Is Sortilin an indicator of subclinical atherosclerosis in patients with psoriasis?

doi:10.21203/rs.3.rs-2739119/v1

Introduction: Systemic comorbidities are quite common in psoriasis, which is a chronic inflammatory disease. These comorbidities are important causes of mortality and morbidity. Atherosclerosis and related cardiovascular events are important causes of death at an early age. Atherosclerosis is a condition that can be detected by radiological examination. We aimed to evaluate the role of serum sortilin as possible markers for subclinical atherosclerosis in patients with psoriasis.

Methods: Serum levels of sotilin was measured by ELISA in 33 psoriasis patients and in 33 healthy controls. Waist circumference and body mass index of both groups were recorded; Fasting plasma glucose(FPG), HOMA-IR, serum lipid and sortilin levels were measured. Carotid and femoral intima-media thicknesses (CIMT, FIMT) were measured by USG. Demographic characteristics, the severity of psoriasis (PASI), age of onset, total duration and presence of nail involvement of patients included in the study were recorded.

Results: The mean serum sortilin level was 6.20 ± 3.11 ng / mL in the patient group and 7.82 ± 4.97 ng / mL in the control group. There was no statistically significant difference between serum sortilin levels in both groups (p = 0.729). There was no statistically significant relationship between serum levels of sortilin and disease severity (p = 0.597). The right and left CIMT values of the patients were significantly higher than the controls (p = 0.012, p = 0.020). There was no significant difference between the two groups in terms of FIMT values. There was a statistically significant relationship between serum sortilin levels and right CIMT in patients (p = 0.031).

Discussion: The positive correlation between the level of sortilin and the right CIMT in our patient group confirmed that sortilin may be an indicator of subclinical atherosclerosis in psoriasis patients.

Psoriasis is a systemic inflammatory disease and the inflammatory process is responsible for the development of psoriatic comorbidities. It is suggested that psoriasis is an independent risk factor for atherosclerosis and cardiovascular diseases(CVD) [1]. Although psoriasis is a risk factor for atherosclerosis; smoking, MS, high BMI, alcohol consumption and atherogenic lipoprotein profile in patients with psoriasis may increase the risk of CVD [2].

Sortilin is a 95 kDa protein encoded by the SORT1 gene on chromosome 13, and it is both the receptor of neurotensin (NTR-3) and the coreceptor of pro-NGF [3]. Sortilin was first described in brain tissue. It has also been shown to be found in the spinal cord, skeletal muscle, testis, heart, liver, thyroid gland, adipose tissue, placenta, pancreas, prostate, small intestines, and immune system. It has also been detected in cells such as melanocytes and keratinocytes in the skin. Although sortilin is known as a neurotensin receptor, it is also the receptor for lipoprotein lipase, pro-NGF and pro-BDGF. It performs different functions depending on the region where it produces, the receptors it binds to, and the extracellular environment it is released [4–8].

Sortilin acts as a low-density lipoprotein (LDL) receptor in macrophages and plays a role in foam cell formation, which is an important sign of atherosclerotic plaque formation [3]. Sortilin is a high-affinity receptor for the proinflammatory cytokines IL-6 and IFN-γ. It exerts its effect on the inflammatory process by increasing IL-6 and IFN-γ levels. It has also been shown to support microcalcification in smooth muscle cells, which disrupts plaque stability. Thus sortilin plays a role in both inflammatory and non-inflammatory mechanisms during atherosclerotic plaque formation and progression [3,9,10].

Sortilin also plays a role in the pathogenesis of vascular and metabolic diseases by causing atherosclerosis through Type 2 diabetes mellitus (DM) (via insulin resistance), arterial wall inflammation, calcification, and lipoprotein metabolism [9]. .There are studies showing that serum sortilin level is associated with atherosclerosis severity in type 2 DM, cardiovascular system diseases and metabolic syndrome [3,9]. In psoriatic epithelium, the amount of sortilin is shown to be increased [11,12].

Endothelial function and carotid intima-media thickness are prominent indicators of subclinical atherosclerosis. Early detection of subclinical coronary atherosclerosis and taking the first preventive measures can minimize the risk of CAD in psoriasis patients [13].

In our study, we wanted to evaluate the relation of serum sortilin levels with disease severity and the usability of this condition to show subclinical atherosclerosis. It is an original study because it is the first study to evaluate the levels of serum sortilin in psoriasis patients.

The study protocol was approved by the local institutional ethics committee and followed the International Ethical Guidelines of the Declaration of Helsinki. Informed consent was obtained from all participants prior to initiation of the study.

Thirty-three adult patients with chronic plaque psoriasis who attended the Department of Dermatology at Universty of Health Sciences, Dışkapı Yıldırım Beyazıt Training and Research Hospital (18 men and 15 women; mean age 37.55±13.41 years), and 33 sex- and age-matched healthy control subjects who were randomly recruited from hospital visitors (18 men and 15 women; mean age, 35.97±12.35 years), were included in the study. The diagnosis of psoriasis was made both clinically and histopathologically.

Exclusion criteria were: age < 18 or > 65 years; pregnancy or lactation; patients with chronic inﬂammatory disorders, immunological disorders, disorders with associated endothelial dysfunction, infections, and any systemic psoriasis treatment in the preceding 3 months or medications affecting endothelial function (Table 1).

A detailed anamnesis was taken from all patients and their physical examinations were performed. Disease duration and treatments of the patients were questioned, psoriasis type was determined. Psoriasis area severity index (PASI) was used to evaluate the severity of the disease in patients with psoriasis.

The body weight, height, Body mass index (BMI), and waist circumference measurements were obtained for all subjects. BMI was calculated as the weight in kilograms divided by the square of the height in meters. Accordingly, patients were divided into normal weight (BMI 20 to <25 kg/m2), overweight (BMI ≥25 to <30 kg/m2), and obese (BMI ≥30 kg/m2).

Intima–media thickness assessment

Images were obtained using the Esaote MyLab60 platform (Esaote Medical Systems, Italy) Ultrasonography(USG) device using a high resolution 12 MHz linear array transducer (LA523) located in the Radiology outpatient clinic USG unit.

The main carotid artery measurements were made from the distal 10 mm segment, and the main femoral artery measurements were made 1-2 cm proximal to the bifurcation by the same specialist radiologist.

Laboratory tests

Peripheral venous blood samples were taken from all participants following a minimum of 12 hours of overnight fast; FPG, HOMA-IR, LDL, VLDL, HDL, total cholesterol, and triglyceride levels were measured. Existing parameters were studied with routine techniques in our hospital's biochemistry laboratory.

Serum sortilin levels were measured by enzyme-linked immunosorbent assay (ELISA) using commercial kits (Sandwich-ELISA, Sunred Bio, Catalog Number: 201-12-4967, Shanghai, China) in Diskapi Yildirim Beyazit Training and Research Hospital Laboratories. Sortilin concentration of the samples was interpolated from the standard curve. The detection range for the assay was 0.08–22 ng/mL for sortilin.

Statistical analysis

The data obtained were transferred to the computer environment and necessary statistical analyzes were performed by using appropriate package programs for our study (Statistical Package for Social Sciences (SPSS) version 15.0). Results were considered statistically significant at P < 0.05. Quantitative data were described using ranges (minimum and maximum): mean, standard deviation, and median. After testing the normal distribution and suitability of the data, suitable tests were used for intergroup comparisons.

A total of 66 individuals, including 33 patients and 33 healthy controls, were included in the study. The patient group consisted of 15 (45.5%) women and 18 (54.4%) men, the control group consisted of 15 (45.5%) women and 18 (54.4%) men. There was no statistically significant difference between the patient and control groups in terms of gender distribution. The mean age was 37.55 ± 13.41 years (18-61 years) in the patient group and 35.97 ± 12.35 years (18-57 years) in the control group. There was no statistically significant difference between the mean age of the patient and control groups.

The PASI scores of the individuals in the patient group ranged from 5.0 to 21.6, with a mean of 9.12 ± 4.20. There was no difference between the patient and control groups in terms of smoking, alcohol consumption, BMI, and abdominal obesity. There was no significant difference between LDL, HDL, VLDL, cholesterol, TG levels, HOMA-IR value, waist circumference, and BMI in the patient and control groups.

Insulin resistance was detected in 3 (9.1%) of the individuals in the patient group and 4 (12.1%) of the individuals in the control group. The sortilin level was higher in individuals with insulin resistance in the study group (0≤0.05). The sortilin levels of individuals with insulin resistance in the patient group were higher than those in the patient group without insulin resistance (p = 0.045). In the control group, there was no relationship between insulin resistance and sortilin level (p = 0.348).

There was no significant difference between the patient and control groups in terms of serum sortilin levels (p> 0.05). (Table 2)

There was no correlation between lipid profile, waist circumference, BMI, and sortilin levels; but there was a positive correlation between insulin resistance and sortilin level in the study group(p=0.046).

In the patient and control groups, while there was no significant difference in terms of right and left FIMT (p> 0.05), there was a significant difference in terms of right and left CIMT (p <0.05). Right and left CIMTs of the patient group were significantly higher than the control group.

There was no significant relationship between serum sortilin levels and right-left FIMT and left CIMT in the patient and control groups (p> 0.05). There was a significant relationship between right CIMT and sortilin level in the patient group (p = 0.031). (Table 3)

In the patient group, there was no significant relationship between serum sortilin levels and CIMT, FIMT, disease duration, and PASI score.

Atherosclerosis; may present as peripheral artery disease, CAD, and cerebrovascular events clinically. One of the most important consequences is the shortening of a lifetime[14]. It is now firmly accepted that psoriasis is an independent risk factor for atherosclerosis and CVD[1].

An increase in CIMT is associated with cardiovascular outcomes, such as the risk of stroke and an increase in the frequency of CAD[15]. In one study, the prevalence of femoral atherosclerotic plaques in patients with psoriasis was significantly higher than the control group. The frequency of femoral atherosclerotic plaques in patients; was two times higher than the carotid plaques [16]. In our study, by most of the literature, the right (p = 0.012) and left CIMT (p = 0.020) values of the patient group were significantly higher than the control group. However, there was no significant difference between the two groups in terms of right and left FIMT values. This indicates that the thickening of the carotid artery occurs before the thickening of the femoral artery in patients with psoriasis, similar to other inflammatory diseases [17,18].

Sortilin is thought to achieve its effects on atherosclerosis, independent of hepatic lipoprotein mechanism [19]. In our study, there was no significant relationship between serum sortilin levels and LDL, HDL, VLDL, cholesterol, and TG in the patient and control groups. The findings in our study also prove the effectiveness of sortilin on lipid mechanism, which is not fully understood.

The source of circulating sortilin, which contributes to cardiovascular risk, is not yet well understood [9,20,21]. In many studies, sortilin levels are associated with CAD and peripheral artery disease (PAD) [3,22,23]. In a study conducted by Japanese researchers, a statistically significant decrease in serum sortilin levels (12 ± 27%) were shown in 90 patients with CAD after using statin group antihyperlipidemics for eight months [24]. Statin group antihyperlipidemics are also known to stabilize atherosclerotic plaque. However, its mechanism is not fully understood. Sortilin also increases vascular calcification on smooth muscle cells. Although statins are thought to have these effects on sortilin, additional studies are needed to evaluate the relationship between statins and sortilin on arterial microcalcification.

There is no study conducted to investigate the serum sortilin levels in psoriasis patients. In our study, serum sortilin levels in psoriasis patients were compared with the control group, and no significant difference was found between the two groups (p = 0.749). With these findings, it may not be possible to say that sortilin is not involved in pathogenesis. The small sample size and the mean of PASI (9.12 ± 4.20) below the definition of moderate-severe psoriasis (PASI> 10) may be the reason for not finding a difference. Also, sortilin may show activity only in tissue in psoriasis.

In our study, a significant positive correlation was found between serum sortilin levels and right CIMT in the patient group (p = 0.031). Due to the anatomical position, left- CIMT usually occurs earlier than the right- CIMT. Because the left carotid artery separates directly from the aortic arch. Interestingly, a study showed that left-CIMT was associated with biochemical parameters such as TG, LDL, and fasting blood glucose, while right -CIMT was associated with hemodynamic factors[25]. In our study, we found a correlation between sortilin levels, which is a biochemical parameter, and right-CIMT in the patient group. These indicate that sortilin can use to show right-CIMT before the clinical signs of systemic inflammation appear.

In the patient group, there was no significant relationship between serum sortilin levels and HOMA-IR, waist circumference, and BMI. The absence of a relationship with insulin resistance in the patient group may be due to the low number of patients with insulin resistance in our patient group (n = 3, 9.1%). Because when we evaluated the patient and control groups together, there is a significant positive correlation between the sortilin levels and insulin resistance (p = 0.046). There are studies in the literature showing that there is a positive and negative relationship between insulin resistance and sortilin [5,9,22]. In most of the studies, this relationship is positive. Our research is compatible with the literature in this respect.

Sortilin is a protein affected by comorbid conditions such as DM, hypertension, obesity, and MS[3]. In our study, we selected the patient group whose systemic complications of psoriasis had not occurred clinically yet and evaluated whether the level of sortilin could be an indicator of subclinical atherosclerosis. There is no other study in the literature evaluating the serum sortilin levels and subclinical atherosclerosis. Therefore, our research has an original study feature. The detection of a positive correlation between the sortilin levels and right-CIMT confirmed that sortilin could be a marker for indicating subclinical atherosclerosis. Also, sortilin can be an indicator of insulin resistance. In our study, we evaluated whether there was a correlation between the presence and severity of psoriasis and the level of serum sortilin, and we found no relationship.

Studies with larger patient populations, including patient groups with and without comorbid conditions, will allow a better evaluation of the role of sortilin in terms of the risk of developing atherosclerosis in patients with psoriasis. Drugs such as statin that can target sortilin may be new treatment options to prevent the development of atherosclerosis in psoriasis patients.

As we know in the literature, our study is the first study conducted on this subject since there is no study evaluating the levels of sortilin as an indicator of subclinical atherosclerosis in psoriasis. There was a statistically significant correlation between serum sortilin level and right CIMT in the patient group (p = 0.031). The detection of a positive correlation between the sortilin level and the right CIMT confirmed that sortilin could be an indicator of subclinical atherosclerosis.

Scientific Responsibility Statement

The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

Animal and human rights statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

Funding: None

Conflict of interest

The authors declare that they have no conflicts of interest.

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Table 1: Patients inclusion and exclusion criteria

Inclusion criteria	Exclusion criteria
Active, untreated, moderate (PASI 5–10) or severe (PASI >10) psoriasis	Arterial hypertension
	Diabetes mellitus
	Metabolic syndrome
	Chronic renal disease
	Chronic hepatic disease
	Active malignancy / history of malignant disease
	Active local or systemic infection, previous history of infection (<3 months)
	Body mass index (BMI) ≥30
	Hyperlipidemia patients receiving statin therapy
	Inﬂammatory disorders (e.g. crohn’s disease, ulcerative colitis).
	Patients receiving treatment for psoriasis up to 3 months prior to the onset of the study.
	Cardiac disease and stent history

Table 2: Serum sortilin levels of the study participants

Cases

Control

p

Mean±SD

Min.-Max.

Mean±SD

Min.-Max.

Serum Sortilin (mg/dl)

6.20±3.11

3.52-15.22

7.82±4.97

3.18-16.88

0.729

Mann-Whitney U Test

Table 3: Correlations between serum sortilin levels and CIMT-FIMT

The mean of Intima media thickness	Sortilin
	Cases	Control
	r,p	r,p
Right fermoral artery	0.280;0.114	-0.256, 0.150
Left femoral artery	0.278;0.118	-0.142; 0.432
Right carotid artery	0.377; 0.031	-0.359; 0.055
Left carotid artery	0.182; 0.310	-149; 0.408

Spearman correlation

No competing interests reported.

Is Sortilin an indicator of subclinical atherosclerosis in patients with psoriasis?

Status:

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Abstract

Introduction

Methods

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Status:

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