Genetics of Psoriasis and Pharmacogenetics of Biological Drugs

Table 1

Single-nucleotide polymorphisms (SNPs) in genes associated with psoriasis.

Gene	Role in immune system*	SNP	MAF**	Minor allele	Population	References
IL23R	Encodes a subunit of the receptor required for IL23A signaling. This protein associates constitutively with JAK2 and binds to transcription activator STAT3	rs7530511	0.125	T	Caucasian, Japanese, Chinese	[33, 34, 36–38, 41]
		rs2201841	0.275	C	Caucasian	[44, 45]
		rs11209026	0.067	A	Caucasian	[2, 33, 34, 36, 37, 41–43]
		rs11465817	0.279	A	Chinese	[39]
		rs1343152	0.357	C	Chinese	[39]
		rs2066808	0.092	C	Caucasian	[44]
IL10	Encodes a cytokine produced by monocytes and lymphocytes that downregulates the expression of Th1 cytokines and blocks NF-𝜅B activity. It enhances B-cell survival, proliferation, and antibody production and regulates the JAK-STAT signaling pathway	rs1800896	0.467	A	Caucasian, Egyptian	[25, 60]
TNFα	Encodes a proinflammatory cytokine produced by macrophages. TNFα is implicated in multiple roles such as cell proliferation, differentiation, and apoptosis	rs1800629	0.217	A	Caucasian, Egyptian, Korean	[19–22, 25–29]
		rs361525	0.131	A	Caucasian	[19, 20, 22–24, 26–29]
		rs1799724	0.158	A	Caucasian	[14]^#
IL12B	IL12B is a cytokine expressed by activated macrophages that serves as an essential inducer of Th1 cell development	rs6887695	0.217	T	Caucasian, Chinese	[33, 36, 37, 39, 41, 42]
		rs3212227	0.225	C	Caucasian, Japanese, Chinese	[33, 36–38, 40–43, 46, 103]
		rs2082412	0.225	A	Caucasian	[44]
		rs2546890	0.438	G	Caucasian	[45]
GBP6	Interferon induces GBP that hydrolyzes GTP to both GDP and GMP	rs928655	0.288	G	Caucasian	[42]
IL6	Encodes a cytokine that induces inflammatory responses through IL6Rα and maturation of B cells	rs1800795	0.467	G	Egyptian	[25]
IL13	Encodes a cytokine produced by activated Th2 that is involved in maturation and differentiation of B cells. IL13 downregulates macrophage activity and inhibits the production of proinflammatory cytokines and chemokines	rs20541	0.233	T	Caucasian	[2, 44, 61]
		rs848	0.242	T	Caucasian	[61]
		rs1800925	0.196	T	Caucasian	[61]
TNFAIP3	TNF induces the expression of TNFAIP3, which inhibits NF-𝜅B activation and TNF-mediated apoptosis. TNFAIP3 is involved in cytokine-mediated immune and inflammatory responses	rs610604	0.408	C	Caucasian	[2, 15, 44]^#
		rs6920220	0.175	A	Caucasian	[33, 44, 47]
		rs10499194	0.175	T	Caucasian	[33, 44, 47]
		rs5029939	0.042	G	Caucasian	[44, 47, 48]
		rs2230926	0.027	G	Caucasian	[15]^#
TNIP1	Encodes TNFAIP3 interacting protein 1, which plays a role in the regulation of NF-𝜅B activation	rs17728338	0.075	A	Caucasian	[2, 44]
IL1RN	IL1RN inhibits IL1 and modulates immune and inflammatory responses	rs397211	0.164	G	Caucasian	[44]
HLA-C	HLA class I molecules play a central role in the immune system by presenting peptides derived from endoplasmic reticulum lumen	rs12191877	0.125	T	Caucasian	[44, 45, 51]
		rs10484554	0.135	T	Caucasian, Chinese	[2, 42, 104]
		rs1265181	0.258	C	Chinese	[35, 104]
		rs3134792	0.111	G	Caucasian	[105]
NF-𝜅BIA	Encodes a member of the NF-𝜅B inhibitor family, which interacts with REL dimers to inhibit NF-𝜅B/REL complexes, which are involved in inflammatory responses	rs2145623	0.290	C	Caucasian	[45]
		rs8016947	0.465	T	Caucasian	[50]
APOE	APOE plays a role in the proliferation of T lymphocytes and protects against some infections in patients with psoriasis [73]	rs429358	0.078	APOE*4	Caucasian	[75]
		rs7412	—	—	Caucasian	[75]
VDR	Encodes the nuclear hormone receptor for vitamin D3, which regulates immune response pathways	rs4516035	0.381	C	Caucasian	[76]
IFNγ	Encodes a soluble cytokine with antiviral, immunoregulatory, and antitumor properties, and it is a potent activator of macrophages	rs2430561	—	—	Caucasian	[54]
IL2	Encodes a cytokine that is important for the proliferation of T and B lymphocytes	rs2069762	—	—	Korean	[53]
IL4	IL4 is a pleiotropic cytokine involved in the modulation of Th2 immune responses. IL4 receptor also binds to IL13, which may contribute to many overlapping functions of this cytokine and IL13	rs2243250	0.137	T	Korean	[53]
IL15	Encodes a cytokine that regulates T-cell and natural killer activation and proliferation. IL15 also induces the activation of JAK kinases, as well as the phosphorylation and activation of STAT3, STAT5, and STAT6	rs2857261	0.431	G	Chinese	[69]
		rs10519613	0.102	A	Chinese	[69]
		rs1057972	—	—	Chinese	[69]
TNFRSF1B	TNFRSF1B is a TNFα receptor that mediates the recruitment of antiapoptotic proteins	rs1061622	0.239	G	Caucasian, Japanese	[14]^#
MCP1	MCP1 encodes a cytokine characterized by two cysteines separated by a single amino acid that displays chemotactic activity for monocytes and basophils	rs1024611	0.305	G	Caucasian	[71]
CTLA4	Encodes a protein which inhibits T cells	rs3087243	0.460	A	Caucasian	[81]^##
		rs231775	0.389	G	Caucasian	[81]^##
DEFB4	DEFB4 is a member of a family of microbicidal and cytotoxic peptides made by neutrophils	rs2740091	—	—	Caucasian	[56]
		rs2737532	—	—	Caucasian	[56]
STAT4	In response to cytokines, the STAT proteins are phosphorylated and translocate to the cell nucleus, where they act as transcription activators. STAT transduces IL12, IL23, and IFN type I signals in T lymphocytes and regulates the differentiation of Th cells	rs7574865	0.230	T	Caucasian	[72]
IL18	IL18 stimulates production of IFNγ in Th1	rs187238	—	—	Japanese	[58]
IL19	IL19 is a member of the IL10 cytokine subfamily with a role in inflammatory responses	rs2243188	0.230	A	Caucasian	[64, 68]
		rs2243158	0.085	C	Caucasian	[64]
IL20	Encodes a cytokine structurally related to IL10 and transduces its signal through STAT3 in keratinocytes	rs1713239	0.177	G	Chinese	[65]
		rs2981572	—	—	Caucasian	[64, 66, 68]
IL20RA	Encodes a receptor for IL20, a cytokine that may be involved in epidermal function	rs1342642	0.314	A	Caucasian	[67]
		rs1184860	—	—	Caucasian	[67]
		rs1167846	0.246	T	Caucasian	[67]
		rs1167849	0.285	A	Caucasian	[67]
ERAP1	Encodes an aminopeptidase involved in trimming HLA class I-binding precursors so that they can be presented on HLA class I	rs151823	0.093	A	Chinese	[52]
		rs27524	0.332	A	Caucasian	[50]
IL1B	Encodes a cytokine produced by activated macrophages which plays an important role in the inflammatory response	rs16944	0.358	A	Caucasian	[24]
TRAF3IP2	Encodes a protein that interacts with TRAF proteins and plays a central role in innate immunity in response to pathogens, inflammatory signals, and stress	rs13210247	0.080	G	Caucasian	[45, 49]
		rs33980500	—	—	Caucasian	[45, 49]
		rs13196377	0.053	A	Caucasian	[49]
		rs13190932	0.058	A	Caucasian	[49]
		rs240993	0.250	T	Caucasian	[50]
IL28RA	Encodes a receptor complex that interacts with IL28A, IL28B, and IL29. The expression of these cytokines can be induced by viral infection	rs4649203	0.239	G	Caucasian	[50]
TYK2	Encodes a member of the JAK protein family that promulgate cytokine signals by phosphorylating receptor subunits. TYK2 is a component of IFN I and II signaling pathways and may play a role in antiviral immunity	rs12720356	0.124	C	Caucasian	[50]
IFIH1	Encodes a protein that mediates induction of IFN response to viral RNA [83]	rs17716942	0.195	C	Caucasian	[50]
LCE	Encodes a protein that plays a role in skin barrier function [83]	rs4085613	0.403	T	Caucasian	[50]
		rs4845454	0.403	C	Caucasian	[50]
		rs1886734	0.407	A	Caucasian	[50]
		rs4112788	0.403	A	Caucasian	[50]
		rs6701216	0.137	T	Caucasian	[42]
		rs4112788	0.417	T	Chinese	[85]
ZNF313	Encodes a protein that is involved in T-cell activation [83]	rs2235617	0.432	G	Caucasian	[50]
		rs495337	0.430	A	Caucasian	[105]

∗Data from NCBI web page [57]; ∗∗MAF: minor allele frequency for Caucasian population (data from HapMap web page [106] and Alfred [107]). IL: interleukin; R: receptor; JAK: Janus kinase; STAT: signal transducer and activator of transcription; Th1: type 1 helper T lymphocyte; TNF: tumor necrosis factor; GBP: guanylate-binding protein; GTP: guanosine triphosphate; GDP: guanosine diphosphate; GMP: guanosine monophosphate; TNFAIP: TNF-alpha interacting protein; TNIP1: TNFAIP3 interacting protein; IL1RN: interleukin 1 receptor antagonist; HLA: human leukocyte antigen; NF-𝜅BIA: nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha; REL: v-rel reticuloendotheliosis viral oncogene; APOE: apolipoprotein E; VDR: vitamin D receptor; TNFRSF1: tumor necrosis factor receptor superfamily; MCP: monocyte chemoattractant protein; CTLA4: cytotoxic T lymphocyte-associated protein 4; DEFB4: defensin beta 4A; IFN: interferon; ERAP: endoplasmic reticulum aminopeptidase; TRAF3IP: TRAF3 (TNF receptor-associated factor 3) interacting protein; IRAK: interleukin-1 receptor-associated kinase; TYK: tyrosine kinase; IFIH1: interferon induced with helicase C domain 1; LCE: late cornified envelope; RNF114: ring finger protein 114; #association between psoriasis and response to anti-TNF treatment; ##haplotype GG of rs3087243-rs231775 associated with psoriasis.