Autophagy-related 16-like 1gene polymorphism, risk factors for cardiovascular disease and associated carotid intima-media thickness in postmenopausal women
Introduction
In women, aging and menopause are considered cardiovascular risk factors [1] because of estrogen deprivation due to ovarian insufficiency [2]. Coronary heart disease (CHD) is often fatal and over one-half of postmenopausal women (PW) with CHD do not present early symptoms [3]. Therefore, early identification of asymptomatic PW, who are more predisposed to developing CHD, is an important preventive strategy [4]. Detecting early markers enables recognition of subclinical atherosclerotic disease and early intervention in modifiable risk factors [5].
In CHD, conventional risk factors - dyslipidemia, hypertension, diabetes, obesity, smoking - are important [6]. However, individual differences in the immune-genetic profile may modulate the severity of the CHD process [7,8]. The main mechanisms in the installation and development of systemic inflammatory response comprise the complement cascade system, the activation of immune cells by releasing cytokines and the endothelial dysfunction [9]. Studies have shown an immune influence associated with the development of CHD in postmenopausal women by cytokine production and expression of receptors [10,11], heat-shock proteins [12] and genetic polymorphism [13]. The expression of inflammatory molecules is stimulated by risk factors and are under the control of inflammatory cytokines and hemodynamic factors, making its characterization extremely important [14].
Autophagy is an important host defense mechanism, interacting with the innate and acquired immunity to both identify and defend against aggressors [15]. Autophagy is a self-protecting cellular catabolic pathway. At a basal level, autophagy is involved in maintaining normal cellular homeostasis [16,17]. Autophagy is associated with a variety of diseases, including cardiovascular diseases, tumors, neurodegenerative diseases and disorders of the immune system [18,19] in response to environmental stress, such as a sedentary lifestyle, hypoxia or oxidative stress [16,19]. Autophagy-related 16-like 1 (ATG16L1) is an autophagy gene known to control host immune responses [20]. ATG16L1 single nucleotide polymorphism (SNP), rs2241880, encodes a missense variant resulting in a substitution of threonine with alanine at amino acid position 300 (T300A) [20]. The T300A variant is the most prevalent of all ATG16L1 variants, representing approximately 55% of the alleles in the European population and 20–40% of alleles in other populations [20]. A SNP in this gene results in decreased autophagy activity [20]. Evidence shows that autophagy plays an important role in inflammation and inhibition of apoptosis and it has been demonstrated that autophagy plays a protective role in atherosclerosis [21], which acts as a cholesterol efflux promoter [22,23], suggesting that autophagy is a potential mechanism in atherosclerosis [24]. However, there is little evidence regarding the contribution of ATG16L1 polymorphism variants to the regulation of atherosclerosis.
To assess the relationship between autophagy and atherosclerosis, we investigated whether the ATG16L1 polymorphism variant is associated with subclinical carotid atherosclerosis and risk factors in asymptomatic postmenopausal women. This paper presents an association between the ATG16L1 polymorphism and carotid intima-media thickness in the development of atherosclerosis in PW and discusses the theory behind autophagy in the atherosclerosis process.
Section snippets
Study design and sample selection
This is a clinical, analytical and cross-sectional study. The study population was postmenopausal women, aged 45–70 years, seen at the Climacteric and Menopause Outpatient Clinic at the Botucatu Medical School-UNESP, who took part in a study that evaluated clinical and inflammatory markers of subclinical carotid atherosclerosis, which were previously described in detail [25]. Women whose last menstruation was at least 12 months prior to the beginning of the study and aged ≥ 45 years old were
Results
The genotype distributions and allele frequencies for the ATG16L1 polymorphism variant in this population present the dominance was 168 (49.87%) heterozygous (AG), homozygous (AA) with 47 (23.53%) patients and 61 (27.6%) patients with polymorphic homozygote (GG). Note that the allelic frequency of (A) is 262, 47.46% and (G) is 290, 52.54%. Both distributions were in Hardy-Weinberg equilibrium, and there were no differences in the frequency of the homozygous GG polymorphic variant or of the G
Discussion
In this study in an unprecedented way, we have shown that ATG16L1 polymorphism variant is associated with subclinical carotid atherosclerosis in postmenopausal women and that it is important to identify polymorphic targets in women at risk for cardiovascular disease. Many postmenopausal women in urban societies have risk factors for CVD. Detecting conventional risk factors for CVD continues to be important, however new approaches at the immune-inflammatory and molecular levels have shown to be
Conclusion
In conclusion, the ATG16L1 polymorphism variant is associated with subclinical carotid atherosclerosis in postmenopausal women. We have shown that it is important to identify polymorphic targets in postmenopausal women at risk for cardiovascular disease in order to characterize a future adequate prognosis for CHD.
Acknowledgments
The authors thank the Sao Paulo Research Foundation (FAPESP) for financial supported.
Funding
This study was supported by the Sao Paulo Research Foundation (FAPESP), process number 2009/14884-2 and 2009/18256-6. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests
The authors have declared that no competing interests exist.
References (53)
- et al.
Menopause with cardiovascular disease and its risk factors among rural Chinese women in Beijing: a population-based study
Maturitas
(2012) - et al.
Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study
Lancet
(2004) - et al.
Epigenetic-related therapeutic challenges in cardiovascular disease
Trends Pharmacol. Sci.
(2015) - et al.
The aging cardiovascular system: understanding it at the cellular and clinical levels
J. Am. Coll. Cardiol.
(2017) - et al.
Autophagy in the cellular energetic balance
Cell Metab.
(2011) - et al.
Autophagy links inflammasomes to atherosclerotic progression
Cell Metab.
(2012) - et al.
Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase
Cell Metab.
(2011) - et al.
Mannose-binding lectin gene polymorphism and risk factors for cardiovascular disease in postmenopausal women
Mol. Immunol.
(2014) - et al.
The threshold value for insulin resistance (HOMA-IR) in an admixtured population IR in the Brazilian Metabolic Syndrome Study
Diabetes Res. Clin. Pract.
(2006) - et al.
Polymorphism in the interleukin-1 gene complex and spontaneous preterm delivery
Am. J. Obstet. Gynecol.
(2002)
High-density lipoprotein and inflammation in cardiovascular disease
Transl. Res.
The protein ATG16L1 suppresses inflammatory cytokines induced by the intracellular sensors Nod1 and Nod2 in an autophagy-independent manner
Immunity
Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update
Circulation
Cardiovascular risk assessment in women - an update
Climacteric
Impact of menopause and diabetes on atherogenic lipid profile: is it worth to analyse lipoprotein subfractions to assess cardiovascular risk in women?
Diabetol. Metabol. Syndrome
The impact of obesity on cardiovascular disease risk factors and subclinical vascular disease: the Multi-Ethnic Study of Atherosclerosis
Arch. Intern. Med.
The immunology of atherosclerosis
Nat. Rev. Nephrol.
Effects of hormone replacement therapy on immunological factors in the postmenopausal period
Climacteric
Isolated vitamin D supplementation improves the immune-inflammatory biomarkers in younger postmenopausal women: a randomized, double-blind, placebo-controlled trial
Menopause
Evaluation of clinical and inflammatory markers of subclinical carotid atherosclerosis in postmenopausal women
Menopause
Genetic polymorphisms associated with carotid artery intima-media thickness and coronary artery calcification in women of the Kronos early Estrogen Prevention Study
Physiol. Genomics
The role of heat shock protein (HSP) in atherosclerosis: Pathophysiology and clinical opportunities
Curr. Med. Chem.
Autophagy and female genital tract infections: new insights and research directions
BJOG
Autophagy in immunity and inflammation
Nature
Autophagy fights disease through cellular self-digestion
Nature
Autophagy in human health and disease
N. Engl. J. Med.
Cited by (4)
The Potential of Single Nucleotide Polymorphisms (SNPs) as Biomarkers and Their Association with the Increased Risk of Coronary Heart Disease: A Systematic Review
2023, Vascular Health and Risk ManagementGenetic Variants and Functional Analyses of the ATG16L1 Gene Promoter in Acute Myocardial Infarction
2021, Frontiers in GeneticsSingle nucleotide polymorphism of ATG16L1 gene promoter increases susceptibility to acute myocardial infarction
2021, Zhongguo Dongmai Yinghua Zazhi