Background
Gene and polymorphism | Candidacy | Previous disease associations |
---|---|---|
TAF5L on 1q42 C744A (rs3753886) |
TAF5L encodes a protein that is a component of the PCAF histone acetylase complex. It may participate in basal transcription, serve as a coactivator, function in promoter recognition or modify general transcription factors to facilitate complex assembly and transcription initiation. | T1D: ▪ Chistiakov et al [35] 247 Russian cases and 258 controls, derived OR for C allele = 0.69 (0.52–0.92), P = 0.013. |
PDCD1 on 2q37 7146G>A (rs11568821) 872C>T (rs2227981) | Belongs to the B7-CD28 superfamily. These molecules play a critical role in the development of the immune response by controlling T cell numbers, through a fine balance of stimulation and negative regulation, which is essential for the prevention of autoimmunity. | SLE, RA and T1D: ▪ Prokunina et al [58] SLE: 7146G>A: 443 families and 520 cases of European, Mexican and African-American decent, RR for A allele = 2.6 (1.6–4.4), P = 1.0 × 10-5 for Europeans and RR for A allele = 3.5 (1.4–8.5), P = 9.0 × 10-4 for Mexicans. ▪ Prokunina et al [37] RA: 7146G>A: 1,175 cases and 3,404 controls, OR for A allele = 1.18 (0.99–1.41), P = 0.05. ▪ Lin et al [59] 872C>T: 98 SLE cases and 100 controls, 84 RA cases and 135 controls, OR for T allele = 3.32 (1.78–6.21), P < 0.0001, no association in SLE. ▪ Nielsen et al [36] T1D:7146G>A: 192 Danish cases and 155 controls, OR for A allele = 1.92 (1.1–3.3), P = 0.02. |
TCF7 on 5q31 Pro19Thr (rs5742913) | Role as a transcription factor in regulating key immune response elements and its involvement in T-cell development in the thymus. | T1D: ▪ Noble et al [38] 282 USA families, RR = 1.21, P TDT = 0.12. A allele transmitted from fathers, RR = 1.79, P TDT = 0.007, P ESP = 0.03. To male offspring, P ESP = 0.04. To low HLA risk (non DR3/DR4) offspring, RR = 1.35, P TDT = 0.06, P ESP = 0.04. Early onset offspring, P ESP = 0.09. |
IL12B on 5q33.3 A1159C (rs3212227) Microsatellite D5S2941 | This gene, encoding the p40 subunit of IL-12, drives the differentiation of T lymphocytes into the Th1 subset, which is characterized by the production of cytokines that promote cell-mediated immunity. | T1D: ▪ Morahan et al [49] 249 Eastern Australian multiplex families, RR for A allele = 1.40 (1.11–1.77), P = 0.0025. 235 Australian simplex families, RR for A allele = 1.84 (1.32–2.56), P = 0.00014. ▪ Davoodi-Sermiromi et al [41] 364 USA multiplex families, RR for C allele = 1.23 (0.97–1.56), P = 0.08. haplotype: allele 2 (D5S2941) and 1159C, P = 0.02. ▪ Windsor et al [40] 648 cases and 246 controls – Western Australia, OR allele C = 1.6 (1.2–2.0), P = 0.001. Excess of heterozygotes in cases ≥ 16 yrs diagnosis, OR = 1.8(1.2–2.7), P = 0.005 and ≥ 26 yrs diagnosis, OR = 2.4 (1.5–3.8), P = 0.0002. Five studies failed to find an association: ▪ Dahlman et al [60] 2,873 families from UK, USA, Finland, Romania ▪ McCormack et al [61] 120 cases, 330 controls and 307 families from Northern Ireland ▪ Nistico et al [62] 470 cases and 544 controls from Italy. ▪ Bergholdt et al [63] 337 Danish simplex and 795 European and American multiplex families. ▪ Johansson et al [64] from Norway. |
IL6 on 7p21 174G>C (rs1800795) |
IL6 may contribute to the gradual destruction of the pancreatic beta cells, due to its regulatory role in inflammation and the immune response. | T1D: ▪ Kristiansen et al [43] 253 Danish families, RR allele C = 1.26 (1.01–1.57), P TDT = 0.04. Parent-female-trios: RR for C allele = 1.72 (1.25–2.36), P = 6.5 × 10-4. Parent-male-trios: RR for C allele = 0.91 (0.67–1.24), P = 0.58. Age-at-onset males = 14.04 yrs (11.62–16.46) and females = 8.81 yrs (6.60–11.01), interaction model P = 0.002. ▪ Gillespie et al [44] UK 1,230 cases. IL6-174CC less frequent in females diagnosed after, than in those diagnosed before, 10 years, P = 0.016. ▪ Jahromi et al [65] 257 cases and 120 newborn controls, UK, OR for C allele = 0.54 (0.39–0.74), derived P = 7.8 × 10-5. 53 parent-child trios RR for C allele = 0.83 (0.48–1.43) ▪ Eerligh et al [66] 206 Dutch simplex families, no association. |
ICAM1 on 19p13 G241R (rs1799969) |
ICAM-1 , upregulated during inflammation and hyperglycemia, is involved in the attachment of lymphocytes to the endothelium as well as in the priming of effector T cells. | T1D: Kristiansen et al . [45] 253 Danish families, no association with K469E. Nejentsev et al [67] 3,695 families from Finland, UK, USA, Norway & Romania, RR = 0.91 (0.83–0.99) P = 0.030. 446 families from Bart's-Oxford study RR = 0.60 (0.40–0.89) P = 0.006. Ma et al . [68] 432 cases and 187 controls from Sweden. Tested five SNPs, rs281432 and rs5498 had P -values of 0.026 and <0.001 respectively when genotype model assumed. |
TBX21 on 17q21 His33Gln (rs2240017) |
TBX21 has a role in the complex regulation of T lymphocyte responses, as a master-regulator of Th1 cytokine IFN-γ gene expression. | T1D: ▪ Sasaki et al [46], 153 cases and 200 controls from Japan, OR for G allele = 1.77 (1.08–2.91), P = 0.02. |
IL23R on 1p31 Arg381Gln (rs11209026) | The protein encoded pairs with the receptor molecule IL12RB1/IL12Rbeta1, and both are required for IL23A signaling. This protein associates constitutively with Janus kinase 2 (JAK2), and also binds to transcription activator STAT3 in a ligand-dependent manner. | IBD and psoriasis: ▪ Duerr et al [69] CD: 547 non-Jewish cases and 548 controls, OR = 0.26 (0.15–0.43), P = 5.05 × 10-9. 401 Jewish cases and 433 controls, OR = 0.45 (0.27–0.73), P = 7.95 × 10-4. 883 IBD families, P = 1.32 × 10-10. ▪ Cargill et al [54] Psoriasis: White North American 1446 cases and 1432 controls, OR= 0.63 (0.50–0.79), P = 1.89 × 10-4. |
IRF5 on 7q32.1 -3835 (rs2004640) | Member of a family of transcriptional factors that controls inflammatory and immune responses. | SLE: ▪ Sigurdsson et al [70], 679 cases and 438 controls from Sweden, Finland and Iceland, P = 2.4 × 10-7. ▪ Graham et al [71] 1,661 cases and 2,508 controls from USA, Spain, Sweden and Argentina, OR = 1.47 (1.36–1.60), P = 4.2 × 10-21. T1D: One study failed to find an association. Qu et al [72] 947 T1D families. |
CD40 on 20q12 Kozak (rs1883832) |
CD40 and CD40L signalling is known to play an important role in the immune response. The proteins are expressed in a variety of cell types and ligation causes cells to produce inflammatory cytokines and cellular adhesion molecules. | GD: ▪ Tomer et al [48] 154 cases and 118 controls – Caucasian, OR for CC genotype = 1.6, P = 0.048. ▪ Kim et al [73]132 cases and 164 controls from Korea, OR for CC genotype = 1.93 (1.21–3.09), P = 0.019. ▪ Mukai et al [74] 324 cases and 229 controls from Japan: late onset GD, decrease in TT allele (P = 0.011) Two studies failed to find an association: ▪ Houston et al [75] 451 cases and 446 controls from UK. ▪ Heward et al [76] 800 cases and 785 controls from UK. |
Methods
Subjects
SNP identification and genotyping
Wellcome Trust Case Control Consortium
Statistical Analysis
Results
TAF5L
Alleles | Genotypes | |||||
---|---|---|---|---|---|---|
TAF5L
| C744A (rs3753886) | C | A | CC | CA | AA |
7,497 cases | 7,457 (49.7) | 7,537 (50.3) | 1,827 (24.4) | 3,803 (50.7) | 1,867 (24.9) | |
7,496 controls | 7,671 (51.2) | 7,321 (48.8) | 1,928 (25.7) | 3,815 (50.9) | 1,753 (23.4) | |
OR (95% CI) | 1.00 (reference) | 1.07 (1.02–1.12) | 1.00 (reference) | 1.05 (0.97–1.14) | 1.14 (1.04–1.25) | |
P
| 7.32 × 10-3
| 0.0244 | ||||
PDCD1
| 7146G>A (rs11568821) | G | A | GG | GA | AA |
7,888 cases | 13,966 (88.3) | 1,810 (11.7) | 6,196 (78.6) | 1,574 (20.0) | 118 (1.5) | |
8,858 controls | 15,846 (88.5) | 1,870 (11.5) | 7,088 (80.0) | 1,670 (18.9) | 100 (1.1) | |
OR (95% CI) | 1.00 (reference) | 1.10 (1.02–1.17) | 1.00 (reference) | 1.08 (1.00–1.17) | 1.32 (1.00–1.74) | |
P
| 0.0102 | 0.0268 | ||||
PDCD1
| 872C>T (rs2227981) | C | T | CC | CT | TT |
5,758 cases | 6,699 (58.2) | 4,817 (41.8) | 1,956 (34.0) | 2,787 (48.4) | 1,015 (17.6) | |
7,289 controls | 8,440 (57.9) | 6,138 (42.1) | 2,461 (33.8) | 3,518 (48.3) | 1,310 (18.0) | |
OR (95% CI) | 1.00 (reference) | 1.00 (0.95–1.06) | 1.00 (reference) | 1.00 (0.92–1.08) | 0.97 (0.87–1.07) | |
P
| 0.586 | 0.760 | ||||
TCF7
| Pro19Thr (rs5742913) | C | A | CC | CA | AA |
7,434 cases | 13,022 (87.6) | 1,846 (12.4) | 5,709 (76.8) | 1,604 (21.6) | 121 (1.6) | |
8,637 controls | 15,355 (88.9) | 1,919 (11.1) | 6,826 (79.0) | 1,703 (19.7) | 108 (1.3) | |
OR (95% CI) | 1.00 (reference) | 1.13 (1.06–1.22) | 1.00 (reference) | 1.13 (1.04–1.22) | 1.32 (1.01–1.73) | |
P
| 4.16 × 10-4
| 1.91 × 10-3
| ||||
IL12B
| A1159C (rs3212227) | A | C | AA | AC | CC |
4,321 cases | 6,898 (79.8) | 1,744 (20.2) | 2,748 (63.6) | 1,402 (32.5) | 171 (4.0) | |
4,711 controls | 7,588 (80.5) | 1,834 (19.5) | 3,050 (64.7) | 1,488 (31.6) | 173 (3.7) | |
OR (95% CI) | 1.00 (reference) | 1.06 (0.98–1.14) | 1.00 (reference) | 1.06 (0.96–1.16) | 1.13 (0.90–1.42) | |
P
| 0.134 | 0.324 | ||||
IL6
| 174G>C (rs1800795) | G | C | GG | GC | CC |
7,785 cases | 8,726 (56.0) | 6,844 (44.0) | 2,928 (33.1) | 4,312 (48.7) | 1,612 (18.2) | |
8,852 controls | 10,168 (57.4) | 7,536 (42.6) | 2,456 (31.6) | 3,814 (49.0) | 1,515 (19.5) | |
OR (95% CI) | 1.00 (reference) | 1.05 (1.01–1.10) | 1.00 (reference) | 1.04 (0.97–1.12) | 1.11 (1.01–1.21) | |
P
| 0.0291 | 0.0879 | ||||
ICAM1
| G241R (rs1799969) | G | A | GG | GA | AA |
5,776 cases | 10,257 (88.8) | 1,295 (11.2) | 4,553 (78.8) | 1,151 (19.9) | 72 (1.3) | |
6,094 controls | 10,787 (88.5) | 1,401 (11.5) | 4,787 (78.6) | 1,213 (19.9) | 94 (1.54) | |
OR (95% CI) | 1.00 (reference) | 0.96 (0.89–1.05) | 1.00 (reference) | 1.00 (0.91–1.10) | 0.74 (0.54–1.02) | |
P
| 0.382 | 0.179 | ||||
TBX21
| His33Gln (rs2240017) | C | G | CC | CG | GG |
4,342 cases | 8,456 (97.4) | 228 (2.6) | 4,116 (94.8) | 224 (5.2) | 2 (0.1) | |
4,763 controls | 9,293 (97.6) | 233 (2.4) | 4,533 (95.2) | 227 (4.7) | 3 (0.1) | |
OR (95% CI) | 1.00 (reference) | 1.08 (0.89–1.30) | 1.00 (reference) | 1.08 (0.88–1.31) | 1.10 (0.16–7.54) | |
P
| 0.459 | 0.759 | ||||
IL23R
| Arg381Gln (rs11209026) | G | A | GG | GA | AA |
6,087 cases | 11,413 (93.7) | 761 (6.3) | 5,343 (87.8) | 727 (11.9) | 17 (0.3) | |
6,303 controls | 11,776 (93.4) | 830 (6.6) | 5,499 (87.2) | 778 (12.3) | 26 (0.4) | |
OR (95% CI) | 1.00 (reference) | 0.93 (0.84–1.03) | 1.00 (reference) | 0.95 (0.85–1.06) | 0.67 (0.36–1.26) | |
P
| 0.183 | 0.285 | ||||
IRF5
| -3835 (rs2004640) | T | G | TT | TG | GG |
5,657 cases | 5,834 (51.6) | 5,480 (48.4) | 1,487 (26.3) | 2,860 (50.6) | 1,310 (23.2) | |
6,044 controls | 6,160 (51.0) | 5,928 (49.0) | 1,581 (26.2) | 2,998 (49.6) | 1,465 (24.2) | |
OR (95% CI) | 1.00 (reference) | 0.98 (0.93–1.03) | 1.00 (reference) | 1.03 (0.94–1.12) | 0.96 (0.86–1.06) | |
P
| 0.451 | 0.353 | ||||
CD40
| Kozak (rs1883832) | C | T | CC | CT | TT |
4,392 cases | 6,624 (75.4) | 2,160 (24.6) | 2,500 (56.9) | 1,624 (37.0) | 268 (6.1) | |
4,702 controls | 7,132 (75.8) | 2,272 (24.2) | 2,680 (57.0) | 1,772 (37.7) | 250 (5.3) | |
OR (95% CI) | 1.00 (reference) | 1.03 (0.96–1.10) | 1.00 (reference) | 0.97 (0.89–1.07) | 1.18 (0.97–1.42) | |
P
| 0.456 | 0.162 |
Transmission/disequilibrium test | |||||||
---|---|---|---|---|---|---|---|
Parent-child-trios (families) | Parental MAF | Minor allele | RR (95% CI) |
P
| |||
Transmitted | Untransmitted | ||||||
TAF5L
| A1159C (rs3212227) | 2,645 (2,515) | 46.8 | 1,299 | 1,400 | 0.92 (0.85–0.99) | 0.0519 |
PDCD1
| 7146G>A (rs11568821) | 3,125 (2,742) | 9.3 | 516 | 538 | 0.96 (0.85–1.08) | 0.498 |
PDCD1
| 872C>T (rs2227981) | 2,190 (1,831) | 42.5 | 1,111 | 1,043 | 1.07 (0.98–1.16) | 0.143 |
TCF7
| C883A (rs5742913) | 1,556 (1,224) | 11.2 | 327 | 314 | 1.04 (0.89–1.21) | 0.608 |
IL12B
| A1159C (rs3212227) | 3,015 (2,606) | 18.9 | 949 | 933 | 1.02 (0.93–1.12) | 0.712 |
IL6
| 174G>C (rs1800795) | 2,803 (2,651) | 47.0 | 1,411 | 1,360 | 1.04 (0.97–1.12) | 0.333 |
TBX21
| His33Gln (rs2240017) | 1,989 (1,374) | 2.7 | 111 | 100 | 1.11 (0.85–1.45) | 0.449 |
CD40
| Kozak (rs1883832) | 1,446 (795) | 24.1 | 522 | 542 | 0.96 (0.85–1.08) | 0.540 |
PDCD1
TCF7
IL12B
Multilocus test P -values | ||||||
---|---|---|---|---|---|---|
Exons | Sequencing source | Polyorphisms | Tag SNPs | Families | Cases and controls | |
IL12B
| 8 | Seattle SNPs and in house (23 subjects) | 33 (from Seattle) 4 (in house) 25 had a MAF ≥ 0.10 | 6 | N/A | 0.940 1,590 cases and 1,748 controls |
IL6
| 6 | Seattle SNPs (23 subjects) | 49 12 had MAF ≥ 0.10 | 4 | 0.0231 3,320 parent-child trios | 0.236 3,486 cases and 3,783 controls |