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Original Research

Association between leptin gene rs7799039 polymorphism and lipid profile changes induced by isotretinoin treatment in acne patients

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Pages 949-954 | Published online: 23 May 2018

Abstract

Introduction

Isotretinoin, a vitamin A-derived medication, is one of the effective treatments for severe acne. However, in a fraction of patients, this treatment causes significant adverse effects. Leptin is a pro-inflammatory cytokine that plays a role in apoptosis of adipose cells and sebaceous lipid metabolism. Thus, genetic polymorphisms in the leptin (LEP) gene may modulate the response to isotretinoin therapy. Here, we explore the contribution of rs7799039 polymorphism of the LEP gene in the adverse effects of the oral isotretinoin therapy among acne patients.

Materials and methods

Clinical parameters were obtained from 200 patients before and after isotretinoin treatment for acne. In addition, circulatory lipid profile and aspartate transaminase (AST) and alanine aminotransferase (ALT) enzymes from acne subjects before and 1 month after oral isotretinoin treatment were also measured.

Results

An association between the rs7799039 polymorphism and the following lipid parameters: high-density lipoprotein (HDL) at baseline and after treatment, HDL % change, low-density lipoprotein % change and total cholesterol % change (P < 0.05). In addition, there was an association between the LEP polymorphism and higher AST and ALT at baseline and after treatment (P < 0.05).

Conclusion

In conclusion, rs7799039 LEP polymorphism might modulate lipid parameters and liver enzymes, but not other major side effects of oral isotretinoin therapy.

Introduction

Acne vulgaris is a prevalent inflammatory disease of the human sebaceous follicle that affects the young patients.Citation1,Citation2 It has an estimated prevalence of 70%–90%, and severe acne can affect up to 12% of the adolescent population.Citation3,Citation4 Acne greatly impacts the quality of life of severely affected individuals as it has been shown to be associated with lesions that mostly occur on the face with the potential for permanent scarring.Citation5

The most potent treatment of acne includes the use of isotretinoin.Citation6 Typically, 1–2 months of isotretinoin therapy is required for an effect to be observable.Citation7 Isotretinoin achieves its efficacy by interfering with several cellular processes such as division, growth, survival, differentiation and apoptosis.Citation8 Among the suggested anti-acne effects of isotretinoin are substantial decrease in sebum production, reduction of comedogenesis and suppression of inflammation.Citation9,Citation10 However, isotretinoin therapy is associated with many side effects that may limit its usage. The major adverse event of isotretinoin is teratogenicity.Citation11 Other adverse effects include skeletal and mucocutaneous changes where isotretinoin causes myalgia, arthralgia, skin and nostrils dehydration, leading to nose bleeding and cracked lips.Citation12 Other less common side effects include headache, fatigue and hair loss.Citation13 It also causes psychiatric adverse effects, including mood swings, depression, psychosis, aggressiveness and tendency to commit suicide.Citation14 It was also found that isotretinoin has a negative impact on lipid profile and liver function.Citation6,Citation15 The side effects of isotretinoin therapy vary among individuals, and their possible modulation by genetic background in patient samples still needs investigation.Citation16

It is known that one of the mechanisms by which isotretinoin exerts its activity is by increasing the leptin levels during and after therapy.Citation17 Leptin, which is encoded by LEP gene,Citation18 is an important adipokine that plays important roles in appetite pathwayCitation19 and energy expenditure via the regulation of lipid and sugar metabolism.Citation20,Citation21 Literature also showed that leptin protein is elevated during skin diseases, which suggests a role for leptin in immune network and body defenses.Citation22,Citation23 Thus, collectively previous data suggest a possible role for leptin in mediating some of the effects of isotretinoin.

Among LEP gene polymorphisms is rs7799039. The clinical significance of this polymorphism is well documented as it was associated with higher risk of several diseases including malnutrition inflammation syndrome,Citation24 obesityCitation25 and metabolic syndrome.Citation26 In addition, rs7799039 was associated with blood lipid levels among Southern Chilean population,Citation27 dyslipidemia in patients using atypical antipsychotic agents and lipid profile modulation induced by soluble fiber intake.Citation28,Citation29 In the current study, we examined the impact of leptin gene polymorphism (rs7799039) on lipid profile alterations as adverse effects of isotretinoin in acne patients.

Materials and methods

Study subjects

This was a cross-sectional study that was conducted at Dermatology Clinic of the Health Center at Jordan University of Science and Technology, King Abdullah University Hospital and Prince Hamazh Hospital in Jordan. The study was approved by the Institutional Review Board and University Research Committee. New acne patients who received oral isotretinoin treatment were recruited after obtaining written informed consent from participants/guardian. The inclusion criteria were new patients who were given oral isotretinoin therapy (40 mg/day) for at least 30 days. Lipid profile and aspartate transaminase (AST) and alanine aminotransferase (ALT) enzymes were assessed at baseline (before treatment) and at 30 days of treatment. Patients with liver or renal diseases, history of active neoplasm, recent major surgical operations, alcohol abuse or receiving treatment other than isotretinoin were excluded from the study.Citation30

Data collection

Clinical data were collected from clinical case files and by interviewing the patients. The collected data included patient age, sex, body mass index, alcohol and supplement use, tobacco use and health conditions. Body mass index (BMI) was calculated based on height and weight as previously described.Citation31

Blood sampling

Blood samples were drawn from subjects after fasting for 14 hours. To extract the DNA, 3 mL of blood was collected in EDTA tubes from each patient. For the analysis of biochemical markers, another 3 mL of blood was withdrawn in coagulant-free sterile tubes. Serum was immediately collected after coagulation by centrifugation and stored at −80° until used.Citation32

Lipid profile and liver function tests

The blood lipid profile that included total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) was analyzed using clinical chemistry analyzers from Roche Diagnostics International Ltd (Indianapolis, IN, USA). In addition, ALT and AST liver enzyme levels were measured using the same analyzer.

DNA extraction

DNA was extracted from whole blood using a commercially available kit as indicated by supplemented manual (ZymoResearch DNA purification system; Irvine, CA, USA). Isolated DNA was stored in TE buffer in the freezer (−20°C) until used in the genotyping analysis.

Genotyping analysis

Genotyping of the rs7799039 LEP gene polymorphism was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using a Promega master mix (Madison, WI, USA) and C1000TM thermos cycler (Bio-Rad Laboratories, Inc, Hercules, CA, USA). In each PCR reaction, about 50 ng of DNA and 100 nM of each primer were used. Primer sequences were as follows: forward: 5′TTTCCTGTAATTTTCCCGTGA3′ and reverse: 5′AAAGCAAAGACAGGCATAAAA3′. PCR conditions were 5 minutes at 96°C followed by 34 cycles: 96°C for 30 seconds, 52°C for 45 seconds and 72°C for 45 seconds. The PCR reaction was terminated by 5 minutes at 72°C. The amplified fragment (242 bp) was restricted with HhaI enzyme (Fermentas Canada). Restriction conditions and visualization of DNA fragments were as previously described.Citation32

Statistical analysis

Data were analyzed using SPSS statistical software version 23 (SPSS, Inc, IL, Chicago, USA). Continuous variables were compared using unpaired t-test or ANOVA tests. Discrete variables were analyzed using the χ2 test. The significance threshold was set at a P-value of <0.05.

Results

Initially, 240 patients were invited to participate in the study, of which 220 gave consent with a response rate of 91.6%. Twenty participants were excluded from the study because of missing data. Therefore, 200 patients were finally included in the study. shows participants’ demographics and their clinical measures. Most of the participants were young adults with a mean age of 23.36 years and a mean BMI of 24.07 kg/m2; the majority of them were female (79.5%).

Table 1 Characteristics of acne patients of the current study (n = 200)

There was a significant increase in the lipid profile (LDL, TC, triglyceride [TG]) and liver enzymes (AST, ALT) after the initiation of the oral isotretinoin therapy when compared to the baseline (P < 0.05). However, the levels of HDL were significantly decreased after therapy (P < 0.05). The concentrations of lipids and liver enzymes measured before and after 30 days of isotretinoin therapy are given in .

Table 2 Modulation of lipid profile and liver enzymes by isotretinoin therapy (n = 200)

The results showed that rs7799039 polymorphism was associated with some lipid parameters and liver enzymes (). The CC genotype of the rs7799039 was associated with lower HDL at baseline and after treatment (P < 0.05) and lower HDL % change (P < 0.05). The same genotype was associated with lower LDL % change (P < 0.05) and TC % change (P < 0.05). For liver enzymes, the AC genotype of the rs7799039 was associated with higher ALT and AST at the baseline and after treatment (P < 0.05).

Table 3 The impact of rs7799039 genotypes on biochemical parameters that are modulated by isotretinoin (n = 200)

Discussion

In this study, the roles of the rs7799039 LEP gene polymorphism and how it might modulate isotretinoin response in acne patients were explored. The results showed an association between rs7799039 and lipid parameters such as HDL at baseline and after treatment, HDL % change, LDL % change and TC % change in isotretinoin-treated acne patients. In addition, there was an association between LEP polymorphism and higher AST and ALT at baseline and after treatment.

Previous literature has shown an altered lipid composition and an increase in the excretion of sebum by sebaceous glands during the development of acneCitation10 and skin inflammation.Citation33 Leptin is known as a pro-inflammatory player in sebaceous glands since sebocytes respond to leptin stimulation with pro-inflammatory changes leading to subsequent increases in the level of inflammatory markers including cytokines.Citation34 In addition, a previous investigation has shown that retinoids modulate the expression of leptin in adipocytes.Citation35,Citation36

The present results showed elevations of TC, TG, AST and ALT levels and decreases in HDL level in acne patients treated with isotretinoin. Such changes have been reported in previous investigations and pointed to increasing risks of cardiovascular complications, hyperlipidemia and the metabolic disorders of isotretinoin therapy.Citation36,Citation37

The results showed an association between the rs7799039 CC genotype and lower HDL at baseline, lower HDL % change, lower LDL % change and lower TC % change after acne treatment. Thus, the rs7799039 polymorphism of LEP gene may be related to lipid profile before and during isotretinoin treatment. The impact of polymorphisms in LEP gene and leptin receptor on lipid profile has been shown by previous studies.Citation38Citation41 In addition, polymorphisms in LEP gene have been shown to modulate the responses to therapeutic agents. For example, a study that was conducted on diabetic patients who were on atorvastatin showed that individuals with GG or GA genotype of LEP 2548 had significantly higher levels of LDL compared to AA genotype of LEP 2548 after treatment.Citation31 Similarly, LEP 2548 polymorphism has been shown to modulate lipid profile in obese adult population.Citation40 These findings are in the same line with the present results that rs7799039 polymorphism of LEP gene might affect the lipid profile in acne patients treated with isotretinoin. The mechanisms by which rs7799039 polymorphism modulates isotretinoin lipid profile side effects require further investigations. However, rs7799039 was associated with changes in leptin level.Citation38,Citation42 For example, a study that was conducted on overweight and obese children showed significantly higher leptin levels in rs7799039 AA genotype compared with other genotypes.Citation38 In addition, AA genotype was associated with higher risk of malnutrition inflammation syndrome,Citation24 obesityCitation25 and metabolic syndrome.Citation26 On the other hand, the CC genotype has been shown to be associated with dyslipidemia in patients using atypical antipsychotic agents.Citation29 Finally, rs7799039 is known to impact body weight,Citation27,Citation43 susceptibility to diseasesCitation26,Citation44Citation46 and response to treatments.Citation47

For liver enzymes, the AC genotype of the rs7799039 was associated with higher ALT and AST at baseline and after treatment. As the impact of isotretinoin on liver function is well documented,Citation6,Citation9,Citation12,Citation48 the current findings suggest a role for the rs7799039 polymorphism in modulating liver functions induced by isotretinoin treatment. The rs7799039 polymorphism was associated with hepatocellular carcinoma.Citation44 Similarly, an association between polymorphisms in the leptin receptor gene and hepatocellular carcinoma has been documented.Citation49 The role of genes involved in the leptin pathway in modulating liver functions requires further investigations.

The abovementioned findings are a first step toward further investigations of the long-term lipid complications of isotretinoin therapy and how such complication might be modulated by genetic variations among patients.Citation36,Citation50,Citation51 The link between isotretinoin therapy complications and genetic background of patients might improve the management of short-term and long-term side effects of isotretinoin use.

Among the limitations of the present study is that it did not cover all common polymorphisms of LEP gene and their relationships with isotretinoin treatment. In addition, other cytokines such as adiponectin might also modulate response and side effects of isotretinoin. Therefore, future studies could confirm present findings in other populations or on other LEP polymorphisms. Furthermore, the effect of multiple dosing levels or total cumulative dose of isotretinoin per month and variation in BMI over treatment period would also be the future directions for this line of research.

Conclusion

In conclusion, rs7799039 LEP polymorphism might modulate lipid parameters, but not major side effects of oral isotretinoin therapy.

Acknowledgments

The authors would like to thank Taibah University for supporting the current investigation.

Disclosure

The authors report no conflicts of interest in this work.

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