Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Jan 2;94(1):47-61.
doi: 10.1016/j.ajhg.2013.12.002.

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

Maureen D Mayes  1 , Lara Bossini-Castillo  2 , Olga Gorlova  3 , José Ezequiel Martin  4 , Xiaodong Zhou  5 , Wei V Chen  3 , Shervin Assassi  5 , Jun Ying  3 , Filemon K Tan  5 , Frank C Arnett  5 , John D Reveille  5 , Sandra Guerra  6 , María Teruel  4 , Francisco David Carmona  4 , Peter K Gregersen  7 , Annette T Lee  7 , Elena López-Isac  4 , Eguzkine Ochoa  4 , Patricia Carreira  8 , Carmen Pilar Simeón  9 , Iván Castellví  10 , Miguel Ángel González-Gay  11 ; Spanish Scleroderma Group; Alexandra Zhernakova  12 , Leonid Padyukov  13 , Marta Alarcón-Riquelme  14 , Cisca Wijmenga  12 , Matthew Brown  15 , Lorenzo Beretta  16 , Gabriela Riemekasten  17 , Torsten Witte  18 , Nicolas Hunzelmann  19 , Alexander Kreuter  20 , Jörg H W Distler  21 , Alexandre E Voskuyl  22 , Annemie J Schuerwegh  23 , Roger Hesselstrand  24 , Annika Nordin  13 , Paolo Airó  25 , Claudio Lunardi  26 , Paul Shiels  27 , Jacob M van Laar  28 , Ariane Herrick  29 , Jane Worthington  29 , Christopher Denton  6 , Fredrick M Wigley  30 , Laura K Hummers  30 , John Varga  31 , Monique E Hinchcliff  31 , Murray Baron  32 , Marie Hudson  32 , Janet E Pope  33 , Daniel E Furst  34 , Dinesh Khanna  35 , Kristin Phillips  35 , Elena Schiopu  35 , Barbara M Segal  36 , Jerry A Molitor  37 , Richard M Silver  38 , Virginia D Steen  39 , Robert W Simms  40 , Robert A Lafyatis  40 , Barri J Fessler  41 , Tracy M Frech  42 , Firas Alkassab  43 , Peter Docherty  44 , Elzbieta Kaminska  45 , Nader Khalidi  46 , Henry Niall Jones  47 , Janet Markland  48 , David Robinson  49 , Jasper Broen  50 , Timothy R D J Radstake  50 , Carmen Fonseca  6 , Bobby P Koeleman  51 , Javier Martin  4
Collaborators, Affiliations

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

Maureen D Mayes et al. Am J Hum Genet. .

Abstract

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

PubMed Disclaimer

Figures

Figure 1
Figure 1
HLA Region: 28,000,000–36,000,000 bp Manhattan plots in which each dot represents the p value of a variant (−log10(p value)) on the vertical axis and the position in chromosome 6 on the horizontal axis. The ACA model comprised HLA-DRβ1 amino acid 13, HLA-DQα1 amino acid 69, and SNPs rs12528892 and rs6933319. The ATA model comprised HLA-DRβ1 amino acids 67 and 86 and HLA-DPβ1 amino acids 76 and 96. The SSc model included the previously described ACA and ATA models and SNPs rs17500468, rs9277052, rs2442719, and rs4713605.
Figure 2
Figure 2
Forest Plots Showing the Population-Specific and Pooled Analyses of the Variants at Genome-wide or Suggestive Significance in the SSc versus Control Analysis (A) rs35677470 in DNASE1L3. (B) rs77583790 in the SCHIP1-IL12A locus. (C) rs9373839 in ATG5. (D) rs7130875 in the TREH-DDX6 locus.
Figure 3
Figure 3
Regional Plots of the Associations Replicated at Genome-wide Significance in SSc Cases or Different Subgroups in the Overall Meta-analysis after Imputation (A) DNASE1L3 associations in the ACA+ versus control comparison. (B) DNASE1L3 associations in the ACA+ versus control comparison after conditioning on the lead variant (rs35677470). (C) SCHIP1-IL12A locus associations in the lcSSc versus control comparison. (D) SCHIP1-IL12A locus associations in the lcSSc versus control comparison after conditioning on the lead variant (rs77583790). (E) ATG5 associations in the dcSSc versus control comparison. (F) ATG5 associations in the dcSSc versus control comparison after conditioning on the lead variant (rs9373839). p values correspond to the discovery phase.
See this image and copyright information in PMC

References

    1. Bolster M.B., Silver R.S. Clinical features of systemic sclerosis. In: Hochberg M.C., Silman A.J., Smolen J.S., Weinblatt M.E., Weisman M.H., editors. Fifth Edition. Mosby, Elsevier; Philadelphia: 2011. pp. 1373–1386. (Rheumatology).
    1. LeRoy E.C., Black C., Fleischmajer R., Jablonska S., Krieg T., Medsger T.A., Jr., Rowell N., Wollheim F. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J. Rheumatol. 1988;15:202–205. - PubMed
    1. Steen V.D. Autoantibodies in systemic sclerosis. Semin. Arthritis Rheum. 2005;35:35–42. - PubMed
    1. Martín J.E., Bossini-Castillo L., Martín J. Unraveling the genetic component of systemic sclerosis. Hum. Genet. 2012;131:1023–1037. - PubMed
    1. Mayes M.D. The genetics of scleroderma: looking into the postgenomic era. Curr. Opin. Rheumatol. 2012;24:677–684. - PMC - PubMed

Publication types

MeSH terms