Genetics of Sjögren’s syndrome in the genome-wide association era
John A. Ice
, Indra Adrianto
, Paul Chee Lin
, Jennifer A. Kelly
, Courtney G. Montgomery
Christopher J. Lessard
, Kathy L. Moser
Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA
Department of Pathology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd, BMSB 451, Oklahoma City, OK 73104, USA
Received 7 January 2012
Accepted 7 January 2012
While Sjögren’s syndrome (SS) is more common than related autoimmune disorders, such as systemic
lupus erythematosus (SLE) and rheumatoid arthritis (RA), scientiﬁc and medical research in SS has lagged
behind signiﬁcantly. This is especially true in the ﬁeld of SS genetics, where efforts to date have relied
heavily on candidate gene approaches. Within the last decade, the advent of the genome-wide associ-
ation (GWA) scan has altered our understanding of disease pathogenesis in hundreds of disorders
through the successful identiﬁcation of novel risk loci. With strong evidence for a genetic component in
SS as evidenced by familial aggregation of SS as well as similarities between SS and SLE and RA, the
application of GWA approaches would likely yield numerous novel risk loci in SS. Here we review the
fundamental scientiﬁc principles employed in GWA scans as well as the limitations of this tool, and we
discuss the application of GWA scans in determining genetic variants at play in complex disease. We also
examine the successful application of GWA scans in SLE, which now has more than 40 conﬁrmed risk
loci, and consider the possibility for a similar trajectory of SS genetic discovery in the era of GWA scans.
Ultimately, the GWA studies that will be performed in SS have the potential to identify a myriad of novel
genetic loci that will allow scientists to begin ﬁlling in the gaps in our understanding of the SS
Ó 2012 Elsevier Ltd. All rights reserved.
Sjögren’s syndrome (SS) is a chronic, progressive exocrinopathy
characterized by lymphocytic inﬁltration and destruction of glan-
dular tissue, namely the salivary and lacrimal glands, with or
without the production of autoantibodies. Primary symptoms
include severe dry eyes and dry mouth, although clinical signs and
symptoms are extremely heterogeneous and can involve virtually
any organ system. Even though SS has a relatively high prevalence
(0.5e1.0%) compared to similar autoimmune diseases like systemic
lupus erythematosus (0.1% for European-Americans and 0.4% for
African-Americans), it remains vastly understudied [1,2]. This
disparity in the research of autoimmune diseases becomes clear if
one considers the number of genetics publications in the ﬁeld of
autoimmunity across the last four decades (Fig. 1). Note that there
are far few SS genetics publications each year than in comparable
autoimmune disorders. The reasons for this lag in SS research are
complex and multifaceted, but stem in large part from challenges of
assembling large cohorts of patients with clearly deﬁned SS.
Nonetheless, with the formation of global partnerships and
collaborations, we are beginning to build the framework for
advanced genetic research to elucidate SS pathogenesis.
While many diseases have clear-cut diagnostic criteria, the same
cannot be said for SS. Since this syndrome was ﬁrst described in
1933, more than eight sets of classiﬁcation criteria for SS have been
developed and published by different groups from across the world.
These variations in criteria have led to extreme heterogeneity and
the potential for inconsistencies in the classiﬁcation process,
making the assembly of large patient cohorts with clearly deﬁned
SS very difﬁcult. Currently, the most widely accepted classiﬁcation
criteria were published in 2002 by the American-European
Consensus Group, which had sought to develop a set of interna-
tionally recognized classiﬁcation criteria, but instead represents
a revision to the previous European criteria . These criteria
require a battery of multi-disciplinary tests, several of which
(including ocular staining and minor salivary gland biopsy) require
the skill of an experienced clinician in order to be reliable.
While SS genetic research has continued in spite of these chal-
lenges, the ﬁeld has fallen short of other autoimmune diseases. The
Corresponding author. Arthritis and Clinical Immunology, Oklahoma Medical
Research Foundation, 825 NE 13th Street, Oklahoma City, Oklahoma 73104, USA.
Tel.: þ1 405 271 2534; fax: þ1 405 271 2536.
E-mail address: firstname.lastname@example.org (K.L. Moser).
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Journal of Autoimmunity
journal homepage: www.elsevier.com/locate/jautimm
0896-8411/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
Journal of Autoimmunity 39 (2012) 57e63