Research paperAssociations between peroxisome proliferator-activated receptor γ (PPAR-γ) polymorphisms and serum lipids: Two cross-sectional studies of community-dwelling adults
Introduction
Cardiovascular disease (ischemic heart disease and stroke) is one of the leading causes of mortality and disability in the world (GBD 2015 Mortality and Causes of Death Collaborators, 2015, GBD 2017 DALYs and HALE Collaborators, 2018). Dyslipidemia is a well-established risk factor for cardiovascular disease (Baigent et al., 2010, Boekholdt et al., 2013, Sarwar et al., 2007); specifically, 1.0 mmol/l (38.67 mg/dl) reduction in low-density lipoprotein-cholesterol (LDL-C) is associated with a 22% risk reduction of cardiovascular disease at 1 year (Baigent et al., 2010). In Japan, 22.0% of men and 23.3% of women aged 20 years or older had a serum LDL-C of 140 mg/dl or higher, and 13.0% of men and 18.0% of women were prescribed cholesterol-lowering drugs according to the National Health and Nutrition Survey in Japan in 2018 Ministry of Health, Labour and Welfare. 2018). Therefore, effective strategies are needed for prevention and treatment of dyslipidemia to reduce mortality and disability caused by cardiovascular disease.
Dyslipidemia results from both genetic and environmental (lifestyle) factors (Anderson et al., 2013, Asselbergs et al., 2012). In a meta-analysis of 32 genome-wide association studies (GWAS), many genes were proposed as candidate genetic factors, including peroxisome proliferator-activated receptor γ (PPAR-γ) (Asselbergs et al., 2012). In this study, PPAR-γ was associated with LDL-C and high-density lipoprotein-cholesterol (HDL-C). PPARs are ligand-activated nuclear hormone receptors and consist of three isotypes, PPAR-α, PPAR-β/δ, and PPAR-γ. PPAR-γ is highly expressed in adipose tissue and plays an important role in the regulation of adipocyte differentiation, lipogenesis, lipid storage, insulin sensitivity, glucose metabolism, and transcription of genes involved in these metabolic processes (Han et al., 2017). Meta-analyses of observational studies have shown that an rs1801282 polymorphism (PPAR-γ Pro12Ala) is associated with an increased risk of obesity and cardiovascular disease and a decreased risk of type 2 diabetes and diabetic nephropathy (Galbete et al., 2013, Li et al., 2015c, Gouda et al., 2010, Li et al., 2015b). Moreover, an rs3856806 polymorphism (PPAR-γ C161T) is associated with an increased risk of coronary artery disease and a decreased risk of myocardial infarction and acute coronary syndrome (Wang et al., 2015, Qian et al., 2016). Many natural and synthetic ligands influence the expression of PPAR-γ. The synthetic thiazolidinedione agonist, pioglitazone, which is an antidiabetic drug in clinical use, improves not only insulin sensitivity and glycemic control, but also plasma triglycerides, HDL-C, LDL particle concentration, and LDL particle size (Han et al., 2017, Schernthaner et al., 2013). Therefore, PPAR-γ polymorphisms are probably related to the risk of dyslipidemia.
To date, many epidemiological studies have examined associations between PPAR-γ polymorphisms and serum lipid levels (Li et al., 2015a). However, a number of issues remain unclear. First, few studies examined PPAR-γ single nucleotide polymorphisms (SNPs) other than rs1801282 and rs3856806 (Li et al., 2015a). Second, the sample sizes of these epidemiological studies were relatively small, and few had more than 1,000 participants (Tai et al., 2004). Third, few studies adjusted for potential confounding factors (e.g., demographic factors and lifestyle factors) (Tai et al., 2004, Moon et al., 2005, Yang et al., 2009, Gu et al., 2013, Gu et al., 2014a, Chehaibi et al., 2014, Gu et al., 2014b, Rooki et al., 2014, Fan et al., 2015). Fourth, many studies did not include community dwellers but patients with disease (Arashiro et al., 2003, Bhatt et al., 2013, Chao et al., 2004, Chehaibi et al., 2014, Chen et al., 2011, Dongxia et al., 2008, Evangelisti et al., 2009, Gu et al., 2013, Haseeb et al., 2009, Hui et al., 2008, Hung et al., 2012, Moon et al., 2005, Rooki et al., 2014, Tavares et al., 2005, Wan et al., 2010, Wang et al., 1999, Yang et al., 2009, Yilmaz-Aydogan et al., 2011, Zhou et al., 2012). Clarification of the roles of PPAR-γ polymorphisms in general populations is necessary to develop strategies for primary prevention.
We therefore aimed to elucidate the association of PPAR-γ polymorphisms, including rarely studied ones, with serum lipid levels in many community-dwelling adults while considering detailed information about their lifestyle.
Section snippets
Study design and participants
We conducted two cross-sectional studies using baseline and secondary survey data from the Shizuoka part of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study (Hamajima and Group, 2007, Asai et al., 2009). Participants were recruited from health check examinees aged 35–69 years living in central and west parts of Shizuoka Prefecture. Among 13,740 examinees meeting eligibility criteria, 5,040 persons (37%) were enrolled from 2006 to 2007. Lifestyle and medical history including
Characteristics and genotypes of the participants
Of the 4,952 participants (3,356 men and 1,596 women), 2,114 (42.7%, 1,571 men and 543 women) had dyslipidemia and 1,431 (28.9%, 957 men and 474 women) had high LDL-C at the baseline survey. Of the 2,245 participants (1,550 men and 695 women), 933 (41.6%, 674 men and 259 women) had dyslipidemia and 716 (31.9%, 490 men and 226 women) had high LDL-C at the second survey. Table 1 compares characteristics between participants with dyslipidemia and those without at the baseline survey by sex. In
Discussion
In these two cross-sectional studies, we examined associations between PPAR-γ polymorphisms and serum lipids. In the baseline survey, minor allele homozygotes of rs3856806 and rs12497191 were associated with a lower risk of dyslipidemia, and minor allele homozygotes of rs3856806 were correlated with a lower risk of high LDL-C in all and male participants. Similar associations were found in the second survey.
Only a few studies have examined associations between PPAR-γ polymorphisms and
CRediT authorship contribution statement
Takashi Matsunaga: Conceptualization, Formal analysis, Writing - original draft. Mariko Naito: Data curation, Supervision. Guang Yin: Resources. Asahi Hishida: Data curation. Rieko Okada: Data curation. Sayo Kawai: Data curation. Tae Sasakabe: Data curation. Yuka Kadomatsu: Data curation. Mineko Tsukamoto: Data curation. Yoko Kubo: Data curation. Takashi Tamura: Data curation. Kenji Takeuchi: Data curation. Atsuyoshi Mori: Data curation. Nobuyuki Hamajima: Supervision, Project administration.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We greatly appreciate Dr. Yatami Asai and the staff of the Seirei Preventive Health Care Center for their support in conducting this study.
Financial support: This study was supported by Grants-in-Aid for Scientific Research for Special Priority Areas of Cancer (No. 17015018) and Innovative Areas (No. 22150001) and by JSPS KAKENHI Grants (Nos. 16H06277 and 15H02524) from the Japanese Ministry of Education, Culture, Sports, Science and Technology.
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