Background
Methods
Study population
Clinical and epidemiological variablesa
| Discovery cohort | Validation cohort |
P
|
---|---|---|---|
Genetic background | CEU | CEU | - |
Number of individuals (N) | 482 | 425 | - |
Gender (% females) | 443 (91.91%) | 398 (93.65%) | 0.37 |
Average age at onset (m ± SD) | 33.50 ± 14.09 | 32.39 ± 13.32 | 0.22 |
Malar rash (N
+/N
-) | 185/174 | 183/175 | 1.00 |
Discoid rash (N
+/N
-) | 46/313 | 49/309 | 0.74 |
Photosensitivity (N
+/N
-) | 191/168 | 173/185 | 0.20 |
Oral ulcers (N
+/N
-) | 153/206 | 172/186 | 0.15 |
Arthritis (N
+/N
-) | 275/84 | 267/91 | 0.54 |
Serositis (N
+/N
-) | 110/249 | 122/236 | 0.34 |
Renal disorder (N
+/N
-) | 120/239 | 108/250 | 0.38 |
Neurologic disorder (N
+/N
-) | 25/334 | 35/293 | 0.10 |
Hematologic disorder (N
+/N
-) | 341/18 | 337/21 | 0.63 |
Immunologic disorder (N
+/N
-) | 289/70 | 292/66 | 0.77 |
Antinuclear antibodies (N
+/N
-) | 346/13 | 347/11 | 0.84 |
SLE phenotypes
DNA extraction and genome-wide genotyping in the discovery and validation patients
Analysis of association between established SLE risk SNPs and SLE phenotypes
Genetic variants associated with SLE risk
Imputation of genetic variants associated with SLE risk
Statistical association analysis
GWPA
GWPA method
Gene set definition
In silico analysis of VEGF pathway genes after treatment with topical immunotherapies for cutaneous SLE
Results
Phenotypic characterization of the studied cohorts
Identification of SLE risk genetic variants associated with SLE phenotypes
SNP | Chr | Pos | Gene | RA | Phenotype |
P
D
|
P
V
|
P
C
| OR (CI, 95%) |
---|---|---|---|---|---|---|---|---|---|
rs2476601
a
|
1
|
114377568
|
PTPN22
|
A
|
Hematologic disorder
|
0.0039
|
0.0433
|
5.20e-4
|
9.488 (1.310-68.726)
|
Antinuclear antibodies
|
0.0146
|
0.0281
|
0.0011
|
0.168 (0.004-0.990)
| |||||
rs704840 | 1 | 173226195 |
TNFSF4
| G | Renal disorder | 0.0407 | 0.9210 | 0.1290 | 1.199 (0.941-1.527) |
rs3024505
|
1
|
206939904
|
IL10
|
T
|
Arthritis
|
0.0325
|
0.1540
|
0.0170
|
1.557 (1.091-2.221)
|
rs3768792
|
2
|
213871709
|
IKZF2
| C | Photosensitivity | 0.0437 | 0.3320 | 0.4580 | 0.893 (0.674-1.184) |
Hematologic disorder
|
0.0319
|
0.1880
|
0.0143
|
0.507 (0.301-0.855)
| |||||
rs9311676 | 3 | 58470351 |
ABHD6,PXK
| C | Oral ulcers | 0.0338 | 0.7960 | 0.9210 | 0.832 (0.674-1.028) |
rs564799 | 3 | 159728987 |
IL12A
| C | Discoid rash | 0.0411 | 0.1410 | 0.6853 | 0.942 (0.674-1.316) |
rs1270942
|
6
|
31918860
|
MHC class III
|
C
|
Arthritis
|
0.0138
|
0.6670
|
0.0407
|
1.530 (1.010-2.346)
|
rs9462027
|
6
|
34797241
|
UHRF1BP1
|
A
|
Malar rash
|
0.0263
|
0.1730
|
0.0137
|
1.333 (1.071-1.660)
|
Oral ulcers | 0.0251 | 0.8950 | 0.0933 | 1.210 (0.971-1.508) | |||||
rs6932056 | 6 | 138242437 |
TNFAIP3
| C | Serositis | 0.0193 | 0.8140 | 0.1364 | 1.580 (0.898-2.781) |
rs4917014 | 7 | 50305863 |
IKZF1
| T | Oral ulcers | 0.0280 | 0.1550 | 0.5821 | 0.944 (0.753-1.184) |
rs2663052 | 10 | 50069395 |
WDFY4
| C | Neurologic disorder | 0.0370 | 0.1590 | 0.6311 | 0.963 (0.662-1.401) |
rs4948496 | 10 | 63805617 |
ARID5B
| C | Malar rash | 0.0331 | 0.4580 | 0.3258 | 1.116 (0.906-1.375) |
Photosensitivity | 0.0202 | 0.9480 | 0.0911 | 1.203 (0.977-1.483) | |||||
rs2732549 | 11 | 35088399 |
CD44
| T | Immunologic disorder | 0.0163 | 0.9910 | 0.0907 | 1.277 (0.976-1.670) |
rs7941765
|
11
|
128499000
|
ETS1,FLI1
|
C
|
Arthritis
|
0.0072
|
0.0701
|
0.0015
|
1.470 (1.151-1.877)
|
rs10774625
|
12
|
111910219
|
SH2B3
|
A
|
Serositis
|
0.0207
|
0.0756
|
0.0038
|
0.715 (0.571-0.895)
|
Renal disorder | 0.0423 | 0.6410 | 0.0773 | 0.814 (0.650-1.018) | |||||
Immunologic disorder
|
0.0051
|
0.8190
|
0.0321
|
0.738 (0.566-0.964)
| |||||
rs1059312
|
12
|
129278864
|
SLC15A4
|
C
|
Serositis
|
0.0253
|
0.2370
|
0.0156
|
1.321 (1.053-1.658)
|
rs4902562 | 14 | 68731458 |
RAD51B
| A | Renal disorder | 0.0130 | 0.8670 | 0.1010 | 0.834 (0.664-1.047) |
rs2941509 | 17 | 37921194 |
IKZF3
| A | Antinuclear Antibodies | 0.0304 | 0.0413 | 0.4943 | 0.676 (0.237-1.930) |
rs2304256 | 19 | 10475652 |
TYK2
| C | Arthritis | 0.0298 | 0.7690 | 0.1841 | 0.826 (0.622-1.096) |
Identification of genetic pathways associated with SLE phenotypes
Pathway | Phenotype | #Genes | SNPs |
P
D
| FDR D
|
P
V
| FDR V
|
P
C
|
---|---|---|---|---|---|---|---|---|
RIG-I/MDA5 negative regulation signaling | Antinuclear antibodies | 31 | 464 | 2.00e-5 | 0.016 | 0.234 | 0.234 | - |
VEGFa
| Oral ulcers | 29 | 883 | 5.58e-5 | 0.044 | 0.013 | 0.026 | 2.08e-5 |