The cell proliferation protein 123 (CDC123) is involved in the synthesis of the eukaryotic initiation factor 2 (eIF2), which regulates eukaryotic translation. Although CDC123 is considered a candidate oncogene in breast cancer, its expression and role in Hepatocellular Carcinoma (HCC) remain unknown. Herein, we obtained the CDC123 RNA-seq and clinical prognostic data from the TCGA database. The mRNA level revealed that CDC123 was highly expressed in HCC patients, and Kaplan-Meier analysis implied better prognoses in HCC patients with low CDC123 expression (P < 0.001). The multivariate Cox analysis revealed that the CDC123 level was an independent prognostic factor (P < 0.001). We further confirmed a high CDC123 expression in HCC cell lines. Additionally, we found that CDC123 knockdown in HCC cell lines significantly inhibited cellular proliferation, invasion, and migration. Moreover, CDC123 was co-expressed with the CDK5 Regulatory Subunit-Associated Protein 1 Like 1 (CDKAL1), whose mRNA level was decreased after silencing CDC123. Therefore, we hypothesized that CDC123 promotes HCC progression by regulating CDKAL1.

N6-methyladenosine (m6A) modification is the most common mRNA modification that is considered a new layer of mRNA epigenetic regulation. Demethylase fat mass and obesity-associated protein (FTO) are important in the dynamic regulation of m6A, but their role in gastric cancer (GC) is not fully understood. This study revealed that FTO and CDKAL1 were up-regulated in GC cells and tissue. CDKAL1 is the downstream target of FTO-mediated m6A modification, with FTO promoting GC cell proliferation through CDKAL1 and inducing mitochondrial fusion, eventually causing GC chemoresistance. In conclusion, FTO contributes to the increasing resistance of GC cells to 5-fluorouracil (5-Fu) by upregulating CDKAL1 and inducing mitochondrial fusion.

BACKGROUND: Interactions between genetic, metabolic, and environmental factors lead to gestational diabetes mellitus (GDM). We aimed to examine interactive effects of cyclin-dependent kinase 5 regulatory subunit-associated protein1-like 1(CDKAL1) rs7747752 polymorphism with low serum levels of L-carnitine, choline, and betaine for GDM.
METHODS: A nested case-control study of 207 GDM women and their one-to-one, age-matched controls was organized from a prospective cohort of pregnant women in Tianjin, China. Conditional logistic regressions were used to test associations between CDKAL1 rs7747752 and serum levels of L-carnitine, choline, and betaine, and the risk of GDM. Additive interactions were performed to examine interactive effects of rs7747752 and low serum levels of L-carnitine, choline, and betaine on the risk of GDM.
RESULTS: The CDKAL1 rs7747752 G > C was associated with GDM in additive, dominant, and recessive model (P <0.05). The rs7747752 CC genotype enhanced the OR of L-carnitine ≤ vs. > 150 nmol/mL for GDM from 6.14 (2.61-14.4) to 19.6 (5.65-68.1) and the OR of choline ≤ vs. > 110 nmol/mL from 2.37 (1.07-5.28) to 12.1 (3.22-45.6), with significant additive interactions. Similarly, CG genotype also enhanced the OR of L-carnitine ≤ vs. > 150 nmol/mL for GDM from 4.70 (2.01-11.0) to 11.4 (3.98-32.9), with a significant additive interaction. However, the additive interaction between rs7747752 and betaine ≤ 200 nmol/mL on the risk of GDM was not significant.
CONCLUSIONS: The CC or CG genotype carriers in rs7747752 of CDKAL1 who have a low serum level of L-carnitine or choline are at a particular high risk of GDM. Randomized controlled trials are warranted to test the effect of supplement of L-carnitine or choline on the risk of GDM in the high-risk group.

The study aimed to explore additive interactions of CDKAL1 rs7747752 and GUDCA/DCA for GDM risk and whether the interactive effects on the risk of GDM was mediated via increasing lysophosphatidylcholines (LPC) 18:0 and/or saturated fatty acid (SFA) 16:0.
A 1:1 age-matched study nested in a prospective cohort of pregnant women (207 pairs) was organized in Tianjin, China. Additive interactions were used to test interaction effects while mediation analyses and Sobel tests were used to test mediation effects of LPC18:0 and SFA16:0 between copresence of rs7747752 and low GUDCA/DCA, and GDM risk.
The CDKAL1 rs7747752 was associated with GDM (P<0.05). The rs7747752 C polymorphism markedly enhanced ORs of low GUDCA from 4.04 (0.72-22.8) to 9.02 (1.63-49.7) and low DCA from 1.67 (0.68-4.11) to 4.24 (1.84-9.76), both with significant additive interactions. Further adjustment for LPC18:0 attenuated the interactive effects of rs7747752 and low DCA, with a significant mediation effect (P=0.003). High SFA16:0 did not mediate the interactive effects of rs7747752 and low DCA/GUDCA on GDM risk.
The CDKAL1 rs7747752 C carrier status and low GUDCA/DCA had significant additive interactions on the risk of GDM with the effect from interaction with DCA being partially mediated via increasing LPC18:0.

Background: CDK5 regulatory subunit associated protein 1 like 1 (CDKAL1) is a major pathogenesis-related protein for type 2 diabetes mellitus (T2DM). Recently, some studies have investigated the association of CDKAL1 susceptibility variants, including rs4712523, rs4712524, and rs9460546 with T2DM. However, the results were inconsistent. This study aimed to evaluate the association of CDKAL1 variants and T2DM patients. Methods: A comprehensive meta-analysis was performed to assess the association between CDKAL1 SNPs and T2DM among dominant, recessive, additive, and allele models. Results: We investigated these three CDKAL1 variants to identify T2DM risk. Our findings were as follows: rs4712523 was associated with an increased risk of T2DM for the allele model (G vs A: OR = 1.172; 95% CI: 1.103-1.244; p < 0.001) and dominant model (GG + AG vs AA: OR = 1.464; 95% CI: 1.073-1.996; p = 0.016); rs4712524 was significantly associated with an increased risk of T2DM for the allele model (G vs A: OR = 1.146; 95% CI: 1.056-1.245; p = 0.001), additive model (GG vs AA: OR = 1.455; 95% CI: 1.265-1.673; p < 0.001) recessive model (GG vs AA + AG: OR = 1.343; 95% CI: 1.187-1.518; p < 0.001) and dominant model (GG + AG vs AA: OR = 1.221; 95% CI: 1.155-1.292; p < 0.001); and rs9460546 was associated with an increased risk of T2DM for the allele model (G vs T: OR = 1.215; 95% CI: 1.167-1.264; p = 0.023). The same results were found in the East Asian subgroup for the allele model. Conclusions: Our findings suggest that CDKAL1 polymorphisms (rs4712523, rs4712524, and rs9460546) are significantly associated with T2DM.

Interactions between genetic and nutritional factors can contribute to the risk of gestational diabetes mellitus (GDM).
We aimed to explore the associations of cyclin-dependent kinase 5 regulatory subunit associated protein 1-like 1 (CDKAL1) single-nucleotide polymorphism (SNP) rs7747752 and serum concentrations of SFAs with the risk of GDM in Chinese women.
We conducted a 1:1 case-control study in a prospective cohort of pregnant women in Tianjin, China. Serum SFA data were collected from a total of 243 women with GDM and their controls matched by maternal age (±1 y). Among them, 207 case-control pairs had high-quality sequencing data. P/L and S/P ratios were defined as palmitic acid (16:0)/lauric acid (12:0) and stearic acid (18:0)/palmitic acid, respectively. Conditional logistic regression analysis was performed to estimate associations of CDKAL1 SNP rs7747752 and serum concentrations of SFAs with the risk of GDM. An additive interaction between rs7747752 and palmitic acid was analyzed to test the contribution of their interaction to the risk of GDM.
Among the 5 tested SFAs, palmitic acid was positively whereas lauric acid was negatively associated with the risk of GDM. A P/L ratio ≥12.2 and an S/P ratio ≤0.71 were independently and synergistically associated with an increased risk of GDM. The CDKAL1 rs7747752 G > C variant was significantly associated with an increased risk of GDM (P < 0.05). Furthermore, the presence of the rs7747752 G > C variant increased the OR (95% CI) of high palmitic acid concentration from 1.55 (0.61, 3.97) to 4.34 (2.04, 9.23), with a significant additive interaction.
The interaction between high serum palmitic acid concentration and the CDKAL1 rs7747752 G > C variant played a critical role in GDM. Given that a hypocaloric low-carbohydrate diet can lower palmitic acid concentrations, it is worthwhile to test whether such a diet is effective in reducing the risk of GDM, especially among women who have both risk factors.

UNASSIGNED: The aim of this study was to investigate the influence of CDK5 regulatory subunit-associated protein 1-like 1 (CDKAL1) expression on the survival of nasopharyngeal carcinoma (NPC) patients.
UNASSIGNED: A total of 140 non-metastatic NPC patients were retrospectively analyzed. The expression of CDKAL1 was detected by immunohistochemistry.
UNASSIGNED: The CDKAL1-negative group exhibited better overall survival (OS) according to Kaplan-Meier curve analysis (p = 0.006), with 5-year OS rates for the CDKAL1-negative and -positive groups of 89.7% and 70.2%, respectively. The CDKAL1-negative group also exhibited a tendency toward a better progression-free survival (PFS) rate. Multivariate analysis showed that CDKAL1 expression was independently associated with both OS (p = 0.002) and PFS (p = 0.043).
UNASSIGNED: CDKAL1 expression is an independent negative predictor of patient survival in non-metastatic NPC.

BACKGROUND: Patients with schizophrenia have an increased prevalence of type 2 diabetes mellitus that has shown a significant association with the rs7754840 polymorphism in the gene encoding the cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1 (CDKAL1).
OBJECTIVE: To examine whether this polymorphism was involved in the susceptibility in first-episode drug-naive schizophrenic patients (FDSP), and further influenced their clinical symptoms.
METHODS: This polymorphism was genotyped in 239 FDSP and 368 healthy controls. The clinical symptoms in FDSP were assessed using the Positive and Negative Syndrome Scale (PANSS) five-factor models.
RESULTS: There was no significant difference in the allelic and genotypic frequencies of this polymorphism between two groups (both p > 0.05) after adjusting for covariates. However, the PANSS depressive score significantly differed by genotype in FDSP after adjusting for covariates (F = 5.25, p = 0.006). This significant difference also persisted after Bonferroni correction (p < 0.05). FDSP with C/C genotype had significantly higher PANSS depressive score than those with C/G genotype (p = 0.007) and those with G/G genotype (p = 0.005). Moreover, further stepwise multivariate regression analysis showed the significant association between the rs7754840 polymorphism and PANSS depressive score in FDSP (β = -1.07, t = -2.75, p = 0.007).
CONCLUSIONS: Our findings demonstrated that although the CDKAL1 rs7754840 polymorphism did not contribute to the susceptibility to FDSP, it might be implicated in depressive symptoms in this patient group.

The understanding of the genetic basis of type 2 diabetes mellitus (T2DM) has progressed rapidly, but the interactions among common genetic variants and metabolic risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and metabolic environments on the risk of T2DM. Obesity is emerging as an independent risk factor for T2DM and arterial stiffness. Here, we examined the effect of the rs9356744 polymorphism in the body mass index (BMI) gene CDKAL1 on the risk of T2DM in East Asians and particularly assessed the interactions between this polymorphism and other metabolic risk factors. A total of 1975 subjects in whom the rs9356744 polymorphism had been detected in the CDKAL1 gene were enrolled in this study. The height, weight, blood pressure and relevant markers, including glucose, lipids, liver and renal function, of the participants were successfully measured. Pulse wave velocity (PWV) was measured using an automatic wave form analyzer. At baseline, we found a significant association between BMI and rs9356744 genotypes (CC, CT, TT) (P = 0.048). After adjusting for confounding factors, including sex, age and BMI, participants carrying the T allele of rs9356744 showed a lower incidence of T2DM. Further adjustment for blood pressure and lipids did not appreciably change the results (P = 0.019, 0.009, 0.015, respectively). We found significant interactions between the rs9356744 polymorphism and high-density lipoprotein (HDL), serum uric acid (SUA) and carotid-femoral pulse wave velocity (cf-PWV) in relation to T2DM incidence (P for interaction = 0.007, 0.002, 0.004, respectively), especially in the group with the lowest SUA level and the group with the highest HDL and cf-PWV levels (P for trend = 0.006, 0.008, 0.018, respectively). Furthermore, we found a significant interaction between the rs9356744 polymorphism and cf-PWV in relation to the level of 2-h plasma glucose in the oral glucose tolerance test (OGTT) (P for interaction = 0.0341). In summary, the T allele of rs9356744 was an independent protective factor for T2DM. There were significant interactions between rs9356744 and HDL, SUA, and cf-PWV in relation to T2DM risk.

UNASSIGNED: Type 2 diabetes mellitus (T2DM) has a high global prevalence, and the interaction of environmental factors and genetic factors may contribute to the risk of T2DM. We aimed to investigate the association between T2DM and the single nucleotide polymorphisms (SNPs) in genes (CDKAL1 and HHEX) associated with insulin secretion.
UNASSIGNED: T2DM (n=1,169) and nondiabetic (NDM) (n=1,277) subjects were enrolled and the eight SNPs in CDKAL1 and HHEX genes associated with insulin secretion were genotyped in a Chinese population using MassARRAY. Then, the association of these SNPs with T2DM was analyzed.
UNASSIGNED: Our results revealed that four SNPs (rs4712524, rs10946398, rs7754840 in CDKAL1, and rs5015480 in HHEX) showed significantly different distributions between the T2DM and NDM groups (P<0.00625). The G allele of rs4712524 (P=0.004, OR=1.184; 95% CI=1.057-1.327), C allele of rs10946398 (P<0.001, OR=1.247; 95% CI=1.112-1.398), and C allele of rs775480 in CDKAL1 (P<0.001, OR=1.229; 95% CI=1.096-1.387) functioned as risk alleles of T2DM. The C allele of rs5015480 in HHEX (P<0.001, OR=1.295; 95% CI=1.124-1.493) was also the risk factor for T2DM. The haplotype analysis revealed that CDKAL1 haplotype rs4712524G-rs10946398C-rs7754840C-rs9460546G (P=0.001, OR=1.210; 95% CI=1.076-1.360) and HHEX haplotype rs1111875C-rs5015480C (P<0.001, OR=1.364; 95% CI=1.180-1.576) were the risk factors of T2DM.
UNASSIGNED: Our results revealed that genetic variations in CDKAL1 and HHEX were associated with T2DM susceptibility in Chinese population.