A Common Genetic Background for Psoriasis and Cardiovascular Diseases: A Narrative Review

ABSTRACT

Background and Aims

Psoriasis is an immune‐mediated disease affecting primarily the skin and joints, but which also has systemic implications. There are assumptions about a common genetic background between psoriasis and cardiovascular diseases. This narrative review aims to provide an overview of the existing data regarding the IL‐23 rs2066808, IL‐23R rs2201841, IL‐17RA rs4819554, and IL‐17A rs2275913 polymorphisms and their link to psoriasis and cardiovascular diseases.

Methods

PubMed, Web of Science, Scopus, and “SNPedia” searches were conducted to identify the relevant studies between 2007 and 2025 that investigated the association between psoriasis, cardiovascular diseases, and the IL‐23 rs2066808, IL‐23R rs2201841, IL‐17RA rs4819554, and IL17A rs2275913 polymorphisms.

Results

The existing data are conflicting. The polymorphisms could be implicated in psoriasis onset, disease susceptibility, and treatment response. Some of them are also linked to coronary artery disease. Contradictory data could result from the heterogeneity of the population included in the studies and the laboratory techniques used for polymorphism determination.

Conclusion

The interplay between IL‐17, IL‐23, and genetic polymorphisms illustrates a complex landscape in psoriasis and its associated comorbidities. More standardized case‐control studies are needed to confirm this hypothesis. Moreover, extensive studies in diverse populations would be important to clarify these relationships and the potential implications for treatment and management.

Abbreviations

BC

base change

BMI

body mass index

BSA

body surface area

C

codominant

CAD

coronary artery disease

CoD

codominant model

CVD

cardiovascular disease

CVM

cardiovascular mortality

D

dominant model

DC

dilated cardiomyopathy

DCs

dendritic cells

DLQI

dermatology life quality index

GPSS

genital psoriasis symptoms scale

HDL‐c

high‐density lipoprotein cholesterol

HF

heart failure

IL

interleukin

LA

log‐additive

LDL‐c

low‐density lipoprotein cholesterol

LNPEP

leucyl and cystinyl aminopeptidase, an insulin‐responsive aminopeptidase

NK

natural killer cells

OR

odds ratio after adjustment

OvD

overdominant

p _adj

p value adjusting for age, sex, BMI, hypertension, diabetes mellitus, smoking history

PASI

psoriasis area and severity index

p _hwe

p value of the Hardy–Weinberg equilibrium tests

p _obs

observed p value

R

recessive model

RA

rheumatoid arthritis

SNP_(s)

single‐nucleotide polymorphism(s)

TNF

tumor necrosis factor

UVB

ultraviolet type B rays

1. Introduction

Psoriasis is an immune‐mediated disease with a global prevalence of 2%–3%, with significant inter‐regional variations [1]. Psoriasis affects primarily the skin and joints; however, it is now recognized as a systemic inflammatory disease [2]. The dermatological manifestations of psoriasis range from thick, red, scaly plaques (the plaque type) to multiple yellow sterile pustules on an erythematous skin, associated with systemic inflammation (generalized pustular psoriasis‐ von Zumbusch type) [3, 4, 5]. Other clinical presentations are inverse psoriasis, acrodermatitis continua of Hallopeau, palmoplantar pustulosis (localized pustular psoriasis), guttate psoriasis, and erythrodermic psoriasis [3, 4, 5]. The most common clinical presentation of the disease is psoriasis vulgaris (plaque‐type psoriasis) with elbows, knees, the umbilical area, the perianal region, and the scalp being most affected [6].

Psoriasis is a clinical diagnosis, based on the typical erythematous plaques with silvery scales affecting predilection areas, therefore a skin biopsy is rarely necessary. The severity of the disease is assessed using clinical scores such as psoriasis area and severity index (PASI), body surface area (BSA) [7], nail psoriasis severity index (NAPSI) [8], psoriasis scalp severity index (PSSI) [9], and the genital psoriasis symptoms scale (GPSS) [10]. A validated self‐reported questionnaire that evaluates the impact of the disease on the patient's quality of life is the dermatology life quality index (DLQI) [11]. Histopathological characteristics of the psoriasis plaque are epidermal hyperplasia (acanthosis) with hyperkeratosis and parakeratosis, hypogranulosis and dermal vessel dilation and elongation, and inflammatory infiltration consisting of dendritic cells (DCs), macrophages, T cells, and neutrophils [12, 13]. At the level of the parakeratotic epidermis, Munro micro‐abscesses containing polymorphonuclear leukocytes are present [13, 14].

From a pathophysiological perspective, psoriasis is characterized by disruptions in both innate and adaptative immune responses [15]. The disease is triggered or worsened by non‐specific danger signals consisting of infections, drugs, physical trauma (Koebner phenomenon), autoantigens [cathelicidin LL‐37, keratin 17, melanocytic ADAMTSL5, PLA2G4D, heterogeneous nuclear ribonucleoprotein A1 (hnRNP‐A1)] [15, 16, 17]. The natural killer cells (NK), NKT cells, neutrophils, mast cells, γδ T cells, and DCs are innate immune cells, increased in psoriatic lesions, and they are responsible for the release of cytokines (IL‐23, TNF‐alpha) [15, 18, 19]. In the initial stages of the disease, a major role belongs to DCs, antigen‐presenting cells which recognize antimicrobial peptides released by damaged keratinocytes [15, 18, 19]. Plasmacytoid DC activation is decisive in plaque formation. Consequently, IFN‐α ensure dermal DC maturation, which is responsible for Th1 and Th17 activation and differentiation [15, 18, 19]. After their activation, the myeloid DCs migrate into draining lymph nodes and secrete tumor necrosis factor (TNF)‐α, IL‐23, and IL‐12. The aforementioned cytokines induce Th17 and/or Th22 cell subsets, through activation of the IL‐23 and/or IL‐22 pathway [15, 18]. As a consequence, the abundance of psoriatic cytokines resulting from this process, namely TNF‐α, IFN‐γ, IL‐17, and IL‐22, disrupt the keratinocyte function and intensify the inflammation [18].

The TNFα‐IL‐23‐Th17 axis perpetuates inflammation in psoriasis [20]. The role played by IL‐17 in skin inflammation is well known and can be combated both directly and indirectly by blocking IL‐17 and its receptor (IL‐17R), respectively [20]. IL‐17 represents a family of proinflammatory cytokines consisting of 6 members, IL‐17A‐IL‐17F [15, 21]. In healthy skin, IL‐17 plays an important role in maintaining the integrity of the skin barrier and providing protection against fungal and bacterial infections [15, 21]. Dysfunctions of the IL‐17 signaling pathway drive the chronic inflammation characteristic of psoriasis [15, 21]. IL‐23 is produced both by keratinocytes and antigen‐presenting cells and induces Th17 activation and the secondary production of IL‐17, TNF‐alpha, and IL‐6 [22]. IL‐23 is a heterodimeric cytokine consisting of two subunits, p19 and p40 [23]. The IL‐23/IL‐17 axis is implicated in the pathogenesis of chronic inflammation that characterizes many autoimmune inflammatory diseases such as inflammatory bowel disease [24], rheumatoid arthritis (RA), Sjogren syndrome, and multiple sclerosis [25].

Of interest in recent years are the comorbidities associated with psoriasis, mainly cardiovascular diseases (CVDs) [26]. There is an independent association between psoriasis and myocardial infarction (MI), especially in young patients with severe psoriasis [27], as the prevalence of coronary atherosclerosis is twice higher in psoriasis patients compared to controls [28]. Cardiovascular mortality (CVM) was studied in a meta‐analysis by Armstrong et al. [29] among 4 cohorts of patients from the USA and Europe. The results showed a significant increase in CVM among patients with severe psoriasis. On the other hand, the risk of MI was increased in both mild and severe psoriasis [29]. Additionally, psoriasis is associated with an increased risk of stroke as shown in a meta‐analysis by Liu et al. [30].

The complexity of psoriasis pathogenesis and the characteristic chronic inflammatory state, objectified by serum biomarkers, justify the concept of a systemic disease [31]. The concept of multisystemic afflictions in psoriasis is generally accepted, with the development of guidelines that focus on managing these comorbidities, therefore every psoriasis patient should be explored beyond the skin [32]. While the association between psoriasis and CVDs is evident [33], accelerated atherosclerosis in patients with severe or longstanding psoriasis is responsible for the higher incidence of major cardiovascular events in these patients [34]. Garshick et al. [35] proposed a link between psoriasis and atherosclerosis, describing the overlapping inflammatory processes dominated by IFN‐gamma and TNF‐alpha that cause endothelial inflammation and the increased expression of the inflammatory chemokine CXCL10 and the adhesion protein VCAM‐1 [35]. Endothelial cells of psoriasis patients express a significant (2–8‐fold) upregulation of proinflammatory and chemotactic factors (VCAM‐1, IL‐1β, CXCL10, and COX‐2) compared to control subjects [35, 36]. The pattern of expression is similar to that of endothelial cells stimulated in vitro by specific combinations of cytokines like TNF‐α, IL‐17A, and IFNγ, thus supporting the pathogenetic similarities between psoriasis and atherosclerosis [35, 37]. The overlapping mechanisms of psoriasis and atherosclerotic disease are far more complex and extend beyond the focus of the present review [34, 38, 39].

Psoriasis is associated with diseases that represent risk factors for atherosclerosis, such as obesity, diabetes mellitus [40], hypertension, dyslipidemia, and metabolic syndrome [41]. Thus, the hypothesis of a common genetic background, in particular polymorphism in the IL‐23R and IL‐23 genes, of psoriasis and cardiovascular comorbidities has emerged [40]. The potential genetic link between psoriasis, hypertension, and diabetes mellitus, is supported by the presence of a missense mutation in the insulin‐responsive aminopeptidase LNPEP (leucyl and cystinyl aminopeptidase) gene, identified in a study conducted by Cheng et al. [42]. The results of a study conducted by Gupta et al. [43] contradict the aforementioned findings and support the genetic independence of psoriasis from the metabolic syndrome and coronary artery disease. The frequent association results from common environmental risk factors such as Western diet [43].

This review aims to provide an synopsis of the existing data regarding the IL‐23 rs2066808, IL‐23R rs2201841, IL‐17RA rs4819554, and IL17A rs2275913 polymorphisms that link psoriasis and its cardio‐metabolic comorbidities.

2. Materials and Methods

2.1. Literature Search

To identify all relevant studies that investigated the association between IL‐23, IL‐23R, and IL‐17 and IL‐17R polymorphisms (IL‐23 rs2066808, IL‐23R rs2201841, IL‐17RA rs4819554, and IL17A rs2275913) and psoriasis and cardiometabolic diseases, we conducted a PubMed, Web of Science and Scopus search using the terms “IL‐23R rs2201841 and psoriasis”, “IL‐23 rs2066808 and psoriasis“, “IL‐17RA rs4819554 and psoriasis”, “IL17A rs2275913 and psoriasis”, “IL‐23 rs2066808 and cardiovascular disease”, “IL‐23 rs2066808 and atherosclerosis”, “IL‐23 rs2066808 and heart failure”, “IL‐23 rs2066808 and coronary artery disease”, “IL‐23 rs2066808 and dilated cardiomyopathy”, “IL‐23 rs2066808 and metabolic syndrome”, “IL‐23R rs2201841 and cardiovascular disease”, “IL‐23R rs2201841 and atherosclerosis”, “IL‐23R rs2201841 and heart failure”, “IL‐23R rs2201841 and coronary artery disease”, “IL‐23R rs2201841 and dilated cardiomyopathy”, “IL‐23R rs2201841 and metabolic syndrome”, “IL‐17RA rs4819554 and cardiovascular disease”, “IL‐17RA rs4819554 and atherosclerosis”, “IL‐17RA rs4819554 and heart failure”, “IL‐17RA rs4819554 and coronary artery disease”, “IL‐17RA rs4819554 and dilated cardiomyopathy”, “IL‐17RA rs4819554 and metabolic syndrome”, “IL‐17A rs2275913 and cardiovascular disease”, “IL‐17A rs2275913 and atherosclerosis”, “IL‐17A rs2275913 and heart failure”, “IL‐17A rs2275913 and coronary artery disease”, “IL‐17A rs2275913 and dilated cardiomyopathy”, “IL‐17A rs2275913 and metabolic syndrome”.

We also search “SNPedia” for relevant studies. The reference lists of the included studies were checked for other relevant publications. We included in the review case‐control studies published between 2007 and 2025, written in English, which provided data regarding allele frequency or genotype distribution. We excluded duplicates, and studies that investigated family members. Of the 237 identified documents, after the full‐text review, only 22 articles were eligible for inclusion. The references of the studies were also screened for other studies suitable for inclusion in the present review. Figure 1 shows the literature search performed for the present study.

Figure 1.

Article selection protocol.

2.2. Data Collection

We extracted the following data from original studies: first author, year of publication, ethnicity, the number or ratio of cases and controls with minor allele, and the number or ratio of cases and controls with genotypes of the three variations, if available.

3. Results

3.1. IL‐23R rs2201841 and IL‐23 rs2066808 and Psoriasis

Indhumathi et al. [44] investigated the association between IL‐23R polymorphism and psoriatic risk in the Indian population. The case‐control study mentioned above included 360 psoriasis patients and 360 controls [44]. The results showed an increased risk of psoriasis associated with IL‐23R rs2201841 polymorphism in South Indian Tamils [44]. Additionally, the plasma level of IL‐23 was increased in the case of the minor variant genotype CC when compared with that of CT heterozygous and TT major variant genotypes of rs2201841 [44]. However, no significant association between IL‐23R rs2201841 polymorphism, IL‐23 levels and PASI score was found [44]. A more than twofold increase in the CC genotype in psoriasis patients compared to controls was also identified in a study conducted by Safrany et al. [45]. On the other hand, in a study also conducted by Safrany [46] in 2013, which investigated the differences between IL‐23 polymorphism rs220184 in ulcerative colitis compared to Crohn's disease and psoriasis, the only association found was with ulcerative colitis [46]. The association between psoriasis and IL‐23R rs2201841 polymorphism was demonstrated in a case‐control study by Nair et al. [47] in 2009. The results were further confirmed by another case‐control study by Eirís et al. [48]. The same case control‐study identified an association between the minor genotypic variant IL23R rs2201841‐GG and diabetes mellitus Type 2 (p = 0.027) [48]. Nikamo et al. [49] demonstrated that the rs2201841 is not only associated with severe forms (p = 0.004) of psoriasis but also with mild disease forms (p = 0.006). Contrarily, Popadic et al. [50] found an association between IL‐23R rs2201841 polymorphism and psoriatic arthritis, but not with psoriasis. No association between rs2201841 polymorphism and an increase in psoriasis risk [51, 52, 53, 54], psoriasis severity (PASI SCORE) [54], and no influence on treatment response (PASI value) was shown in another study either [53].

In a study conducted on the Spanish population, no association between rs2066808 (A > G) and psoriasis was found [48], but an association with psoriatic arthritis (AA homozygotes, p = 0.02) and nail psoriasis (p = 0.03) was present [48]. Contrarily, Nair et al. [47] in a case‐control study, found a strong association between the rs2066808 and psoriasis, further confirmed by an analysis of follow‐up samples (5048 cases, and 5051 controls) [47]. A higher risk of developing psoriasis in patients presenting the polymorphism above was demonstrated by Chen at el. [55] in a study conducted in the USA on 713 psoriasis cases and 2084 controls. IL‐23 rs2066808 is also associated with severe forms when analyzing severe versus control and severe versus mild cases [49]. The collected data regarding the implication of IL‐23R rs2201841 and IL‐23 rs2066808 polymorphisms in psoriasis development are presented in Table 1.

Table 1.

The association between the IL‐23R rs2201841 and IL‐23 rs2066808 polymorphisms and psoriasis.

Gene and SNP	Year	Population	Genotype/allele	Psoriasis patients	Frequency of risk allele	Control group	Frequency of risk allele	p value	OR	95% CI	Genotyping	Reference
IL‐23R rs2201841	Capon (2007)	British		N = 318	MAF 0.35 (218/624)	N = 288	MAF = 0.32 (186/574)	N/S	1.10		Applied Biosystems‐ TaqMan assays or SnapShot assay protocol‐single‐base primer extension	[52]
	Nair (2009)	USA	Risk allele: G	N = 1359		N = 1400		p = 2.9 × 10−7	1.347		Applied Biosystems‐TaqMan assays or Sequenom single base extension assays or allele‐specific kinetic PCR.	[47]
			Non‐risk allele: A		0.350		0.286
			G/G	158		117
			G/A	635		565
			A/A	566		717
		USA		N = 1642		N = 1101		p = 0.0081	1.172			[47]
			Risk allele G		0.325		0.291
			Non‐risk allele A
			G/G	167		93
			G/A	724		454
			A/A	735		551
		Canada	Risk allele: G	N = 368		N = 358		p = 0.571	0.937			[47]
			Non‐risk allele: A		0.314		0.328
			G/G	33		44
			G/A	154		138
			A/A	163		162
		Canada	Risk allele: G	N = 691		N = 217		p = 0.730	1.041			[47]
			Non‐risk allele: A		0.335		0.326
			G/G	83		23
			G/A	289		94
			A/A	308		98
						98
		Germany	Risk allele: G	N = 718		N = 1464		p = 0.014	1.190			[47]
			Non‐risk allele: A		0.312		0.276
			G/G	71		122
			G/A	301		559
			A/A	337		772
		USA	Risk allele: G	N = 302		N = 500		p = 0.312	1.119			[47]
			Non‐risk allele: A		0.332		0.307
			G/G	31		49
			G/A	137		205
			A/A	132		239
		France	Risk allele: G	N = 346		N = 486		p = 0.521	1.214			[47]
			Non‐risk allele: A		0.313		0.273
			G/G	35		38
			G/A	144		187
			A/A	163		257
		USA	Risk allele: G	N = 498		N = 498		p = 0.468	1.073			[47]
			Non‐risk allele: A		0.325		0.310
			G/G	63		49
			G/A	194		207
			A/A	235		236
		USA	Risk allele: G	N = 483		N = 427		p = 0.276	1.115			[47]
			Non‐risk allele: A		0.343		0.319
			G/G	61		44
			G/A	209		184
			A/A	212		198
	Sarany (2011)	Hungarian		N = 214		N = 189					PCR‐RFLP	[45]
			Genotype
			TT	102 (47.7%)		101 (53.4%)
			TC	87 (40.7%)		79 (41.8%)
			CC	25 (11.7%)		9 (4.76%)		p = 0.016	2.64	1.20–5.81
			TC + CC	112 (52.3%)		88 (46.6%)
			MAF	0.32		0.26
	Safrany (2013)	Hungarian		N = 263		N = 253		NS			PCR‐RFLP	[46]
			Genotype
			TT	33.8%		48.6%
			TC	48.7%		45.1%
			CC	17.5%		6.32%
			MAF	0.42		0.29
	Popadic (2014)	Serbia		N = 103		N = 291					Applied Biosystems‐TaqMan assays	[50]
			Allele:
			A	136	0.660	403	0.692	0.393
			G	70	0.340	179	0.308
			Genotype
			AA	44	0.427	145	0.498	0.215
			GA	48	0.466	113	0.388	0.168
			GG	11	0.107	33	0.113	0.862
	Eirís (2014)	Spanish		N = 405		N = 426					Applied Biosystems‐TaqMan assays	[48]
			Allele:
			A		0.70		0.65
			G		0.30		0.35
			Genotype
			AA	197	0.49	175	0.41
			GG	174	0.43	200	0.47
			AG	34	0.08	51	0.12
			AA vs. (AG + GG)					p = 0.03	1.36	1.03–1.79
	Nikamo (2015)	Caucasians/Sweden		N = 1411		N = 1529					Applied Biosystems‐TaqMan assays	[49]
			Severe vs. Controls	Severe = 715				p = 0.004	1.22	(1.07–1.40)
			Mild vs. Controls	Mild = 696				p = 0.006	0.99	(0.86–1.14)
	Indhumathi (2016)	Indian		N = 360		N = 360					TaqMan assays	[44]
			Genotype
			TT vs. CT + CC	280 (77.8%)		239 (66.4%)		p = 0.0009	1.77	1.27–2.47
			CC	114 (31.7%)		90 (25%)		p = 0.002	1.92	1.29–2.85
			CT	166 (46.1%)		149 (41.4%)		p = 0.006	1.69	1.18–2.41
			TT	80 (22.2%)		121 (33.6%)
			Allele:
			C	394 (54.7%)		329 (45.7%)		p = 0.0007	1.44	1.17–1.77
			T	326 (45.3%)		391 (54.3%)
	Bojko (2018)	Poland		N = 507		N = 396		p = 0.874	0.99	0.75–1.30	Applied Biosystems‐TaqMan assays	[53]
			Risk allele
			G		MAF = 0.284		MAF = 0.280
	Filiz (2019)	Turkish		N = 60		N = 60		p = 0.673			Competitive allele‐specific PCR (KASP) assay	[51]
			Allele/Genotype
			AA	16 (26.7%)		17 (28.4%)
			GA	29 (48.3%)		32 (53.3%)
			GG	15 (25%)		11 (18.3%)
	Lin (2022)	Asian (China)		N = 43		N = 24					MALDI‐TOF mass spectrometry	[54]
			Genotype
			GG	29		15		p = 0. 303
			AG	13		6
			AA	1		3
			Allele
			A	71		36		p = 0.296	1.578	0.669–3.723
			G	15		12			1.57
IL‐23 rs2066808	Nair (2009)	USA		N = 1359		N = 1400		p = 1.7E‐05	1.676		Applied Biosystems‐TaqMan assays or Sequenom single base extension assays or allele‐specific kinetic PCR.	[47]
			Allele:
			A‐risk		0.958		0.931
			G‐non‐risk
			Genotype:
			AA	1246		1215
			AG	111		177
			GG	2		8
		USA		N = 1642		N = 1101		p = 0.0014	1.447			[47]
			Allele:
			A‐risk		0.951		0.930
			G‐non‐risk
			Genotype:
			AA	1472		947
			AG	151		139
			GG	5		7
		Canada		N = 368		N = 358		p = 0.206	1.318			[47]
			Allele:
			A‐risk		0.946		0.929
			G‐non‐risk
			Genotype:
			AA	328		304
			AG	38		50
			GG	1		0
		Canada		N = 691		N = 217		p = 0.145	1.395			[47]
			Allele:
			A‐risk		0.951		0.933
			G‐non‐risk
			Genotype:
			AA	620		190
			AG	65		25
			GG	1		2
		Germany		N = 718		N = 1464		p = 0.014	1.405			[47]
			Allele:
			A‐risk		0.948		0.928
			G‐non‐risk
			Genotype:
			AA	635		1256
			AG	72		185
			GG	1		12
		USA		N = 302		N = 500		p = 0.0079	1.882			[47]
			Allele:
			A‐risk		0.960		0.927
			G‐non‐risk
			Genotype:
			AA	276		425
			AG	24		68
			GG	0		2
		France		N = 346		N = 486		p = 0.877	0.851			[47]
			Allele:
			A‐risk		0.958		0.964
			G‐non‐risk
			Genotype:
			AA	313		447
			AG	29		35
			GG	0		0
		USA		N = 498		N = 498		p = 0.953	0.990			[47]
			Allele:
			A‐risk		0.924		0.925
			G‐non‐risk
			Genotype:
			AA	420		420
			AG	71		68
			GG	2		3
		USA		N = 483		N = 427		p = 0.526	1.131			[47]
			Allele:
			A‐risk		0.941		0.933
			G‐non‐risk
			Genotype:
			AA	424		367
			AG	57		52
			GG	0		2
	Chen (2011)	USA		N = 731		N = 2084		p = 0.0001			Illumina GoldenGate assay	[55]
			Risk allele: T
			Nonrisk allele: C		0.955		0.920		1.82	1.34–2.45
	Eirís (2014)	Spanish		N = 405		N = 426					Applied Biosystems‐TaqMan assays	[48]
			Allele:
			A		0.93		0.92
			G		0.07		0.08
			Genotype
			AA	350	0.86	362	0.85
			AG	55	0.14	63	0.147
			GG	0	0	1	0.003
			AA vs. (AG + GG)					p = 0.55	1.13	0.76–1.66
	Nikamo (2015)	Caucasians/Sweden		N = 1411		N = 1529					Applied Biosystems‐TaqMan assays	[49]
				Severe = 715
				Mild = 696
			Severe vs. Controls					p = 2 × 10−7	0.44	(0.32–0.60)
			Mild vs. controls					p = 0.0005	0.78	(0.61–1.01)

Note: *p < 0.05, **p value for homozygosity of minor allele, N/S not significant, PCR‐RFLPolymerase chain reaction–restriction fragment length polymorphism

Abbreviation: MAF, minor allele frequency.

3.2. IL‐23R rs2201841 and IL‐23 rs2066808 and Cardiometabolic Diseases

Psoriasis patients have a higher prevalence of cardiovascular risk factors [56]. The risk of myocardial infarction and stroke is increased even in patients with mild psoriasis [26].

The IL‐23 receptor (IL‐23R) gene polymorphism rs2201841 has been implicated in CVD through its role in inflammatory pathways [57]. Research indicates that variations in IL‐23R can influence susceptibility to atherosclerosis and coronary artery disease (CAD) [57]. The Th17/IL‐23 axis is recognized for its role in inflammation, which is a critical factor in both CAD and other cardiometabolic disorders [57]. Eirís et al. [48] in their study published in 2014, showed an association between Type 2 diabetes mellitus in psoriasis patients and the minor genotypic variant of IL‐23R rs2201841‐GG. Additionally, factors such as age, dyslipidemia, hypertension or ischemic cardiomyopathy did not represent confounding factors after logistic regression [48]. There was no association found between IL‐23 rs2066808 and cardiometabolic diseases or cardiovascular risk factors [48, 58].

3.3. IL‐17RA rs4819554 and IL17A rs2275913 and Psoriasis

Batalla et al. [59] in a case‐control study, conducted in the Spanish population found an association between IL17RA rs4819554 SNP and the risk for psoriasis, namely the G carriers (AG + GG) were significantly more common (p = 0.017, OR = 1.33 (95% CI = 1.05–1.69). The presence of the aforementioned polymorphism had no impact on the psoriasis severity, presence of PsA, or demographics [59]. Additionally, the number of the IL17RA rs4819554 G‐carriers was higher in the Cw6‐positive subgroup, an association that lost statistical significance after adjusting for age of onset as a confounding factor [59]. Sabry et al. [60] found a significantly increased expression of IL‐17 in psoriasis patients vs. controls (p = 0.0006) and in patients with AA, GG and AG rs4819554 genotypes compared to the same genotypes controls (p = 0.0004). Also, the serum levels of IL‐17 and psoriasin were significantly higher in psoriasis patients compared to controls, especially in the AA and AG genotypes. No significant IL‐17 serum levels differences were found in GG genotypes in patients and controls [60].

A prospective, longitudinal, analytical cohort study by Puscaș et al. [61] published in 2023, including 81 patients with moderate to severe plaque psoriasis, found an association between IL‐17RA rs4819554 polymorphism, the GG genotype compared to those with GA/AA genotype and nail psoriasis and a higher BMI in the psoriasis patients.

A meta‐analysis by Villalpando‐Vargas et al. [62] showed that the presence of AG genotype of the rs4819554 polymorphism was associated with an almost significant reduction in the psoriasis risk when compared to the GG genotype (p = 0.050).

Lin et al. [54] included in a study conducted on Asian population 43 psoriasis patients and 24 controls. The results showed no association between 17RA rs4819554 polymorphism and psoriasis. In a case‐control study, conducted on the Polish population, Białecka et al. [63] found no association between IL17A rs2275913 polymorphisms and psoriasis, but they found that the IL‐17F polymorphisms could predict the treatment response to UVB‐nb phototherapy.

Kim et al. [64] in a case‐control study conducted on the Korean population, concluded that there is no association between the IL17A rs2275913 polymorphism and psoriasis. The same results were found in the Spanish population in a case‐control study by Prieto‐Pérez et al. [65] in 2015. The collected data regarding the implication of the IL‐17RA rs4819554 and IL17A rs2275913 polymorphisms in psoriasis development are presented in Table 2.

Table 2.

The association between the IL‐17RA rs4819554 and IL17A rs2275913 polymorphisms and psoriasis.

Gene and SNP	Study	Population	Genotype/allele	Psoriasis patients	Control group	p value	OR	95% CI	Genotyping	Reference
rs4819554	Batalla (2015)	Spanish		N = 580	N = 567				Applied Biosystems‐TaqMan assays	[59]
			Genotype:
			AA	57	63
			AG	38	33
			GG	5	4
			Allele:
			A	0.76	0.80
			G	0.24	0.20
			AG + GG vs. AA			p = 0.017	1.33	1.05–1.69
	Sabry (2020)	Egyptian		N = 100	N = 100				Applied Biosystems‐TaqMan assays	[60]
			Genotype:
			AA	20%	48%	p = 0.007	2.283	1.321–3.946
			GG	22%	6%	p = 0.029	0.344	0.132–0.895
			AG	58%	46%
			Allele:
			A	49%	71%	p = 0.003	2.283	1.321–3.946
	Lin (2022)	Asian		N = 43	N = 24				MALDI‐TOF MS	[54]
			Genotype:
			AG	13	12	p = 0.142
			AA	21	6
			GG	9	6
			Allele
			A	55	24	p = 0.115	1.774	0.866–3.634
			G	31	24
rs2275913	Prieto‐Pérez (2015)	Spanish		N = 194	N = 197				Applied Biosystems‐TaqMan assays	[65]
			Genotype:
			AA	16 (8%)	24 (12%)
			GA	93 (48%)	77 (39%)	p = 0.135; C;GA	1.40	0.92–2.13
			GG	83 (43%)	96 (49%)
			Allele:
			A	125 (32.2%)	125 (31.7%)
	Białecka (2016)	Polish		N = 407	N = 205	p = 0.70			Applied Biosystems‐TaqMan assays	[63]
			Genotype:
			AA	53 (13.18%)	28 (13.73%)
			GA	173 (43.03%)	94 (46.08%)
			GG	176 (43.78%)	82 (40.20%)
			AA + GA vs. GG			p = 0.43	0.86	0.61–1.22
			AA vs. GA + GG			p = 0.90	0.95	0.58–1.56
			AA vs. GG			p = 0.68	0.88	0.52–1.49
	Kim (2016)	Korean		N = 208	N = 266				PCR	[64]
			Alleles
			G > A	0.463	0.434	p = 0.38	1.12	0.86–1.46
	Ozkol (2020)	Turkish		N = 83	N = 69				Thermo Scientific, USA‐ TaqMan SNP Assay mix	[66]
			Genotype:
			AA	11 (57.9%)	8 (42.1%)
			GA	38 (55.9%)	30 (44.1%)
			GG	34 (53.1%)	31 (46.9%)	p = 0.992

Abbreviations: C, codominant; MALDI‐TOF MS, matrix assisted laser desorption ionization‐time of flight mass spectrometry; PCR, polymerase chain reaction.

3.4. IL‐17RA rs4819554 and IL17A rs2275913 and Cardiometabolic Diseases

Psoriasis patients present a higher risk of CVDs and metabolic syndrome compared to the general population [67]. A common genetic background is speculated as presented in a review by Piaserico et al. [40]. One of the IL‐17RA polymorphisms, namely rs4819554, which is associated with psoriasis, is also linked to CVM, but not with heart failure [68]. Additionally, Coto et al. [69] found a higher IL‐17RA rs4819554 transcript in coronary artery disease patients, but no difference in genotype frequencies in patients and controls.

Regarding the IL‐17A rs2275913 and CVDs, no association was found with heart failure or cardiovascular death [68]. On the other hand, Geng et al. [70] found that IL‐17A rs2275913 may be implicated in the development of coronary artery disease (CAD) in codominant (p = 0.01) and recessive (p = 0.03) models. This association between the 17A rs2275913 and CAD was further found in another case‐control study [71] and seems to be linked to an early onset of CAD [71]. Zhang et al. [72] also studied the implications of the aforementioned polymorphism in CAD [72]. They included in their study 1031 patients with CAD and 935 controls. They defined the presence of CAD by 50% stenosis in major coronary arteries, or a prior history of angioplasty, major cardiac event, or bypass surgery. They did not find any association between the IL‐17A rs2275913 and coronary artery disease [72]. A statistically significant association between the IL‐17A rs2275913 and CAD was identified by Zhao et al. [73] but, after adjusting for confounding factors such as age, gender, smoking, drinking, hypertension, and Type 2 diabetes mellitus, the association was no longer valid. Su et al. [74] in a case‐control study conducted in the Chinese population in 2016, also found no association between the aforementioned polymorphism and CAD. Furthermore, there is no link between the aforementioned polymorphism and dilated cardiomyopathy [75]. The collected data regarding the implication of the IL‐17RA rs4819554 and IL17A rs2275913 polymorphisms in cardiometabolic diseases are presented in Table 3.

Table 3.

The association between the IL‐17RA rs4819554 and IL17A rs2275913 polymorphisms and cardiometabolic diseases.

Gene and SNP	Study	Disease	Population	Genotype/allele	Patient group (%)	Control group (%)	Model	p value	OR	95% CI	Genotyping	Reference
IL‐17RA rs4819554	Sandip (2016)	HF	Chinese		N = 1713	N = 1713		p = 0.46	1.04	0.94–1.46	Applied Biosystems‐TaqMan assays	[68]
				Genotype:	554 (32.3%)	560 (32.7%)
				GG
				GA	769 (44.9%)	780 (45.5%)
				AA	390 (22.8%)	373 (21.8%)
				MAF	45.2%	44.5%
IL17A rs2275913	Zhang (2011)	CAD	Chinese		N = 1031	N = 935					PCR	[72]
				Genotype:	290 (28.1%)	266 (28.4%)		0.92
				GG
				GA	535 (51.9%)	489 (52.3%)
				AA	206 (20.0%)	180 (19.3%)
				AlleleG	1115 (54.1%)	1021 (54.6%)		0.74	1.02	0.90‐1.15
				A	947 (45.9%)	849 (45.4%)
	Peng (2013)	DC	Chinese		N = 288	N = 421					Applied Biosystems‐TaqMan assays	[75]
				Genotype:	96 (33.3%)	155 (36.8%)	CoD	0.64	1	Ref.
				GG
				AG	142 (49.3%)	193 (45.8%)			0.85	0.61–1.19
				AA	50 (17.4%)	73 (17.3%)			0.91	0.58‐1.42
				GG	96 (33.3%)	155 (36.8%)	D	0.37	1	Ref.
				AG/AA	192 (66.7%)	266 (63.2%)			0.87	0.63‐1.19
				GG/AG	238 (82.6%)	348 (82.6%)	R	1	1	Ref.
				AA	50 (17.4%)	73 (17.5%)			1	0.67‐1.49
				GG/AA	146 (50.7%)	228 (54.2%)	Ovd	0.4	1	Ref.
				AG	142 (49.3%)	193 (45.8%)			0.88	0.65‐1.19
				—	—	—	LA	0.54	0.94	0.75‐1.16
	Geng (2015)	CAD	Chinese		N = 306	N = 306					PCR‐RFLP	[70]
				Genotype: GG	123 (40.2%)	146 (47.71%)	CoD	—	Ref.
				GA	140 (45.75%)	134 (43.79%)		0.21	1.24	0.87‐1.76
				AA	43 (14.05%)	26 (8.5%)		0.01	1.96	1.10‐3.53
				GG	123 (40.2%)	146 (47.71%)	D	—	Ref.
				GA+AA	183 (59.8%)	160 (52.29%)		0.06	1.36	0.97‐1.89
				GG+GA	263 (85.95%)	280 (91.5%)	R	—	Ref.
				AA	43 (14.05%)	26 (8.5%)		0.03	1.76	1.02‐3.07
	Vargas‐Alarcón (2015)	CAD	Mexican	Genotypes	N = 900	N = 667	D	0.55/0.62	0.91	0.70‐1.17	Applied Biosystems‐TaqMan assays	[76]
					616 (0.68)	439 (0.66)
					259 (0.28)	202 (0.30)
					23 (0.03)	26 (0.04)
				MAF	0.16	0.19		0.44
	Shuang (2015)	CAD	Asian/Chinese		N = 415	N = 448					PCR‐RFLP	[77]
				Genotypes GG	168 (40.48%)	220 (49.11%)		—	1.0	Ref.
				GA	187 (45.06%)	196 (43.75%)		0.12	1.25	0.93‐1.68
				AA; BC: G>A	60 (14.46%)	36 (8.04%)	Phwe = 0.4	0.001	2.18	1.35‐3.56
				GA+AA	247 (59.52%)	232(51.79%)		0.02	1.39	1.06‐1.84
	Sandip (2016)	HF	Chinese		N = 1713	N = 1713		P=0.30	0.95	0.85–1.05	Applied Biosystems‐TaqMan assays	[68]
				Genotype: GG	494 (28.8%)	461 (26.9%)
				GA	840 (49.0%)	876 (51.1%)
		AA	379 (21.1%)	376 (21.9%)
		MAF	46.6%	47.5%
	Zheng (2016)	CAD	Asian/Chinese		N = 372	N = 372					PCR‐RFLP	[78]
				Grnotypes GG	162 (43.55%)	179 (48.12%)			1.0	Ref.
				GA	170 (45.7%)	163 (43.82%)			1.15	0.84‐1.58
				AA, BC: G>A	40 (10.75%)	30 (8.06%)		0.4	1.47	0.85‐2.57
				GA+AA	210 (56.45%)	193 (51.88%)			1.20	0.89‐1.62
	Su (2016)	CAD	Chinese		N = 219	N = 219					SNaPshot SNP genotyping assay (Genesky, Shanghai, China) Td‐PCR	[74]
				Genotypes/alleles:	93 (42.5%)	95 (43.4%)		0.847	0.963	0.660‐1.407
				GG
				AG	102 (46.6%)	101 (46.1%)		0.924	1.019	0.700‐1.483
				AA	24 (11.0%)	23 (10.5%)		0.877	1.049	0.573‐1921
				G	288 (65.8%)	291 (66.4%)		0.830	0.970	0.733‐1.283
				A	150 (34.2%)	147 (33.6%)
	Zhao (2019)	CAD	Chinese		N = 191	N = 131					MALDI‐TOF MS	[73]
				Genotype:	30 (15.71%)	33 (25.19%)			Ref.	Ref.
				GG
				AG	112 (58.64%)	73 (55.73%)			1.45	0.78‐ 2.67
				AA	49 (25.64%)	25 (19.08%)			2.21	0.95‐5.19
				AG/AA	161 (84.29%)	98 (74.81%)			1.62	0.89‐2.93
	Ghaznavi (2020)	CAD	Iran		N = 220	N = 220					PCR‐RFLP	[79]
				Genotypes/alleles	88 (40%)	113 (51.36%)		‐	Ref.
				GG
				GA	98 (44.54%)	89 (40.45%)		0.104	1.41	0.95‐2.10
AA				34 (15.46%)	18 (8.19%)		0.007	2.42	1.26‐4.54
G				274 (62.27)	315 (71.60%)		‐	Ref.
A				166 (37.73%)	125 (28.40%)		0.041	1.53	1.16‐2.03
Zhang (2023)	CAD	Chinese		N = 3042	N = 3216					PCR	[71]
			Genotypes: Allele	883/1950	907/179	DOM	Pobs/padj = 0.059/0.255	1.078	0.947,1.226
			A
				2269/564	2167/537	REC	Pobs/padj = 0.964/0.247	0.914	0.786,1.064
				883/1386/564	907/1260/537	ADD	Pobs/padj = 0.137/0.920	1.004	0.923,1.093
			MAF	0.44	0.43		Phwe = 0.009	1.004	0.922‐1.095
							Pobs = 0.199
							Padj = 0.919

Abbreviations: BC, base change; CAD, coronary artery disease; CoD, codominant model; D, dominant model; DC, dilated cardiomyopathy; HF, heart failure; LA, log‐additive; MALDI‐TOF MS, matrix assisted laser desorption ionization‐time of flight mass spectrometry; OR, odds ratio after adjustment; OvD, overdominant; p _adj, p value adjusting for age, sex, BMI, hypertension, diabetes mellitus, smoking history, Tch, TG, HDL‐c, and LDL‐c; PCR, polymerase chain reaction; PCR‐RFLP, polymerase chain reaction combined with restriction fragment length polymorphism; p _hwe, p value of the Hardy–Weinberg equilibrium tests; p _obs, observed p value; R, recessive model; Td‐PCR‐touch‐down polymerase chain reaction.

4. Discussion

Interleukin‐17 plays a pivotal role in the pathogenesis of psoriasis. Its multifaceted involvement influences immune responses, keratinocyte behavior, and metabolic processes [80]. T helper cells produce IL‐17A, crucial in mediating psoriasis inflammatory responses [80]. The IL‐23/IL‐17 axis perpetuates the inflammation, leading to keratinocyte activation and hyperproliferation [81], together with IL‐17A‐induced metabolic reprogramming, which also contributes to their proliferation and the formation of psoriatic plaques [82]. IL‐23 triggers the production of IL‐17 [83]. Keratinocytes produce IL‐23, which further contributes to the inflammatory milieu in psoriasis [84]. Figure 2 presents the implication of IL‐17/IL‐23 axis in psoriasis and atherosclerosis.

Figure 2.

(Created in BioRender. Lazar, L. (2025) https://BioRender.com/ln3xljd). Note: The link between psoriasis and atherosclerosis: Psoriasis is triggered by non‐specific danger signals (Triggers) consisting of infections, drugs, physical trauma, alcohol, smoking, and autoantigens that act in an individual with a genetic predisposition for the disease. In the initial stages, a major role is played by DCs, antigen‐presenting cells, that recognize antimicrobial peptides (LL‐Cathelicidin) and self‐DNA released by damaged keratinocytes. The activation of plasmacytoid DC and IFN‐α release lead to dermal DC maturation and the release of TNF‐α, IL‐23, and IL‐12 responsible for Th1, Th17, and Th22 activation, differentiation, and the production of cytokines, namely TNF‐α, IFN‐γ, IL‐17, and IL‐22, that disrupt the keratinocyte function and intensify the inflammation. The TNFα‐IL‐23‐Th17 axis perpetuates inflammation in psoriasis. The keratinocyte activation induced by IL‐17 leads to their proliferation and the release of TNF‐α and CCL20, that chemoattracts T cells that produce more IL‐17. The expression of vascular adhesion factors is higher in psoriasis lesions, and it further enhances the adhesion of inflammatory cells to the endothelial cells, perpetuating the inflammation. The blood flow in psoriatic lesions is altered through the vasodilation of the blood vessels in the papillary dermis. The IL‐17 causes endothelial dysfunction, it mediates the expression of chemokines MCP‐1, MMP‐9, it upregulates the IL‐6 and also the chemokines CCL‐2 and CCL8, thus promoting atherosclerosis. The key cytokines implicated in these processes are the targets for the biological treatments, which could halt the detrimental process. pDC‐ Plasmacytoid DCs, IFN‐α‐Interferon alpha, mDC‐Myeloid DCs, TNF‐α‐Tumor necrosis factor alpha, IL‐12‐ Interleukin‐12, IL‐22‐ Interleukin‐22, IL‐23‐ Interleukin‐23, IL‐17‐ Interleukin‐17, IFN‐γ‐Interferon gamma, CCL‐20‐CC chemokine ligand 20, VAF‐ Vascular adhesion factors, PMN‐Polymorphonuclear neutrophils, MF‐Macrophage, MC‐Mast cells, MCP‐1‐Human monocyte chemoattractant protein‐1, MMP9‐Matrix metalloproteinase‐9, IL‐6‐ Interleukin‐6, CCL2‐C‐C motif ligand 2, CCL8‐C‐C motif ligand 8.

Biologics targeting IL‐23, such as risankizumab and guselkumab, have shown significant efficacy in treating psoriasis by inhibiting the aforementioned pathway [85]. Biologic therapies not only alleviate skin symptoms but may also impact the associated comorbidities [86]. As shown in the present review, the data regarding the association of those comorbidities and IL‐17 or IL‐23 polymorphisms are conflicting. While some studies showed the link between the presence of IL‐23 rs2066808 polymorphism [47, 53, 54], others deny the association [48]. On the other hand, the IL‐23R gene polymorphism rs2201841 has been studied in various autoimmune conditions, revealing mixed associations with disease susceptibility [87, 88, 89]. Conversely, another study found that rs2201841 was linked to higher inflammatory markers in RA patients [90]. Regarding the association with psoriasis, the rs2201841 polymorphism studies do not show a significant association with disease presence [51]. The IL‐17RA gene polymorphism rs4819554 has been implicated in the susceptibility and clinical manifestations of psoriasis [60]. Research indicates that this SNP is associated with increased psoriasis risk, particularly in specific populations such as Egyptian patients [60]. The study conducted by Sabry et al. [60] in 2020 found a strong association with psoriasis susceptibility. On the other hand, Villalpando‐Vargas et al. [62] contradict the aforementioned findings through the results of their meta‐analysis that showed a near‐significant reduction in psoriasis risk associated with the AG genotypes in comparison to the GG genotype (OR = 0.604, p = 0.050).

IL‐17RA is crucial for the signaling of IL‐17 cytokines, which are central to the inflammatory processes in psoriasis [91]. These receptors’ polymorphisms may alter their function, impacting disease severity and treatment response [91]. No significant differences in genotype frequencies of IL17A rs2275913 were found between psoriatic patients and controls, suggesting it may not be a direct risk factor for psoriasis [66]. However, the AA genotype was associated with shorter disease duration and better treatment responses, indicating a potential role in disease management rather than susceptibility [91].

Polymorphisms of the genes encoding the interleukins implicated in the psoriasis pathophysiology may represent the missing key to the puzzle in the case of non‐responders. For instance, there is an association between the interleukin 17 family polymorphisms, the severity of the psoriasis and response to both classical and biological treatment [92]. In addition, these polymorphisms are also implicated in the risk of developing other conditions such as autoimmune diseases, including inflammatory bowel disease [93], multiple sclerosis [94], rheumatoid arthritis [95], and hematologic neoplasias [96] or carcinomas [97].

The influence of polymorphisms on treatment response has been studied. Thus, Prieto‐Pérez, in a review published in 2013 [98], identified that the G allele of the SNP rs610604 and the T allele of the SNP rs2230926 are associated with a good response to TNFi therapy [98, 99]. A good response to etanercept, but not to infliximab and adalimumab, is associated with the polymorphisms TNF‐a –857 (rs1799724) and TNFRSF1B (rs1061622) [100]. In 2015, Prieto‐Pérez et al. [65] in a study conducted on 194 psoriasis patients and 197 controls, found an association between IL‐17F SNP rs763780 and the treatment response to ustekinumab and infliximab and a link between rs763780 and the response to adalimumab. Batalla et al. [101] conducted a study on the Caucasian population and investigated the IL‐17RA rs4819554 and rs879577 polymorphisms [101]. The IL‐17RA rs4819554 (allele A) polymorphism was associated with the anti‐TNF‐α treatment response at week 12 (p = 0.01) and 24 (p = 0.04) [101]. In a cohort study conducted on 250 Caucasian Greek patients with psoriasis, Masouri et al. [102] showed that the presence of Rs10484554 polymorphism was associated with a good response to anti‐TNF‐α agents but not to the anti‐IL12/IL23 agent, Ustekinumab. On the other hand, the rs151823 and rs26653 are linked to a good response to anti‐IL‐12/23 therapy [102]. However, the aforementioned study has several limitations, namely the small sample size and the fact that the follow‐up was performed only at 6 months, without further evaluations of the included subjects [102]. A good response to Ustekinumab treatment was also associated with the presence of HLA‐Cw6 [103, 104]. The success of phototherapy treatment could also be predicted by the presence of the IL17A and IL17F polymorphisms in psoriasis patients [63]. The patients presenting the IL17F rs2397084 (allele C) polymorphism were more resistant to phototherapy and required a higher number of treatment sessions when compared to the TT homozygotes [63]. Ozkol et al. [66] did not find any association between IL‐17A rs2275913 and IL‐17F rs763780 and psoriasis in the Turkish population. However, the rs2275913 polymorphism was linked to a shorter disease duration and the treatment response (AA genotype) [66].

Contrarily, van Vugt et al. [105] in a cohort study conducted in the European population, concluded that the genetic variations of the IL‐17A gene did not explain the differences in the treatment response to anti‐IL17 biologics.

Given that IL17A's proinflammatory role is common in the pathogenesis of psoriasis, metabolic diseases, and CVDs, anti‐IL17 therapy has a positive effect not only on the cutaneous manifestations of psoriasis, but also on the cardiovascular system and concomitant metabolic disorders [106]. The IL‐17A effect on the cardiovascular system is promoted by IL‐6 and TNF‐α [107]. Psoriasis patients present subclinical endothelial alterations detectable by flow‐mediated dilation (FMD) [108]. Compared to healthy controls, the psoriasis patients, without known CVDs, present a lower FMD [108]. Interestingly, after 52 weeks’ treatment with secukinumab 300 mg the FMD was significantly improved compared to the baseline measurements when compared to placebo, suggesting that secukinumab improves endothelial function in such patients [108]. Additionally, the biological treatments has a beneficial effect on the reduction of the coronary non‐calcified atherosclerotic plaques [109]. The most effective biological treatment for reducing the coronary atherosclerotic burden are the therapies targeting IL‐17 when compared to anti‐IL12/23 and anti‐TNF treatments [109]. Furthermore, the biological treatment was associated with a reduction in coronary inflammation [110]. Other studies also evidenced the superiority of anti‐IL17 and anti‐IL‐23 targeted therapies for skin disease and the associated cardiovascular comorbidities or metabolic syndrome [37, 106, 111].

Jain et al. [112] published a meta‐analysis regarding the presence of coronary artery microvascular dysfunction assessed by Echocardiographic Coronary Flow Reserve Parameters. In psoriasis patients, the coronary flow velocity reserve was reduced, which pointed to a coronary microvascular dysfunction [112]. Additionally, the psoriasis patients present reduced GLS and GCS, which suggests a subclinical cardiac dysfunction that may predict the future cardiovascular events [113]. Moreover, the atrial fibrillation risk seems to be higher in psoriatic patients [114]. However, there are still conflicting data regarding the link between the anti‐IL12/23 therapies and cardiovascular risk [115]. A global population‐based retrospective cohort study showed no differences regarding the all‐cause mortality or major cardiac events risk among biologic therapies, which reduce the risk of death and CVD when compared to classical anti‐psoriatic drugs and apremilast [116]. The aforementioned findings are crucial taking into consideration that psoriasis patients, including young patients with severe forms of the disease, have a higher risk of myocardial infarction [27]. Importantly, the association of severe forms of psoriasis with cardiac mortality is independent of the traditional risk factors for CVDs [117]. Psoriasis was also associated with a higher risk of stroke [117]. A case control study, conducted on the Chinese population, showed an association between the IL‐17A rs2275913 polymorphism and the risk of stroke [118]. Additionally, the IL‐17A levels were higher in patients carrying the rs2275913 GA or GG genotype [118].

As IL‐17 and IL‐23 are implicated in both psoriasis and atherosclerotic disease, more studies should focus on investigating the presence of their polymorphisms in patients with both psoriasis and coronary artery disease vs. psoriasis patients without coronary artery disease.

Some of the polymorphisms implicated in the psoriasis development are also linked to CVD. One of them is the IL‐23 rs2066808 polymorphism that is linked to premature coronary artery disease in specific populations, such as Mexicans [58]. In a Middle Eastern Chinese cohort, polymorphisms in the IL‐23 receptor were associated with increased CAD risk, suggesting a broader role of IL‐23 in cardiovascular pathology [71, 73]. Research indicates that the IL‐23/Th17 pathway plays a significant role in the pathogenesis of psoriasis, which is associated with increased cardiovascular and metabolic disease risk [57]. Elevated IL‐23 levels have been found in atherosclerotic plaques and correlate with disease severity [57]. Additionally, the rs2201841 variant has shown associations with ulcerative colitis and RA, indicating its role in inflammatory processes that may contribute to cardiometabolic diseases [119, 120]. However, the evidence supports a connection between IL‐23R variants and inflammatory diseases, the direct impact of rs2201841 on cardiometabolic outcomes remains to be fully elucidated, necessitating more targeted studies.

In the present review we found that the IL‐17 receptor A (IL‐17RA) polymorphism rs4819554 is associated with increased CVM in heart failure patients, highlighting its potential as a genetic risk factor in this population [68]. The IL17A rs2275913 polymorphism has been linked to increased susceptibility to CAD, particularly in early‐onset cases [71].

The polymorphisms analysis could be a step further for a personalized management of psoriasis patients, especially non‐responders to conventional treatment.

5. Major Open Questions

The data regarding the implication of the above mentioned polymorphisms in the development of psoriasis and cardiometabolic diseases are conflicting. One of the factors that could contribute to contradictory results is the subjects' ethnicity; most of the studies were conducted on Asian populations. It is known that the prevalence of psoriasis varies among populations, and it is highest in Caucasians (3.6%), followed by African Americans 1.9%, and Hispanics 1.6%, and 1.2% in other ethnic groups [121]. One explanation for the discrepancies regarding the psoriasis prevalence in different ethnic groups with a higher frequency in the Caucasioan population, could be explained by the genetic drift [122]. The psoriatic plaques could represent a “chemical shield” for infection control, which favors energy conservation, wound healing, low‐grade inflammation [122]. Another interesting fact is that psoriasis is more frequent in high‐income countries [123]. Additionally, the exacerbating factors differ among different ethnic groups, with stress being a more important exacerbating factor for Asians compared to Hispanics/Latinos and Caucasians [124]. On the other hand, medication was more frequently employed as an exacerbating factor for Caucasians compared to Asians [124].

Furthermore, the techniques used for the polymorphism determination vary between studies, and there is no consensus regarding the type of psoriasis that the subjects in these studies have. Moreover, there are few studies conducted in the European population.

Other important limitations are the small sample sizes of some of the included studies, the sample size differences, the methodological inconsistencies, and the lack of studies that demonstrate the causality relationship.

6. Conclusion and Perspectives

In conclusion, psoriasis and cardiometabolic diseases could have a common genetic background that explains the higher frequency of cardiovascular comorbidities in psoriasis patients. The IL17A rs2275913 polymorphism could be implicated in psoriasis, influencing both disease susceptibility and treatment response. Some of the polymorphisms implicated in the psoriasis development are also linked to CVD. Research indicates that variations in the IL‐23 gene may influence susceptibility to coronary artery disease and other cardiovascular conditions. Furthermore, a larger sample size across diverse populations would provide a more comprehensive understanding of the hypothesis in question. Ultimately, the establishment of robust evidence through these standardized studies will contribute significantly to the field and help in drawing more definitive conclusions regarding the validity of the hypothesis. To validate the hypothesis presented, it is essential to conduct more standardized case‐control studies. These studies should be designed with rigorous methodologies and uniform protocols to ensure consistency and reliability in the results. Understanding the genetic basis of psoriasis and its cardiovascular comorbidities could enhance treatment strategies, particularly in selecting biologic therapies that target IL‐17 and IL‐23 pathways.

Author Contributions

Andrada‐Luciana Lazar: conceptualization, investigation, writing – original draft, methodology, writing – review and editing, formal analysis. Cleopatra Romana Vulturar: supervision, data curation, visualization, validation, writing – review and editing. Adela‐Viviana Sitar‐Tăut: writing – review and editing, formal analysis, supervision, data curation. Ramona Suharoschi: writing – original draft, formal analysis, supervision. Olga Hilda Orășan: conceptualization, methodology, formal analysis. Adina Ancuța Chiș: conceptualization, study design, revising article – intellectual content. Adriana Fodor: validation, formal analysis, writing – review and editing. Brîndușa Tiperciuc: writing – review and editing, formal analysis, visualization. Cezar Login: visualization, writing – review & editing, formal analysis. Angela Cozma: supervision, formal analysis, visualization, writing – review and editing.

Conflicts of Interest

The authors declare no conflicts of interest.

Transparency Statement

The lead author Cleopatra Romana Vulturar affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.