Low CLOCK and CRY2 in 2nd trimester human maternal blood and risk of preterm birth: a nested case-control study†.

Previous studies have observed an association between maternal circadian rhythm disruption and preterm birth (PTB). However, the underlying molecular mechanisms and the potential of circadian clock genes to serve as predictors of PTB remain unexplored. We examined the association of 10 core circadian transcripts in maternal blood with spontaneous PTB (sPTB) vs term births using a nested case-control study design. We used a public gene expression dataset (GSE59491), which was nested within the All Our Babies (AOB) study cohort in Canada. Maternal blood was sampled in Trimesters 2-3 from women with sPTB (n = 51) and term births (n = 106), matched for five demographic variables. In 2nd trimester maternal blood, only CLOCK and CRY2 transcripts were significantly lower in sPTB vs term (P = 0.02-0.03, false discovery rate (FDR) < 0.20). A change of PER3 mRNA from trimesters 2-3 was significantly associated with sPTB (decline in sPTB, P = 0.02, FDR < 0.20). When CLOCK and CRY2 were modeled together in 2nd trimester blood, the odds of being in the low level of both circadian gene transcripts was greater in sPTB vs term (OR = 4.86, 95%CI = (1.75,13.51), P < 0.01). Using GSVA and Pearson correlation, we identified 98 common pathways that were negatively or positively correlated with CLOCK and CRY2 expression (all P < 0.05, FDR < 0.10). The top three identified pathways were amyotrophic lateral sclerosis, degradation of extracellular matrix, and inwardly rectifying potassium channels. These three processes have previously been shown to be involved in neuron death, parturition, and uterine excitability during pregnancy, respectively.

Assessment of Selected Clock Proteins (CLOCK and CRY1) and Their Relationship with Biochemical, Anthropometric, and Lifestyle Parameters in Hypertensive Patients.

BACKGROUND: Circadian rhythms misalignment is associated with hypertension. The aim of the study was to evaluate the concentration of selected clock proteins-cryptochrome 1 (CRY1) and circadian locomotor output cycles kaput (CLOCK) to determine their relationships with biochemical and anthropometric parameters and lifestyle elements (diet, physical activity, and quality of sleep) in hypertensive patients. METHODS: In 31 females with hypertension (HT) and 55 non-hypertensive women (NHT) the CRY1 and CLOCK concentrations, total antioxidant status (TAS), lipid profile, and glycemia were analyzed. Blood pressure and anthropometric measurements, nutritional, exercise, and sleep analyses were performed. RESULTS: In the HT group, the CRY1 level was 37.38% lower than in the NHT group. No differences were noted in CLOCK concentration between groups. BMI, FBG, and TG were higher in the HT group compared to the NHT group, while TC, LDL, and HDL levels were similar. The study showed no relationship between CRY1 or CLOCK concentrations and glucose or lipids profile, amount of physical activity, or sleep quality, although CRY1 was associated with some anthropometric indicators. In the HT group, increased CLOCK and CRY1 values were associated with a high TAS level. CONCLUSIONS: The serum level of CRY1 could be considered in a detailed diagnostic of hypertension risk in populations with abnormal anthropometric indices.

Melatonin and cryptochrome 2 in metabolic syndrome patients with or without diabetes: a cross-sectional study.

Background Metabolic syndrome (MetS) is a cluster of metabolic risk factors which increases the chances for future cardiovascular diseases, as well as diabetes. The underlying causes of MetS include overweight and obesity, physical inactivity and genetic factors. Our intension here was to focus in this study on the importance of the chronobiology, represented by melatonin (MT) and cryptochrome 2 (CRY2), in developing MetS and type 2 diabetes mellitus (T2DM). Thus, we aimed to compare MT and CRY2 plasma levels and correlate both biomarkers with adiposity, atherogenicity and hematological indices in MetS and T2DM cohorts. Methods In a cross-sectional study, 28 normoglycemic lean subjects (controls), 29 normoglycemic MetS subjects and 30 MetS (pre-diabetic/diabetic) were recruited. Results MT (pg/mL) was elevated significantly in MetS arm p-value < 0.05, whereas CRY2 levels (ng/mL) were markedly higher in both MetS groups (non-diabetic and pre-diabetic/diabetic) (all with p-value < 0.001). A reciprocal MT-CRY2 relationship was observed in the MetS (non-diabetic) group (p-value = 0.003). Of note in the total study population, both MT and CRY2 proportionally correlated with each of the following: atherogenicity index of plasma (AIP), waist circumference (WC) and systolic blood pressure (SBP) (all with p-value < 0.05) for MT and CRY2, respectively). Whereas MT correlated inversely with high-density lipoprotein-cholesterol (HDL-C) (p-value < 0.05). Additionally, CRY2 correlated directly with each of the following: diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein (LDL-C), hip circumference (HC), body adiposity index (BAI), weight-to-height (WHtR) ratio, mean platelet volume (MPV) and platelet/lymphocyte ratio (PLR) (p-value < 0.05). Conclusion These findings substantiate that both metabolic risk biomarkers can be prognostic tools and pharmacotherapeutic targets to slowdown the accelerated nature of T2DM.

Circadian clock gene expression is impaired in gestational diabetes mellitus.

Dysfunction of the circadian clock genes is involved in the development of obesity and type 2 diabetes (T2D). Since gestational diabetes mellitus (GDM) and T2D share common genetic and phenotypic features, in the present study, we investigated the status of the circadian clock in a cohort of 40 Greek pregnant women with GDM, four with T2D and 20 normal controls. Peripheral blood mRNA transcript levels of 10 clock genes (CLOCK1, BMAL1, PER1, PER2, PER3, PPARΑ, PPARD, PPARG, CRY1 and CRY2) were determined by real-time quantitative PCR. GDM patients expressed significantly lower transcript levels of BMAL1, PER3, PPARD and CRY2 compared to control women (p < 0.05). No significant difference was documented between GDM women maintained either under insulin treatment or diet. A positive correlation was found between the expression of BMAL1 versus CRY2 (r = 0.45, p = 0.003) and BMAL1 versus PPARD (r = 0.43, p = 0.004). Further investigation on the functional relevance of these clock genes, disclosed that expression of PER3 correlated negatively with HbA1C levels (r = -0.36, p = 0.022). These data document for the first time that the expression of BMAL1, PER3, PPARD and CRY2 genes is altered in GDM compared to normal pregnant women and support the notion that deranged expression of clock genes may play a pathogenic role in GDM.