Table 1.
Genetic regions associated with systemic sclerosis, including evidence for sharing with autoimmune diseases, for natural selection, and implicated agent of selection
| Gene region | Band location | Approach | Phenotype | References | AD overlap | Natural selection | Selective pressure |
| KIAA0319L | 1p34.3 | GWA | lcSSc | [24] | |||
| IL12RB2 * | 1p31.3 | GFU | [28] | BeD, PBC | |||
| IL23R | 1p31.3 | CG | 33, 34 | AS, BeD, CD, IBD, PS, UC | Y | Protozoa | |
| VCAM1 | 1p21.2 | IC | [27▪] | MS | |||
| PTPN22 | 1p13.2 | CG | [35–37] | CD, MG, RA, T1D, VT | Y | Protozoa | |
| CD247 * | 1q24.2 | CG, GWA | [22,23,25,38] | CelD, RA | |||
| TNFSF4 * | 1q25.1 | CG, GWA | ACA | [24,39–41] | MS, RA, SLE | Y | |
| NMNAT2 | 1q25.3 | GWA | ACA | [24] | |||
| RHOB | 2p24.1 | GWA | [22] | ||||
| STAT4 * | 2q32.3 | CG, GWA | [22–25,27▪,42–45] | BeD, IBD,PBC, RA, SLE, SS, CelD + RA | |||
| PPARG | 3p25 | GFU | [32] | ||||
| PLCL2 | 3p24.3 | CG | [73] | MS, PBC, RA | |||
| DNASE1L3-PXK * | 3p14.1 | IC | ACA | [24,26▪,27▪] | RA, SLE | ||
| IL12A * | 3q25.33 | IC | lcSSc | [26▪] | BeD, CelD, MS, PBC | Y | |
| TLR2 | 4q32 | CG | ATA | [46] | |||
| BANK1-NFKB1 | 4q24 | CG, GFU | dcSSc, ATA | [29,73,47,48] | CD, PBC, MS, SLE, UC | ||
| TNIP1 * | 5q33.1 | GFU, GWA | [22,24,30] | IBD, MG, PS, SLE | Y | ||
| HLA region * | 6p21.33 | [70] | All ADs | Y | Bacterial infection | ||
| UHRF1BP1 | 6p21.31 | GWA | [24] | SLE | Y | M. tuberculosis | |
| ATG5 * | 6q21 | IC, GWA | [24,26▪] | RA, SLE | |||
| TNFAIP3 * | 6q23.3 | CG, GWA | SSc, dcSSc and ATA | [24,49–51] | CelD, IBD, MS, PS, RA, SLE, SS, UC | ||
| CCR6 | 6q27 | CG | ATA | [52] | RA | ||
| JAZF1 | 7p15.1 | GWA | [24] | CD, RA, T1D | |||
| GRB10 | 7p12.1 | GWA | lcSSc | [23] | |||
| IRF5 * | 7q32.1 | CG, GWA | [22–25,27▪,53–55] | PBC, RA, SLE, UC | |||
| BLK * | 8p23.1 | CG, GWA | [24,56–58] | KA, RA, SLE | Y | ||
| PSD3 | 8p21.3 | GFU | [29] | ||||
| IL2RA | 10p15.1 | CG | ACA | [59] | AA, CD, IBD, MS, RA, T1D | ||
| FAS | 10q24.1 | CG | 60, 61 | ||||
| IRF7 | 11p15.5 | CG, GWA | ACA | 24, 62 | SLE | ||
| EHF | 11p13 | GWA | lcSSc | [24] | SLE | ||
| TREH-DDX6 | 11q23.3 | IC | [26▪] | SLE, CelD + RA | |||
| KCNA5 | 12p13 | CG | SScPAH | [63] | |||
| SOX5 | 12p12.1 | GWA | ACA | [23] | |||
| RPL41-ESYT1 | 12q13.2 | GWA | dcSSc | [23] | T1D | ||
| PLD4 | 14q32.33 | CG | [50] | RA | |||
| CSK * | 15q24.2 | GFU, GWA | 24, 29 | ||||
| IRF8 * | 16q24.1 | GWA | lcSSc | [23,24,73] | IBD, MS, PBC, RA, UC | Y | |
| NLRP1 | 17p13.2 | CG | [64] | Y | |||
| IKZF3 | 17q12 | GWA | ACA | [24] | IBD, PBC | ||
| TBX21 | 17q21.32 | CG | [64] | AS, MS | |||
| CD226 | 18q22.2 | CG | [65] | IBD, RA, T1D | |||
| IL12RB1 * | 19p13.1 | IC FU | [31] | MS | |||
| MIF | 22q11.23 | CG | 66, 67 | ||||
| IRAK1 | Xq28 | CG | 68, 69 | RA |
Disease abbreviations: AA, alopecia areata; AD, autoimmune disease; AS, ankylosing spondylitis; BeD, Behçet's disease; CelD, celiac disease; CD, Crohn's disease; IBD, inflammatory bowel disease; KA, Kawasaki disease; MG, myasthenia gravis; MS, multiple sclerosis; PBC, primary biliary cirrhosis; PS, psoriasis; RA, rheumatoid arthritis; HLA: human leukocyte antigen; SLE, systemic lupus erythematosus; SS, Sjögren's syndrome; T1D, type 1 diabetes; UC, ulcerative colitis; VT, vitiligo. No overlap was observed for Addison's disease, autoimmune thyroid disease, Graves’ disease, juvenile idiopathic arthritis, primary sclerosing cholangitis, psoriatic arthritis, and sarcoidosis. Genetic regions with strong evidence of selection attributed to host–pathogen coevolution were compiled from a recent review [86▪].
*Established SSc loci (genome-wide significance or two independent replications with P < 5 × 10−4) are denoted by an asterisk. Approaches used include genome-wide association (GWA), candidate gene (CG), Immunochip (IC), GWAS follow-up (GFU), and IC follow-up (IC FU) studies. SSc phenotypes with stronger association than SSc are shown (lcSSC: limited cutaneous SSc; dcSSC: diffuse cutaneous SSc; ATA: antitopoisomerase I antibody; ACA: anticentromere antibody; SScPAH: SSc-associated pulmonary arterial hypertension). Autoimmune disease (AD) sharing based on genetic regions reported in the National Human Genome Research Institute's Catalog of Published Genome-Wide Association Studies (http://www.genome.gov/gwastudies) accessed on 27 March 2015 [80].