Table 1.

Summary of systemic lupus erythematosus-associated loci and potential function of these genes.

Associated pathway	Reported locus/gene	Reported odds ratio	Population	Comments/potential function	Ref.
TLR and type I IFN signaling	IRF5/TNPO3†	1.3–2.0	Asian, European	Transcription of IFN-α and IFN-α-induced genes	[65,79,84,130,131]
	PHRF1 (KIAA1542)/IRF7†	1.3	European, African–American	Associated variant in linkage with IRF7, which is involved in production of IFN-α	[65,84]
	IRF8	1.2	European, African–American	Downstream non-MyD88 dependent signals from TLRs	[68,73]
	TYK2‡	1.1	European	Initiates signaling cascades of a large number of cytokine receptors	[17,126–127]
	IFIH1	1.2	European, African–American	Sensing of intracellular nucleic acid, induces IFN-α and IFN-α-induced genes	[119,120]
	TREX1‡	Rare, high penetrance	European, African–American	DNA degradation as a 3′–5′ exonuclease, high IFN observed in the monogenic syndrome	[132]
	SPP1 (OPN)	1.3	European, African–American	Gene encoding the cytokine OPN, interacts with IFN-α pathway	[100,108,110]
NF-κB signaling	TNIP1†	1.3	Asian, European	Interacts with TNFAIP3 and can act as a negative regulator of the NF-κB pathway downstream of TNF-α, has a key role in modulating cell activation, cytokine signaling and apoptosis	[78,79,131]
	TNFAIP3†	1.7–2.7	Asian, European	Termination of immune responses by protein ubiquitination	[79,80,131]
	HIC2/UBE2L3‡	1.4	Asian, European	Ubiquitination of NF-κB precursor p105	[79,84,131]
	SLC15A4‡	1.4	Asian	Involved in Nod1-dependent NF-κB signaling, with potential participation in the antigen presentation in immune response	[79,131]
TLR/type I IFN, NF-κB and T-cell signaling	IRAK1‡	1.2	European	Critical for TLR-7 and -9 signaling	[133,134]
	STAT4†	1.5–1.8	Asian, European, African–American	Downstream responses to IFN-α and other cytokine signals	[65,78–80,130,131]
T-cell function and signaling	PTPN22†	1.3	European	Modulation of lymphocyte activation and cytokine profile	[65,78] [65,79,131]
	TNFSF4†	1.4–1.5	Asian, European	Involved in T-cell/antigen-presenting cell interactions
	CD80†§	1.3	Asian	T-cell proliferation and cytokine production	[131]
	CDKN1B†§	1.2	Asian	Inhibition of T-lymphocytes cell cycle progression	[131]
	PDCD1	1.2	European	Involved in lymphocyte signaling	[135]
B-cell function and signaling	BLK/FAM167A/XKR6†	1.3–1.5	Asian, European, African–American	Modulation of B-cell activation	[65,79,80,130,131]
	BANK1†	1.4	Asian, European	Modulation of B-cell activation	[131,136]
	PRDM1†	1.3	Asian, European	Repressor of IFN-β gene expression; lymphocyte signaling	[78,79]
	ETS1†	1.3–1.5	Asian	Regulate the development, senescence and death of many immune cells and that play a role in innate and adaptive immune response	[79,91,131]
	IKZF1†	1.2–1.4	Asian	Regulates lymphocyte differentiation and proliferation, as well as self-tolerance through regulation of B-cell receptor signaling	[79]
	RASGRP3‡	1.4	Asian	Responsible for Ras-ERK signaling mediated by B-cell receptor ligation and might be involved in immunoglobulin production and B-cell proliferation	[79,131]
	ARID5B†§	1.2	Asian	Growth and differentiation of B-lymphocyte progenitors and other lymphocytes	[131]
T- and B-cell function and signaling	HLA region†	1.4–2.4	Asian, European,	Multiple immune system genes contained within this locus	[65,79,84,130,131]
	HLA-DQA1,HLA-DQA2,		African–American
	HLA-DR3 and HLA-DRB1
	AFF1†§	1.2	Asian	Important role in helper T cells and B cells, essential for normal lymphocyte development	[137]
Immune complex processing and hagocytosis	Early complement proteins (C1Q, C2, C4A and C4B)	All >2		Rare variants of these genes show high penetrance for systemic lupus erythematosus	[9–12]
	FcGR2A†	1.4	European, African–American	Clearance of immune complexes	[65,138]
	FcGR3A	1.6	European	Clearance of immune complexes	[138]
	CRP	1.3	European	Clearance of immune complexes
Cellular adhesion; neutrophil, monocyte function and signaling	ITGAM/ITGAX†	1.3–1.9	Asian, European, African–American	Facilitates leukocyte adhesion to endothelial cells	[65,78,80,130,131]
Apoptosis	ATG5†	1.3	Asian, European	Required for autophagy	[65,78,79,131]
	DRAM1†	1.2	Asian	Induction of autophagy and apoptosis and target of TP53	[131]
DNA methylation	MECP2	1.2	European	Found on X chromosome, involved in DNA methylation	[134,139,140]
	TET3, DGUOK†	1.3	Asian	Important in DNA demethylation	[131]
Other/unknown immune function	PXK†	1.3	European		[65]
	WDFY4/LRRC18†	1.2–1.5	Asian, European		[79,80,91,131]
	UHRF1BP1†	1.6	European		[78]
	JAZF1†§	1.2	European	Unknown function currently	[78]
	TREH–DDX6†§	1.3	Asian		[79,131]
	GPR19†	1.3	Asian		[130]

^†Confirmed association with p < 10⁻⁷.

^‡Confirmed association with p < 10⁻⁵.

^§Have not been replicated independently.

IFN: Interferon; TLR: Toll-like receptor.