Elsevier

Maturitas

Volume 152, October 2021, Pages 20-25
Maturitas

Variants in clock genes could be associated with lower risk of type 2 diabetes in an elderly Greek population

https://doi.org/10.1016/j.maturitas.2021.07.004Get rights and content

Highlights

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    Variants within PPARA, PPARD, PKDREJ, VAMP2 and CLOCK could protect against type 2 diabetes.

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    Rs6744132, located between HES6 and PER2, is associated with higher risk of type 2 diabetes.

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    Carriers of the recessive allele in variants of PPARD are less susceptible to type 2 diabetes.

Abstract

Objectives

: Recent evidence has linked circadian rhythm dysregulation to an increased risk of metabolic disorders. This study explores a potential association between variation in genes regulating the endogenous circadian timing system (clock genes) and the risk of type 2 diabetes (T2D) in a sample of Greek elderly people.

Study design

: Variants within and upstream or downstream of PPARA, PPARD, CLOCK/TMEM165, PER1, PER2 and PER3 genes were genotyped in 716 individuals with T2D (A) and 569 normoglycemic controls (B), and allele frequencies were compared between the groups in a case control study design.

Main outcome measures

: Samples were genotyped on Illumina Human PsychArray. Permutation test analysis was implemented to determine statistical significance. To avoid the possibility of subjects with prediabetes being included in the control group, people with HbA1c <5.7% and fasting glucose <100 mg/dl comprised group C (n = 393), for whom a separate analysis was performed (secondary analysis).

Results

: A protective role against T2D was identified for 14 variants in the PPARA gene. The rs7291444, rs36125344, rs6008384 in PKDREJ, located upstream of PPARA, and rs2859389 in UTS2, located upstream of PER3, demonstrated a protective role against T2D in both analyses. In contrast, rs6744132, located between HES6 and PER2, was positively correlated with T2D risk. Only in the secondary analysis, rs2278637 in VAMP2, located downstream of PER1, and rs11943456 in CLOCK/TMEM165 were found to confer protection against T2D. In a recessive model analysis of all groups, PPARD variants exhibited a protective role against disease.

Conclusions

: Our findings suggest a possible implication of clock genes in T2D susceptibility. Further studies are needed to clarify the mechanisms that connect circadian rhythm dysfunction and T2D pathogenesis.

Section snippets

1. Introduction

Type 2 diabetes (T2D) is a chronic disorder of glucose metabolism, related to impaired quality of life, severe complications, and significant burden for health care systems, that tends to be a global epidemic [1]. The International Diabetes Federation estimates that the number of people living with the disease globally is expected to reach 700 million by 2045 [2]. T2D confers a four-fold greater risk for the development of cardiovascular (CV) disease compared to the non-diabetic status [3] and

2.1. Study population

Participants aged over 65 years with an established T2D diagnosis (group A) were recruited from two major, Greek, academic diabetes centers, namely AHEPA University Hospital of Thessaloniki and General University Hospital of Alexandroupolis. The diagnosis of diabetes was established according to the criteria of the American Diabetes Association [17]. Exclusion criteria for the diabetes group were severe hepatic disease and treatment with drugs that might affect blood glucose, including

3.1. Study population characteristics

A total of 1285 participants were enrolled in the study. Of these, 716 individuals with T2D were included in group A, whereas groups B and C consisted of 569 and 393 controls, respectively. Females predominated in all groups: A (52 vs. 48%), B (62 vs. 38%) and C (60 vs. 40%). Mean age of participants in groups A, B and C was 68.93 ± 9.53, 73.46 ± 7.25 and 74.00 ± 11.00 years respectively (p<0.05), whereas diabetes duration was 14.39 ± 9.29 years. As expected, patients with T2D had higher body

4. Discussion

To the best of our knowledge, this is the first study to investigate the relationship between variants in clock genes and the risk of developing T2D in the Greek population. Implementation of permutation test analysis enabled us to estimate empirical p-values and reveal potential associations between variation in PPARA, PPARD, PKDRJ, UTS2, CLOCK/TMEM165 and VAMP2 genes and T2D. Our results mostly imply a protective role of SNPs in these genes against the disorder.

It is worth noting that the

Contributors

Xanthippi Tsekmekidou carried out the implementation and wrote the manuscript.

Fotis Tsetsos designed the model and the computational framework and analyzed the data.

Theocharis Koufakis wrote the manuscript.

Marianthi Georgitsi carried out the implementation.

Nikolaos Papanas assisted with control group collection.

Dimitrios Papazoglou assisted with control group collection.

Athanasios Roumeliotis assisted with patient enrollment and study measurements.

Stylianos Panagoutsos assisted with patient

Conflict of interest

The authors declare that they have no conflict of interest.

Funding

This research has been co-financed by the European Union (European Social Fund - ESF) and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program: THALES. Investing in knowledge society through the European Social Fund (MIS 380273). This work was also supported in part by Hellenic Association for the Study and Education of Diabetes Mellitus.

Ethical approval

The study protocol was approved by the Ethics Committee of the Aristotle University of Thessaloniki. Written informed consent was obtained from all participants. All procedures were in accordance with the 1964 Helsinki declaration for research in humans and its later revisions.

Provenance and peer review

This article was not commissioned and was externally peer reviewed.

Research data (data sharing and collaboration)

There are no linked research data sets for this paper. Data will be made available on request.

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