Table 1

Previously associated polymorphisms with other immune-mediated diseases and references.

Gene (locus link id)

Gene Function

Polymorphisms

MAF

Reference and previous association


CRP 1q21-q23 (1401)

Activates the classical pathway of complement. SNP2 alters basal levels of CRP. SNP4 has been associated with SLE and antinuclear autoantibody production. A polymorphic GT repeat in CRP has been associated with SLE.

SNP2 (rs1800947)

SNP4 (rs1205)

Microsatellite (ss28514831)

0.07 & 0.33 respectively, Caucasian parental. GT16 & GT21, 0.62 and 0.24, respectively, Caucasian controls.

SLE: Microsatellite P = 0.007, SNP4 P = 0.0008; 586 families [14].

Microsatellite [15].


FCRL3 1q21-q22 (115352)

FCRL3, a member of the Fc receptor-like family, polymorphism alters the binding affinity of nuclear factor κB and regulates FCRL3 expression. Associated with RA, SLE and autoimmune thyroid disease (GD and HT)

Fcrl3_3 (rs7528684)

0.37 Japanese controls

RA: P = 8.5 × 10-7, OR = 2.15 (95% CI = 1.58–2.93) 830 cases and 658 controls. SLE: P = 0.0017, OR = 1.49 (95% CI = 1.16–1.92) 564 cases. GD: P = 7.4 × 10-5, OR = 1.79 (95% CI = 1.34–2.39) 351 cases. HT: P = 0.022, OR = 1.62 (95% CI = 1.07–2.47) 158 cases [43].


CFH 1q32 (3075)

Complement factor H, a key regulator of the complement system of innate immunity, binds heparin and CRP

His402Tyr (rs1061170)

0.41 controls, white, not of Hispanic origin

Age-related macular degeneration: (nominal P = <10-7) 96 cases and 50 controls [44].


PAD14 1q36.13 (23569)

Peptidylarginine deiminases role in granulocyte & macrophage development, leading to inflammation and immune response, associated with RA.

PADI4-94 (rs2240340)

0.37 Japanese controls

RA: P = 8 × 10-6, OR = 1.97 (95% CI = 1.44–2.69) 830 cases and 736 controls [45].


IL1RN & IL1A 2q14 (3557 & 3552)

Cytokines involved in the inflammatory response, polymorphisms confer susceptibility to RA and Ankylosing spondylitis.

IL1RN+2017 (rs2419598)

IL1A-889 (rs1800587)

0.22 & 0.27, respectively, Caucasian controls

RA: P = 0.008; 406 Dutch cases and 245 controls [46].

Ankylosing spondylitis: P = 0.025; 227 British families, 317 parent-case trios and 200 controls [47].


NFKB1 4q24 (4790)

NFκB is a transcription regulator that is activated by various intra- and extra-cellular stimuli such as cytokines, oxidant-free radicals, ultraviolet irradiation, and bacterial or viral products. Inappropriate activation of NFκB has been associated with a number of inflammatory diseases

(CA) dinucleotide repeat microsatellite

Allele 8, A10 & A14, 0.19, 0.02 and 0.28 respectively, UK controls

T1D: A10: P = 0.000001, OR = 9.4; 434 cases, 222 controls [36]. T1D: no association; 236 Danish families [37].


SLC22A4 5q31 (6583)

The encoded protein is an organic cation transporter and plasma integral membrane protein containing eleven putative transmembrane domains as well as a nucleotide-binding site motif. Polymorphisms confer susceptibility to RA.

SLC22A4:F1 (rs2073838)

SLC22A4:F2 (rs3792876)

0.31 & 0.32 respectively, Japanese controls

RA: P = 0.000034, OR = 1.98 (95% CI = 1.43–2.75) 830 cases and 658 controls [48].

CD: P = 0.001, OR = 2.1 (95% CI = 1.31–3.39) 203 cases and 200 controls [49].


IBD5 locus 5q31 (50941)

Confers susceptibility to Crohn disease.

IGR2198 (rs11739135)

0.36 Canadian parental.

CD: P = 0.000048; 256 trios [50].


SPINK5 5q32 (11005)

Encodes a 15 domain serine proteinase inhibitor (LEKTI) involved in anti-inflammatory and/or antimicrobial protection of mucous epithelial, polymorphisms associated with atopy, Netherton disease.

316G>A (ss28514851)

1103A>G (rs2303064)

1156G>A (rs2303063)

1258G>A (rs2303067)

2475G>T (rs2303070)

2915A>G (ss28514856)

0.03, 0.50, 0.13, 0.48, 0.08 & 0.04, respectively, UK controls

Atopy, Netherton disease: (rs2303064): P = 0.008, (rs2303067): P = 0.002; 148 families [51].

Asthma (rs2303067): P = 0.04, OR = 1.77 (95% CI = 1.02–3.06) 1161 children. Asthma and atopy: P = 0.007, OR = 4.56 (95% CI = 1.37–15.12) 37 German cases and 415 controls [52].


FCER1B 11q13 (2206)

Encodes the beta subunit of the high affinity IgE receptor, a member of the membrane-spanning 4A gene family, and displays unique expression patterns among hematopoietic cells and nonlymphoid tissues. Responsible for initiating the allergic response, associated with atopy and atopic asthma.

Gly237Glu (rs569108)

0.06 Japanese controls

Atopy: two-point lod score 9.35 [17].

Childhood asthma (rs569108): P = <0.002, OR = 3; 200 Japanese cases and 100 controls [16].


LAG3 12p13.32 (3902)

Lymphocyte-activation protein 3 belongs to Ig superfamily and contains 4 extracellular Ig-like domains.

Thr455Ile (rs870849)

N/A

MS: P = 0.005; 576 cases and 662 controls [53].


CARD15 16q12 (64127)

Intracellular sensors of bacterial peptidoglycan These SNPs encode amino acid changes located in or near the leucine-rich repeat region, which is involved in peptidoglycan binding, conferring an increased risk of Crohn disease, PA and Blau syndrome.

SNP8 (rs2066844)

SNP12 (rs2066845)

SNP13 (ss28514842)

0.04, 0.01 & 0.02, respectively, Caucasian controls

CD (SNP13): P = 6 × 10-6; 235 families [54].

P = 0.0046; 416 families[55].

PA: P = 0.0027, OR = 3.5 (95% CI = 1.51–7.01) [56].

Blau Syndrome [57].


SLC9A3R1 17q25 (9368)

Immune synapse formation in T cells, polymorphism associated with psoriasis.

SLC9A3R1 (rs734232)

0.42 European controls

Psoriasis: P = 0.0009; 134 trios [58].


ADAM33 20p13 (80332)

Encodes a disintegrin and metalloprotease (ADAM) domain 33, which is a member of the ADAM protein family. Has a role in cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. Reported as an asthma and bronchial hyper-responsiveness susceptibility locus.

ST+4 (rs44707)

V4 (rs2787094)

Q-1 (rs612709)

ST+7 (rs574174)

T+1 (rs2280089)

T2 (rs2280090)

0.48, 0.25, 0.24, 0.22, 0.08, 0.07 UK & USA controls

Asthma and bronchial hyperresponsiveness: P = 0.03 – 0.02; 130 cases and 217 controls [35].

P = 0.04–0.0009 in ethnically diverse populations [59].


RUNX1 21q22.3 (861)

The RUNX1 transcription factor is expressed mainly in hematopoietic cells and functions both to activate and to repress transcription through interactions with cofactors. This SNP alters a binding site for RUNX1 and has been associated with RA.

RUNX1 (rs2268277)

0.37 Japanese controls

RA: P = 0.0013, OR= 1.28 (95% CI = 1.10–1.48) 719 cases and 441 controls [48].


MAF: minor allele frequency, SLE: systemic lupus erythematosus, RA: rheumatoid arthritis, GD: Graves' disease, HT: Hashimoto thyroiditis, T1D: type 1 diabetes, CD: Crohn disease, MS: multiple sclerosis, PA: Psoriatic arthritis, OR: odds ratio, 95% CI: 95% confidence intervals, N/A: not available

Smyth et al. BMC Medical Genetics 2006 7:20   doi:10.1186/1471-2350-7-20

Open Data