Original Research Paper
The interaction of FTO-rs9939609 polymorphism with artichoke leaf extract effects on cardiometabolic risk factors in hypertriglyceridemia: A randomized clinical trial

https://doi.org/10.1016/j.aimed.2018.08.006Get rights and content

Abstract

Objective

Hypertriglyceridemia is associated with an increased risk of cardiovascular disease. The potential favorable effects of artichoke leaf extract (ALE) on anthropometric and metabolic indices may affect by fat mass and obesity associated (FTO)-rs9939609 polymorphism. This study was designed to evaluate the effects of ALE supplementation on cardiometabolic risk factors in hypertriglyceridemic patients regarding the interaction of rs9939609-FTO polymorphism with intervention outcomes.

Methods

In this double-blind placebo-controlled randomized clinical trial, 52 patients with hypertriglyceridemia randomly allocated to receive ALE (1800 mg/day as four tablets) or matching placebo (consisting of corn starch, lactose, and avicel) for 12 weeks. The measurement of anthropometric indices, fasting blood sugar (FBS), and lipid profile was performed before and after the intervention. The FTO-rs9939609 polymorphism was genotyped by polymerase chain reaction-restriction length polymorphism (PCR-RFLP). The interaction was tested using two-way ANOVA.

Results

Forty-eight patients completed the trial (intervention, n = 24, placebo = 24). ALE and placebo groups were similar in the baseline characteristics. ALE supplementation did not change anthropometric indices and metabolic parameters. However, there was a significant interaction between FTO-rs9939609 polymorphism and TC, LDL-C, and TG level response to ALE supplementation. Moreover, significant changes in TG level were observed in A allele carriers compared to subjects with TT genotype.

Conclusion

No significant effect of ALE supplementation was shown on anthropometric and biochemical indices in Iranian hypertriglyceridemic patients. However, rs9939609 variant of FTO gene seems to affect lipid profile response to ALE supplementation. Further clinical trials with larger sample size are suggested to clarify the possible interaction between rs9939609 variant or other variants of FTO gene and ALE supplementation in hypertriglyceridemia.

Introduction

Elevated serum levels of triglyceride have independently been associated with increased risk of cardiovascular disease [1]. Hypertriglyceridemia commonly coexist with multiple risk factors including prothrombotic and proinflammatory biomarkers, increased plasma glucose levels, hypertension, obesity and metabolic syndrome [2]. Furthermore, patients with very high serum levels of triglyceride (more than 10 mmol/L) are at risk for acute pancreatitis [3].

The fat mass and obesity associated (FTO) gene encodes an enzyme which is present in many tissues, especially in the hypothalamus, the center of energy homeostasis [4]. The rs9939609 polymorphism in FTO gene is a potential candidate genetic variant for obesity and metabolic syndrome [[5], [6], [7]]. Since hypertriglyceridemia is a common feature of obesity and metabolic syndrome [8], the FTO variant rs9939609 may be implicated in the susceptibility to hypertriglyceridemia. Furthermore, A allele of rs9939609 variant gene of FTO, the risk allele of adiposity, is associated with higher triglyceride, insulin and glucose levels, and that these associations are dependent on body mass index (BMI) [7]. Differences in individuals' genetic background may modulate the effect of the intervention on outcome variables [6,[9], [10], [11], [12], [13], [14]].

Artichoke (Cynara scolymus L., Asteraceae family) is used both as a healthy food and as a medicinal herb worldwide [15]. Traditionally, artichoke leaf extract (ALE) was used to treat dyspepsia and hepato-biliary diseases. Scientific researches indicated antioxidant [[16], [17], [18]], hepatoprotective [16,17], anti-atherosclerotic [19,20] and glucose and lipid lowering effects [[21], [22], [23], [24]] for ALE. The safety of ALE supplementation has been demonstrated in animal and human studies. There were no reported mutagenic and genotoxic effects in mice at <2000 mg/kg [25]. Furthermore, only mild and transient adverse events relating to the gastro-intestinal system have been reported in some clinical trials following ALE consumption [[22], [23], [24], [25], [26]].

Recently, some clinical trials have shown the efficacy of ALE in improvement of triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) concentration [14,21,22,24,27,28], whereas others failed to show any improvement [26]. Besides, rs9939609 variant in FTO have shown an association with higher triglyceride level [7]. To best our knowledge, there is limited evidence for effects of ALE supplementation on cardiometabolic parameters in hypertriglyceridemi patients. Thus, the present study was aimed to investigate the effects of artichoke leaf extract on cardiometabolic risk factors in hypertriglyceridemic patients and an interaction with rs9939609 variant in FTO gene.

Section snippets

Study design and participants

The present randomized, double-blind, placebo-controlled clinical trial was a part of a case-control study on metabolic syndrome gene polymorphism with 185 sample size. The intervention part was carried out on hypertriglicerdemic patients. The sample size was calculated based on the changes in serum fasting blood sugar (FBS) level reported by Rondanelli et al. [24]. Considering a confidence level of 95% and power of 80% and anticipating a possible dropout rate of 10%, 26 patients with

Results

Of the 185 subjects who were screened for FTO-rs9939609 polymorphism, 25.9% (n = 48) were homozygous for T allele, 65.4% (n = 121) were heterozygote, and 8.6% (n = 16) were homozygous for C allele (data not shown). During the 12-week follow-up, four patients were withdrawn from the study (2 patients from each intervention and placebo group) as shown in Fig. 1. None of the dropouts were related to the adverse effects of ALE or placebo. Moreover, there were no reports of adverse effects in

Discussion

The present study was found that ALE supplementation did not change the anthropometric and biochemical variables in patients with hypertriglyceridemia over 12 weeks. However, the significant interaction between ALE supplementation and FTO-rs9939609 polymorphism was found on TC, LDL-C and TG level. Moreover, TG level significantly affected by FTO-rs9939609 polymorphism regardless of intervention.

The FTO gene, located on chromosome 16q12.2, encodes a nuclear protein of non-haem Fe(II) and

Conclusion

Our finding showed that ALE supplementation did not affect anthropometric and biochemical indices in Iranian hypertriglyceridemic patients. Moreover, this study suggested the interaction between the response of lipid profile to ALE supplementation and FTO-rs9939609 polymorphism.

Accordingly, polymorphism genotyping helps the clinicians in choosing the appropriate treatment for patients with hypertriglyceridemia. Moreover, individuals carrying A allele of FTO-rs9939609 polymorphism may benefit

Conflict of interest

The authors declare that they have no conflicts of interest.

Acknowledgements

We are grateful to the subjects for their participation in this study. The authors also would like to acknowledge Dineh Iran. Co. for preparing of Artichoke Leaf Extract and placebo tablets. This study was supported by a Grant from the Research Vice Chancellor, Tabriz University of Medical Sciences, Tabriz, Iran (grant number: 5/97/4653). The results of this article are derived from the Ph.D. thesis of Khatereh Rezazadeh (NO, D/41).

References (39)

  • Ž. Reiner

    Hypertriglyceridaemia and risk of coronary artery disease

    Nat. Rev. Cardiol.

    (2017)
  • G. Yuan et al.

    Hypertriglyceridemia: its etiology, effects and treatment

    Can. Med. Assoc. J.

    (2007)
  • T. Gerken et al.

    The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase

    Science

    (2007)
  • C. Povel et al.

    Genetic variants and the metabolic syndrome: a systematic review

    Obes. Rev.

    (2011)
  • R.M. Freathy et al.

    Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI

    Diabetes

    (2008)
  • V. Ebrahimzadeh Attari et al.

    Effect of zingiber officinale supplementation on obesity management with respect to the uncoupling protein 1‐3826A& G and ß3‐adrenergic receptor Trp64Arg polymorphism

    Phytother. Res.

    (2015)
  • C. Razquin et al.

    A 3-year intervention with a Mediterranean diet modified the association between the rs9939609 gene variant in FTO and body weight changes

    Int. J. Obes.

    (2010)
  • D.A. Luis et al.

    Evaluation of weight loss and adipocytokines levels after two hypocaloric diets with different macronutrient distribution in obese subjects with rs9939609 gene variant

    Diabetes/Metab. Res. Rev.

    (2012)
  • T.D. Müller et al.

    ’Fat mass and obesity associated’gene (FTO): No significant association of variant rs9939609 with weight loss in a lifestyle intervention and lipid metabolism markers in German obese children and adolescents

    BMC Med. Genet.

    (2008)
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