erythroblast transformation specific; HMG, high‐mobility group; IRF, interferon‐regulatory factor; NR, nuclear receptors; RUNX, runt‐related transcription factor; STAT, signal transducer and activator of transcription; ZF, zinc finger. The following are transcription factor abbreviations: DUX, double homeobox; SIX4, sine oculis homeobox homolog 4; GLI3, GLI family zinc finger 3; MAFK, MAF BZIP transcription factor K; GLI2, GLI family zinc finger 2; IRF8, interferon regulatory factor 8; SREBP1A, sterol regulatory element binding transcription factor 1; STAT6, signal transducer and activator of transcription 6; ZNF264, zinc finger protein 264; RUNX1, RUNX family transcription factor 1; RUNX‐AML, RUNX family transcription factor related to acute myeloid leukemia; OCT6, POU class 3 homeobox 1; SOX9, SRY‐box transcription factor 9; RUNX2, RUNX family transcription factor 2; EHF, ETS homologous factor; KLF5, Kruppel‐like factor 5; PR, progesterone receptor. SNP, single‐nucleotide polymorphism.

Figure 3

Gene ontologies (Biological Process) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways main clusters enriched in Takayasu arteritis‐related loci. Genes annotated from Takayasu arteritis‐associated single‐nucleotide polymorphisms in large‐scale genetic studies, variants in high linkage disequilibrium with them (r² > 0.8), and overlapping genes among eQTL and physical interaction annotations were used as input. Metascape web‐based portal was used to perform this analysis. Only terms with a P <1 × 10⁻³ and at least three genes in the term were reported. eQTL, expression quantitative trait loci.

Figure 4

Cumulative GRS for Takayasu arteritis–associated loci across the major populations of the 1000 Genomes Project phase 3 release. The red histogram represents the GRS including all the genetic susceptibility loci (P < 5 × 10⁻⁸), and the blue line depicts the genetic risk in loci annotated to HLA genes. One‐way analysis of variance P was < 1 × 10⁻⁴ for both the total GRS and the GRS for HLA genes. Tukey's multiple comparisons tests were used to evaluate pairwise differences among populations, and P values represent the analysis for the total GRS. Error bars represent the standard error of mean for each population. **P < 0.01; ****P < 0.0001. GRS, genetic risk score.