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


      • Variants within PPARA, PPARD, PKDREJ, VAMP2 and CLOCK could protect against type 2 diabetes.
      • Rs6744132, located between HES6 and PER2, is associated with higher risk of type 2 diabetes.
      • Carriers of the recessive allele in variants of PPARD are less susceptible to type 2 diabetes.



      : 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).


      : 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.


      : 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.



      BMI (body mass index), CI (Confidence Interval), HbA1c (glycated hemoglobin), MAF (Minor Allele Frequency), OR (Odds Ratio), pperm (permutation analysis p-value), SNP (Single Nucleotide Polymorphism), T2D (type 2 diabetes), WC (waist circumference)
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