Supplementary Table 1 | Loci associated with SSc and its clinical phenotypes in candidate-gene studies and genome-wide
association studies
Gene
SNP (associated
allele/genotype)
Association
with
Population
STAT4
rs7574865 (T
allele)
lcSSc
lcSSc
ACA+
SSc
SSc
European
Japanese
Japanese
French
NorthAmerican
SSc
ANA+
Fibrosing
alveolitis
SSc
dcSSc
ATA+
SSc
dcSSc
SSc
dcSSc
ATA+
SSc
IRF5
rs11889341
(dominant A
allele)
rs2004640 (TT
genotype)
rs10954213 (AA
genotype)
rs2280714 (AA
genotype)
TBX21
BANK1
rs11650354 (TT
genotype)
rs10516487 (G
allele)
SSc
dcSSc
ATA+
rs10516487 (T
allele)
rs17266594 (T
allele)
dcSSc
SSc
dcSSc
ATA+
rs3733197 (G
allele)
dcSSc
ATA+
BLK
rs3733197 (A
allele)
rs2736340 (TT
genotype)
dcSSc
SSc
ACA+
Size (tested
phenotype/HC
)
1317/3113
282/590
87/590
885/970
902/4745
Odds Ratio (95%
Confidence
interval)
1.54 (1.36–1.74)
1.35 (1.10–1.66)
1.62 (1.17–2.22)
1.29 (1.11–1.51)
1.29 (1.20–1.50)
Reference
French
French
French
881/760
608/760
280/760
1.58 (1.18–2.11)
1.59 (1.16–2.17)
2.07 (1.38–3.11)
Dieude et al. (2009)S3
Dieude et al. (2009)S3
Dieude et al. (2009)S3
Japanese
Japanese
Japanese
Japanese
Japanese
Japanese
Japanese
Japanese
NorthAmerican
European and
North
American
European and
North
American
European and
North
American
European
281/477
142/477
87/477
281/477
142/477
281/477
142/477
87/477
902/4745
1.23
1.27
1.56
1.41
1.38
1.72
2.05
2.10
3.37
Ito et al. (2009)S5
Ito et al. (2009)S5
Ito et al. (2009)S5
Ito et al. (2009)S5
Ito et al. (2009)S5
Ito et al. (2009)S5
Ito et al. (2009)S5
Ito et al. (2009)S5
Gourh et al. (2009)S4
2362/3248
1.12 (1.03–1.22)
Rueda et al. (2010)S6
770/3284
1.20 (1.05–1.37)
Rueda et al. (2010)S6
435/3284
1.20 (1.02–1.41)
Rueda et al. (2010)S6
431/1118
0.77 (0.64–0.93)
Dieude et al. (2009)S7
European
North
American
European
North
American
European
North
American
European
North
American
European
North
American
European
and
2351/3231
1.14 (1.05–1.25)
Rueda et al. (2010)S6
and
613/3231
1.23 (1.08–1.41)
Rueda et al. (2010)S6
and
478/3231
1.24 (1.05–1.46)
Rueda et al. (2010)S6
and
613/3143
1.15 (1.02–1.31)
Rueda et al. (2010)S6
and
447/3143
1.26 (1.07–1.47)
Rueda et al. (2010)S6
431/1137
0.73 (0.61–0.87)
Dieude et al. (2009)S7
1639/1416
1.71 (1.2–2.4)
Gourh et al. (2010)S8
510/1416
2.27 (1.5–3.5)
Gourh et al. (2010)S8
European and
North
American
European and
North
American
(0.91–1.65)
(0.87–1.85)
(0.98-2.49)
(1.0.1–1.96)
(0.90–2.10)
(1.18–2.50)
(1.23–3.41)
(1.12–3.95)
(2.40–4.60)
Rueda et al. (2009)S1
Tsuchiya et al. (2009)S2
Tsuchiya et al. (2009)S2
Dieude et al. (2009)S3
Gourh et al. (2009)S4
rs2736340 (CT
genotype)
and
1639/1416
1.31 (1.1–1.5)
Gourh et al. (2010)S8
and
510/1416
1.6 (1.2–2.0)
Gourh et al. (2010)S8
and
1639/1416
1.25 (1.1–1.4)
Gourh et al. (2010)S8
and
510/1416
1.42 (1.2–1.7)
Gourh et al. (2010)S8
309/769
1.45 (1.17–1.79)
Ito et al. (2010)S9
1059/698
1.2 (1.1–1.5)
Gourh et al. (2010)S8
174/698
1.4 (1.1–1.9)
Gourh et al. (2010)S8
1059/698
1.2 (1.04–1.4)
Gourh et al. (2010)S8
300/698
1.3 (1.1–1.6)
Gourh et al. (2010)S8
174/698
1.3 (1.02–1.7)
Gourh et al. (2010)S8
SSc
NorthAmerican
NorthAmerican
NorthAmerican
NorthAmerican
NorthAmerican
European
2856/2920
1.15 (1.02–1.31)
lcSSc
European
1608/2920
1.22 (1.07–1.38)
ACA+
European
828/2920
1.23 (1.10–1.37)
SSc
1059/698
0.8 (0.7–0.97)
193/698
1.4 (1.1–1.8)
Gourh et al. (2010)S8
lcSSc
NorthAmerican
NorthAmerican
European
Bossini-Castillo et al.
(2011)S10
Bossini-Castillo et al.
(2011)S10
Bossini-Castillo et al.
(2011)S10
Gourh et al. (2010)S8
1673/2977
1.1 (1.01–1.20)
ACA+
European
860/2977
1.12 (1.01–1.25)
lcSSc
European
1653/2946
0.91 (0.83–0.99)
ACA+
European
856/2912
0.90 (0.80–1.00)
SSc
European
2894/2991
1.18 (1.08-1.29)
lcSSc
European
1639/2991
1.20 (1.09–1.33)
ACA+
European
840/2991
1.22 (1.07–1.38)
FA
ATA+
SSc
European
European
European and
North
American
French
French
French
French
European and
US
European and
US
674/1587
536/1587
5049/9740
1.19 (1.05–1.36)
1.23 (1.07–1.41)
0.85 (0.81–0.89)
Bossini-Castillo et al.
(2011)S10
Bossini-Castillo et al.
(2011)S10
Bossini-Castillo et al.
(2011)S10
Bossini-Castillo et al.
(2011)S10
Bossini-Castillo et al.
(2011)S10
Bossini-Castillo et al.
(2011)S10
Bossini-Castillo et al.
(2011)S10
Dieude et al. (2011)S11
Dieude et al. (2011)S11
Radstake et al.
(2010)S12
1031/1014
308/1014
643/1014
346/1014
3360/10143
0.78
0.79
0.79
0.78
0.75
(0.68–0.88)
(0.65–0.95)
(0.69–0.92)
(0.65–0.93)
(0.69–0.81)
Dieude et al. (2011)S13
Dieude et al. (2011)S13
Dieude et al. (2011)S13
Dieude et al. (2011)S13
Gorlova et al. (2011)S14
3360/10143
1.15 (1.09–1.22)
Gorlova et al. (2011)S14
SSc
ACA+
rs13277113 (AA
genotype)
SSc
ACA+
TNFSF4/
OX40L
rs13277113 (A
allele)
rs2205960 (T
allele)
SSc
SSc
ATA+
rs1234314 (G
allele)
SSc
ACA+
ATA+
rs844648 (A
allele)
ARA+
rs844644 (A
allele)
rs12039904 (T
allele)
NLRP1
rs8182352 (C
allele)
CD247
rs2056626 (G
allele)
IRF8
GRB10
rs11642873 (A
allele)
rs12540874 (A
allele)
SSc
dcSSc
lcSSc
FA
lcSSc
lcSSc
European
North
American
European
North
American
European
North
American
European
North
American
Japanese
SOX5
TNIP1
rs11047102 (C
allele)
rs2233287 (A
allele)
rs2233287 (A
allele)
rs4958881
ACA+
SSc
European and
US
European
1791/10143
1.36 (1.21–1.52)
Gorlova et al. (2011)S14
2246/ 4684
1.31 (1.15–1.43)
Allanore et al. (2011)S15
European and
4389/7611
1.19
Bossini-Castillo et al.
US
(2013)S16
SSc
European and
4389/7611
1.19
Bossini-Castillo et al.
US
(2013)S16
rs3792783
SSc
European and
4389/7611
1.19
Bossini-Castillo et al.
US
(2013)S16
IL12RB
rs3790567 (A
SSc
European and
5991/10080
1.17 (1.11–1.24)
Bossini-Castillo et al.
allele)
US
(2012)S17
DNASE1I rs35677470
SSc
European and
1833/3466
1.47
Mayes et al. (2014)S18
L3
US
lcSSc
European and
1833/3466
1.62
Mayes et al. (2014)S18
US
ACA+
European and
1833/3466
2.03
Mayes et al. (2014)S18
US
SCHIP1/I Rs77583790
SSc
European and
1833/3466
2.57
Mayes et al. (2014)S18
L12A
US
lcSSc
European and
1833/3466
2.81
Mayes et al. (2014)S18
US
ACA+
European and
1833/3466
2.76
Mayes et al. (2014)S18
US
ATG5
rs9373839
SSc
European and
1833/3466
1.19
Mayes et al. (2014)S18
US
IRAK1
rs1059702
FA
European
849/625
2.09 (1.35–3.24)
Dieude et al. (2011)S19
European and
3065/2630
1.30 (1.07–1.58)
Carmona et al.
US
(2013)S20
Abbreviations: ACA+, anti-centromere antibody in serum; ATA+, anti-topoisomerase antibody in serum); dcSSc, diffuse
cutaneous systemic sclerosis; FA, fibrosing alveolitis; lcSSc, limited cutaneous systemic sclerosis; SSc, systemic sclerosis; SNP,
single nucleotide polymorphism.
SSc
Supplementary references
S1. Rueda, B. et al. The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype. Hum.
Mol. Genet. 18, 2071–2077 (2009).
S2. Tsuchiya, N. et al. Association of STAT4 polymorphism with systemic sclerosis in a Japanese population. Ann.
Rheum. Dis. 68, 1375–1376 (2009).
S3. Dieude, P. et al. STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on
disease susceptibility and related pulmonary fibrosis. Arthritis Rheum. 60, 2472–2479 (2009).
S4. Gourh, P. et al. Polymorphisms in TBX21 and STAT4 increase the risk of systemic sclerosis: evidence of
possible gene-gene interaction and alterations in Th1/Th2 cytokines. Arthritis Rheum. 60, 3794–3806 (2009).
S5. Ito, I. et al.. Association of a functional polymorphism in the IRF5 region with systemic sclerosis in a Japanese
population. Arthritis Rheum. 60, 1845–1850 (2009).
S6. Rueda, B. et al. BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in
Caucasians. Ann. Rheum. Dis. 69, 700–705 (2010).
S7. Dieude, P. et al. BANK1 is a genetic risk factor for diffuse cutaneous systemic sclerosis and has additive effects
with IRF5 and STAT4. Arthritis Rheum. 60, 3447–3454 (2009).
S8. Gourh, P. et al. Association of the C8orf13-BLK region with systemic sclerosis in North-American and European
populations. J. Autoimmun. 34, 155–162 (2010).
S9. Ito, I. et al. Association of the FAM167A-BLK region with systemic sclerosis. Arthritis Rheum. 62, 890–895
(2010).
S10.
Bossini-Castillo, L. et al. A replication study confirms the association of TNFSF4 (OX40L) polymorphisms
with systemic sclerosis in a large European cohort. Ann. Rheum. Dis. 70, 638–641 (2011).
S11.
Dieude, P. et al. NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of
innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis. Ann. Rheum. Dis. 70, 668–674
(2011).
S12.
Radstake, T. R. et al. Genome-wide association study of systemic sclerosis identifies CD247 as a new
susceptibility locus. Nat. Genet. 42, 426–429 (2010).
S13.
Dieude, P. et al. Independent replication establishes the CD247 gene as a genetic systemic sclerosis
susceptibility factor. Ann. Rheum. Dis. 70, 1695–1696 (2011).
S14.
Gorlova, O. et al. Identification of novel genetic markers associated with clinical phenotypes of systemic
sclerosis through a genome-wide association strategy. PLoS. Genet. 7, e1002178 (2011).
S15.
Allanore, Y. et al. Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for
systemic sclerosis. PLoS. Genet. 7, e1002091 (2011).
S16.
Bossini-Castillo, L. et al. Confirmation of TNIP1 but not RHOB and PSORS1C1 as systemic sclerosis risk
factors in a large independent replication study. Ann. Rheum. Dis. 72, 602–607 (2013).
S17.
Bossini-Castillo, L. et al. A GWAS follow-up study reveals the association of the IL12RB2 gene with
systemic sclerosis in Caucasian populations. Hum. Mol. Genet. 21, 926–933 (2012).
S18.
Mayes, M. D. et al. Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis. Am.
J. Hum. Genet. 94, 47–61 (2014).
S19.
Dieude, P. et al. Evidence of the contribution of the X chromosome to systemic sclerosis susceptibility:
association with the functional IRAK1 196Phe/532Ser haplotype. Arthritis Rheum. 63, 3979–3987 (2011).
S20.
Carmona, F. D. et al. New insight on the Xq28 association with systemic sclerosis. Ann. Rheum. Dis. 72,
2032–2038 (2013).