Association between brain-muscle-ARNT-like protein-2 (BMAL2) gene polymorphism and type 2 diabetes mellitus in obese Japanese individuals: A cross-sectional analysis of the Japan Multi-institutional Collaborative Cohort Study

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Highlights

  • This is a cross-sectional study among 35–69-year-old Japanese individuals.

  • We examined BMAL genotype–environment (obesity) interactions in type 2 diabetes.

  • BMAL2 rs7958822 genotype is associated with type 2 diabetes in obese men and women.

  • An interaction between BMAL2 rs7958822 genotype and obesity was observed in men.

Abstract

Aims

Brain-muscle-Arnt-like protein-1 (BMAL1) and BMAL2 genes are essential components of the circadian clock, and are considered to be involved in glucose homeostasis. We examined whether single nucleotide polymorphisms (SNPs) of BMAL1 and BMAL2 were associated with the prevalence of type 2 diabetes (T2DM) in the general Japanese population.

Methods

We studied 2467 subjects (1232 men and 1235 women, 35–69 years old), including 105 men and 57 women with T2DM, from the participants of the Japan Multi-institutional Collaborative Cohort Study. The association between SNPs in the BMAL1 (rs11022775 and rs2290035) and BMAL2 (rs7958822) genes and T2DM were analyzed by multiple logistic regression after adjustment for potential confounders. Analysis was also performed after stratification by body mass index (≥25 kg/m2 and <25 kg/m2) to investigate an interaction between genotypes and obesity.

Results

The A/G and A/A genotypes of BMAL2 rs7958822 showed significantly higher adjusted odds ratios (OR) for T2DM than the G/G genotype among obese men (OR = 2.2, 95% confidence intervals [CI] 1.1, 4.6, P for interaction = 0.0495) and obese women (OR = 2.7, 95% CI 1.1, 6.7, P for interaction = 0.199). There were no significant associations between BMAL1 rs11022775 or rs2290035 genotypes and T2DM.

Conclusions

To the best of our knowledge, this is the first study to show the significant association between BMAL2 rs7958822 genotype and T2DM among obese subjects.

Introduction

The prevalence of type 2 diabetes mellitus (T2DM) has been increasing worldwide [1]. It is well recognized that several genetic, as well as lifestyle factors are associated with T2DM [2], [3]. Although various single nucleotide polymorphisms (SNPs) have significant associations with T2DM [4], the mechanisms have not been fully elucidated. Interestingly, individuals may exhibit different susceptibility to T2DM, due to genetic variation, when their lifestyle is conducive to a high risk of T2DM.

Recently, the relationship between the circadian clock and the development of various diseases has attracted attention, and it has been suggested that SNPs in the clock gene are candidate variants associated with T2DM or glucose intolerance. Brain-muscle-Arnt-like protein 1 (BMAL1, ARNTL) gene is located in the region of human chromosome 11p15, and is involved in the regulation of circadian rhythm [5]. An AC haplotype of BMAL1 rs7950226–rs11022775 showed a significant association with T2DM in 1304 individuals from 424 British families [6]. In a Greek population study, a positive relationship between BMAL1 rs11022775 (T > C) C-allele and gestational diabetes mellitus was observed [7]. A recent report also indicated a significant association between the combination of NOC (CCR4 carbon catabolite repression 4-like gene, CCRN4L) rs9684900 and BMAL1 rs2290035 with fasting blood glucose levels among 1510 non-diabetic Chinese subjects [8]. However, there have been no reports regarding the interaction between BMAL1 rs11022775 and rs2290035, and obesity in T2DM.

BMAL2 (ARNTL2) is another clock gene that lies in the 12p12.2-p11.2 region [9]. Several SNPs of this gene have been linked to psychiatric disorders [10], [11], but not to metabolic syndrome or its components in Europe [12]. However, it is unknown whether BMAL2 rs7958822 is linked to the risk of T2DM in Asian populations.

Therefore, the goal of the present study was to investigate whether intronic SNPs BMAL1 rs11022775 and rs2290035, and BMAL2 rs7958822, are associated with T2DM, as well as to determine whether there are gene–environment interactions between BMAL1- and BMAL2-genotypes and obesity in T2DM.

Section snippets

Study subjects

Our data were collected from the baseline survey (2005–2008) of the Japan Multi-institutional Collaborative Cohort Study (J-MICC Study), a large genome cohort study that was designed to detect and confirm gene–environment interactions in lifestyle-related diseases. The J-MICC Study involved ten research institutes and universities [13], [14]. A total of 4490 subjects (2109 men, 2381 women) aged 35–69 years were selected from the participants in the baseline survey. We excluded subjects who had

Samples and diagnostic criteria

HbA1c was measured in laboratories of each study area, and the results of these measurements were collected. To convert HbA1c values from the units of the Japan Diabetes Society (JDS) to the units of the National Glycohemoglobin Standardization Program (NGSP), we used the following officially approved equation: NGSP (%) = 1.02 × JDS (%) + 0.25 [15]. The diagnostic criterion for T2DM was HbA1c  6.5% in NGSP (47 mmol/mol in IFCC units) and/or being on medication for high blood glucose, taking into

Characteristics of participants and genotype frequencies of BMAL1 and BMAL2

Table 1 shows the characteristics of the participants according to sex. The median age was 59 years for men and 58 years for women. BMI (kg/m2), the proportion of obesity, and weight change since 20 years old (±kg) were significantly higher in men than women. There was a significantly higher proportion of T2DM in men than in women. There were also significant sex differences in the proportion of subjects with first-degree family history of T2DM, smoking and drinking habits, total energy intake,

Discussion

Many physiological functions and behaviors of living organisms involve circadian variation controlled by the circadian clock. In mammals, the transcription factors circadian locomotor output cycles kaput (CLOCK) and BMAL1, together with their target genes PER and CRY constitute the core feedback loop of the circadian oscillator [25]. BMAL2 is another known transcription factor that also plays an essential role in the core feedback loop of the circadian clock [26]. It has been reported that

Conflict of interest

The authors declare that they have no conflict of interest.

Role of the funding source

This study was supported in part by Grants-in-Aid for Scientific Research on Priority Areas of Cancer (no. 17015018) and on Innovative Areas (no. 221S0001) from the Japanese Ministry of Education, Culture, Sports, Science and Technology.

Acknowledgements

The authors would like to acknowledge the contribution of Kyota Ashikawa, Tomomi Aoi, and other members of the Laboratory for Genotyping Development. We would also like to thank the Center for Genomic Medicine, RIKEN for support with genotyping, and Yoko Mitsuda, Keiko Shibata, and Etsuko Kimura at the Department of Preventive Medicine, Nagoya University Graduate School of Medicine for their technical assistance. The authors also thank Shinkan Tokudome at National Institute of Health and

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