Table 1 Candidate genes and their previous 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.