Cyclin-dependent Kinase 5 Regulatory Subunit-associated Protein 1-like 1 Research Articles

Association of the CDKAL1 gene polymorphism with gestational diabetes mellitus in Chinese women

IntroductionTo identify the association of the cyclin-dependent kinase 5 regulatory subunit associated protein 1-like 1 (CDKAL1) gene polymorphism with gestational diabetes mellitus (GDM) in the Chinese population.Research design and methodsThis...

Interactions of CDKAL1 rs7747752 polymorphism and serum levels of L-carnitine and choline are related to increased risk of gestational diabetes mellitus

BackgroundInteractions 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.MethodsA 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.ResultsThe 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.ConclusionsThe 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.

CDKAL1 gene rs7756992 A/G and rs7754840 G/C polymorphisms are associated with gestational diabetes mellitus in a sample of Bangladeshi population: implication for future T2DM prophylaxis

BackgroundAssociation of single nucleotide polymorphisms (SNP) rs7756992 A/G and rs7754840 G/C of cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) gene with the susceptibility of gestational diabetes mellitus (GDM) has been studied in a group of Bangladeshi women.MethodsIn this case–control study, 212 GDM patients and 256 control subjects were genotyped for rs7756992 and rs7754840 by PCR-RFLP and TaqMan™ allelic discrimination assay method respectively. Genotyping results were confirmed by DNA sequencing and replicated TaqMan™ assay. The odds ratios and their 95% confidence interval were calculated by logistic regression to determine the associations between genotypes and GDM.ResultsThe genotype frequencies of rs7756992-AA/AG/GG in the GDM group and the control group were 37%/48%, 53%/45%, 10%/7% and those of rs7754840-CC/CG/GG were 51%/55%, 40.1%/39.8%, 9%/5% respectively. Under dominant and log additive models rs7756992 was revealed significantly associated with GDM after being adjusted for family history of diabetes (FHD) and gravidity. Conversely, rs7754840 was significantly associated (P = 0.047) with GDM only under the recessive model after the same adjustment. The risk allele frequency of both SNPs was higher in the GDM group but significantly (P = 0.029) increased prevalence was observed in the rs7756992 G allele. When positive FHD and risk alleles of these SNPs were synergistically present in any pregnant woman, the chance of developing GDM was augmented by many folds. The codominant model revealed 2.5 and 2.1 folds increase in odds by AG (rs7756992) and GC (rs7754840) genotypes and 3.7 and 4.5 folds by GG (rs7756992) and CC (rs7754840) genotypes respectively. A significant 2.7 folds (P = 0.038) increase in odds of GDM resulted from the interaction of rs7756992 and family history of diabetes under the dominant model. The cumulative effect of multigravidity and risk alleles of these SNPs increased the odds of GDM more than 1.5 folds in different genotypes.ConclusionThis study not only revealed a significant association between rs7756992 and rs7754840 with GDM but also provided the possibility as potential markers for foretelling about GDM and type 2 diabetes mellitus in Bangladeshi women.

Serum concentrations of SFAs and CDKAL1 single-nucleotide polymorphism rs7747752 are related to an increased risk of gestational diabetes mellitus

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.

The risk variant of CDKAL1 (rs7756992) impairs fasting glucose levels and insulin resistance improvements after a partial meal-replacement hypocaloric diet

BackgroundThe CDKAL1 (CDK5 Regulatory Subunit Associated Protein 1 Like 1) gene encodes cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated proten1 like 1. This protein has been shown to contribute to the glucose-dependent regulation of insulin secretion in pancreatic islets. AimsThe aim of our study was to analyze the effects of the rs7756992 genetic variant of CDKAL1 gene on fasting glucose and insulin resistance after weight loss secondary to partial meal replacement hypocaloric diet (pMRHD). MethodsThis was a non-randomized, single-treatment study with a formula-diet in 44 obese subjects. The patients received nutritional education and a modified diet with two intakes of a normocaloric hyperproteic formula for 3-months. Anthropometric parameter and biochemical profile were measured at basal time and after 3 months. The variant of CDKAL1 gene rs7756992 was assessed. ResultsThe following genetic distribution was observed; [27AA (61.3%), 12 AG (27.3%) and 5 GG (11.4%)]. After the pMRHD, body weight, the body mass index (BMI), fat mass, waist circumference and blood pressure decreased in both genotypes. Non-G allele carriers showed a significant improvement in fasting glucose levels (AA vs. AG + GG) (−6.1 ± 1.4 md/dl vs. −1.2 ± 0.7 mg/dl; p = 0.01), fasting insulin levels (−3.6 ± 0.2 mU/l vs. −1.3 ± 0.6 mU/l; p = 0.02) and HOMA-IR (−1.2 ± 0.2 units vs. −0.3 ± 0.2 units; p = 0.01). Fasting plasma glucose levels were higher in G allele carriers than non G allele carriers. ConclusionsOur data suggest that the genetic variant (rs7756992) of CDKAL1 gene is associated with glycaemic status after a pMRHD, with greater improvements in fasting glucose, insulin and HOMA-IR in subjects without the G allele.

La presencia de la variante de riesgo de CDKAL1 (rs7756992) altera los niveles de glucosa en ayunas y la resistencia a la insulina después de una dieta hipocalórica con reemplazo parcial de comidas

BackgroundThe CDKAL1 (CDK5 Regulatory Subunit Associated Protein 1 Like 1) gene encodes cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated proten1 like 1. This protein has been shown to contribute to the glucose-dependent regulation of insulin secretion in pancreatic islets. AimsThe aim of our study was to analyze the effects of the rs7756992 genetic variant of CDKAL1 gene on fasting glucose and insulin resistance after weight loss secondary to partial meal replacement hypocaloric diet (pMRHD). MethodsThis was a non-randomized, single-treatment study with a formula-diet in 44 obese subjects. The patients received nutritional education and a modified diet with two intakes of a normocaloric hyperproteic formula for 3-months. Anthropometric parameter and biochemical profile were measured at basal time and after 3 months. The variant of CDKAL1 gene rs7756992 was assessed. ResultsThe following genetic distribution was observed; [27AA (61.3%), 12 AG (27.3%) and 5 GG (11.4%)]. After the pMRHD, body weight, the body mass index (BMI), fat mass, waist circumference and blood pressure decreased in both genotypes. Non-G allele carriers showed a significant improvement in fasting glucose levels (AA vs. AG + GG) (-6.1 ± 1.4 md/dL vs. -1.2 ± 0.7 mg/dl; p = 0.01), fasting insulin levels (-3.6 ± 0.2 mU/L vs. -1.3 ± 0.6 mU/L; p = 0.02) and HOMA-IR (-1.2 ± 0.2 units vs. -0.3 ± 0.2 units; p = 0.01). Fasting plasma glucose levels were higher in G allele carriers than non G allele carriers. ConclusionsOur data suggest that the genetic variant (rs7756992) of CDKAL1 gene is associated with glycaemic status after a pMRHD, with greater improvements in fasting glucose, insulin and HOMA-IR in subjects without the G allele.

The type 2 diabetes mellitus susceptibility gene CDKAL1 polymorphism is associated with depressive symptom in first-episode drug-naive schizophrenic patients.

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). To examine whether this polymorphism was involved in the susceptibility in first-episode drug-naive schizophrenic patients (FDSP), and further influenced their clinical symptoms. 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. 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). 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.

Dietary Protein and Fat Intake Affects Diabetes Risk with CDKAL1 Genetic Variants in Korean Adults.

Cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) is one of the strongest diabetes loci identified to date; evidence suggests that it plays an important role in insulin secretion. Dietary factors that affect insulin demand might enhance the risk of diabetes associated with CDKAL1 variants. Our aim was to examine the interactions between dietary protein and fat intake and CDKAL1 genetic variants in relation to the risk of diabetes in Korean adults. Single nucleotide polymorphisms (SNPs) were selected with a genome-wide association study (GWAS) for diabetes after adjustment for age, gender, and examination site. Using data from the Health Examinees (HEXA) Study of the Korean Genome and Epidemiology Study (KoGES), 3988 middle-aged Korean adults between 40–76 years of age (2034 men and 1954 women) were included in the study. Finally, rs7756992 located within the CDKAL1 gene region was selected from GWAS (p-value < 5 × 10−8). Multivariable logistic regression models were used to evaluate the interactions between genotypes and dietary protein and fat intake in relation to diabetes risk after adjustment for age, gender, BMI, waist circumference, physical activity, smoking status, drinking habits, and examination site. Significant interactions between CDKAL1 rs7756992 and dietary protein and fat intake for the risk of diabetes were observed in men (p-value < 0.05). In women, significant interactions between dietary protein and fat intake and CDKAL1 variants (rs7756992) were associated with increased risk of diabetes (p-value < 0.05). Dietary protein and fat intake interacted differently with CDKAL1 variants in relation to the risk of diabetes in Korean adults of both genders. These findings indicate that CDKAL1 variants play a significant role in diabetes and that dietary protein and fat intake could affect these associations.

No association detected between seven common variants in the CDKAL1 gene and gestational glycemic traits

Elevated plasma glucose levels in pregnancy increase adverse pregnancy outcomes. Cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) has been shown to be involved in insulin secretion in pancreatic β cells. In this study, we investigated the impact of genetic variants in CDKAL1 on plasma glucose, insulin values, β cell function and insulin resistance in the fasted state as well as plasma glucose 1 h after the consumption of a 50-g oral glucose load between 24 and 28 weeks of pregnancy among 929 unrelated pregnant Han Chinese women. Seven common variants previously reported to associate with diabetes were genotyped. Insulin resistance and β cell function were assessed by homeostasis model assessment. The genetic impacts were analyzed using analysis of variance and analysis of covariance. The results showed that there was no significant association between any of the seven variants and those gestational glycemic traits. Therefore, this study suggests that the seven common variants in CDKAL1 are not significant factors for the variations of several gestational glycemic traits in the Han Chinese population. However, further well-designed studies with larger sample size, more ethnic groups and more CDKAL1 variants are required to validate the association between CDKAL1 and gestational glycemic traits.

Common variants in TCF7L2 and CDKAL1 genes and risk of type 2 diabetes mellitus in Egyptians.

In this work we studied association of common variants in transcription factor 7-like 2 (TCF7L2) and cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) genes with type 2 diabetes mellitus (T2DM) in Egyptians.Subjects and methodsThis is a case–control study; 180 T2DM patients and 210 control subjects were genotyped for TCF7L2 rs7903146 and rs12255372 and CDKAL1 rs7756992 single nucleotide polymorphisms (SNPs) by TaqMan method on real time polymerase chain reaction system (real time-PCR).ResultsTCF7L2 rs12255372 and rs7903146 associated with T2DM (p = 0.0001 and 0.003; respectively). The rs12255372 variant T allele associated with 2-fold increased risk for T2DM and TT genotype carriers were at 3.58-folds higher risk to develop T2DM than wild genotype (GG) carriers. Meanwhile, rs7903146 variant T allele associated with 1.6-fold increased risk for T2DM and TT genotype carriers were at 2.3-folds higher risk than wild genotype (CC) carriers. Both TCF7L2 SNPs significantly associated with T2DM under additive and dominant models and after adjustment for other covariates. On the other hand, CDKAL1 rs7756992 showed no significant association with T2DM under any genetic model. Both TCF7L2 SNPs were in strong LD (P = 0.02; D′ = 0.85). Taking common TCF7L2 rs12255372/rs7903146 GC haplotype as reference, multivariate analysis confirmed the association of rs12255372 T allele-containing haplotypes (TC and TT) with T2DM. Haplotype TC associated with 6.32 times-higher risk for T2DM (95%CI = 0.55–76.17, Pc = 0.04) followed by haplotype TT which associated with 3.88 times-higher risk for the disease (95%CI = 1.09–13.76, Pc = 0.03).ConclusionTCF7L2 rs12255372 and rs7903146 common variants associate with T2DM risk in Egyptians.

The CDKAL1 gene is associated with impaired insulin secretion and glucose-related traits: the Cardiometabolic Risk in Chinese (CRC) study.

Insulin secretion and insulin resistance, which affect metabolic homoeostasis, each have a significant genetic component. Cyclin- dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1 (CDKAL1) rs10946398, a novel body mass index (BMI)-associated locus specifically in the Asian population, may impair insulin secretion and may be associated with insulin resistance and type 2 diabetes. Our objective was to investigate the impact of the rs10946398 polymorphism of CDKAL1 on insulin secretion, insulin resistance and glucose-related traits in the Chinese population. The study samples were based on a community-based health examination survey conducted in central China. Indices of insulin resistance and insulin secretion were derived from fasting glucose measurements and oral glucose tolerance tests (OGTTs). Using multivariate linear regression models, the relationships between the rs10946398 polymorphism of CDKAL1 and insulin secretion, insulin resistance and quantitative glucose-related traits were investigated in 2313 participants. The CDKAL1 rs10946398 C allele showed a significant association with decreased insulin secretion (β = -0·05, P < 0·0005), but not with insulin resistance (β = 0·02, P = 0·08). We also found that the CDKAL1 rs10946398 C allele was significantly associated with glucose-related traits (fasting glucose, fasting insulin, 2-h glucose and HbA1c). There was no significant relationship between rs10946398 and other metabolic traits. rs10946398 of CDKAL1 was associated with markers of impaired insulin secretion. It is reasonable to infer that the relationship between CDKAL1 and metabolic diseases is mediated by its effect on glucose-related traits.

Contribution of CDKAL1 rs7756992 and IGF2BP2 rs4402960 polymorphisms in type 2 diabetes, diabetic complications, obesity risk and hypertension in the Tunisian population 在突尼斯人群中，CDKAL1 rs7756992与IGF2BP2 rs4402960的多态性对2型糖尿病、糖尿病并发症、肥胖风险以及高血压的影响

The insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and the cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) identified through genome-wide association (GWA) studies have been shown to be associated with Type 2 diabetes in various ethnic groups. In this study, we investigated the association of the rs7756992 of CDKAL1 and the rs4402960 of IGF2BP2 with Type 2 diabetes, diabetic complications (nephropathy, retinopathy and cardiovascular disease), obesity and hypertension in a Tunisian population. A case-control association study including 200 Type 2 diabetes Tunisian patients (World Health Organization criteria) and 208 controls (age ≥40; fasting plasma glucose <6.1 mmol/L; without first degree family history of diabetes) has been performed. Other parameters such as diabetic nephropathy, diabetic retinopathy, cardiovascular disease, overweight/obesity and hypertension have been also collected. Genotyping was performed using TaqMan technology. A significant association between the rs4402960 and Type 2 diabetes (OR = 1.86, 95% CI = 1.34-2.58, P < 10(-4) ) has been found. Overweight/obese subjects bearing the T-allele have an increased risk to develop Type 2 diabetes (OR = 2.06, 95% CI = 1.40-3.03, P < 10(-4) ). Furthermore, the rs7756992 was found to be associated with the reduced risk of diabetic nephropathy in patients with diabetes (OR = 0.44, 95% CI = 0.27-0.73, P = 0.001). The present study confirms that the rs4402960 of IGF2BP2 gene is a strong candidate for Type 2 diabetes susceptibility and overweight/obesity risk in the Tunisian population. Interestingly, our data suggest that the rs7756992 of CDKAL1 gene have a protective effect against diabetic nephropathy.

CDNA cloning and mRNA expression of cat and dog Cdkal1.

The cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) gene encodes methylthiotransferase, and the gene contains risk variants for type 2 diabetes in humans. In this study, we performed complementary DNA cloning for Cdkal1 in the cat and dog and characterized the tissue expression profiles of its messenger RNA. Cat and dog Cdkal1 complementary DNA encoded 576 and 578 amino acids, showing very high sequence homology to mammalian CDKAL1 (>88.4%). Real-time polymerase chain reaction analyses revealed that Cdkal1 messenger RNA is highly expressed in smooth muscle and that tissue distribution of Cdkal1 is similar in cats and dogs. Genotyping analysis of single-nucleotide polymorphism for cat Cdkal1 revealed that obese cats had different tendencies from normal cats. These findings suggest that the cat and dog Cdkal1 gene is highly conserved among mammals and that cat Cdkal1 may be a candidate marker for genetic diagnosis of obesity.

Genetic variants on chromosome 6p21.1 and 6p22.3 are associated with type 2 diabetes risk: a case–control study in Han Chinese

Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) on chromosome 6p21.1 and 6p22.3 as type 2 diabetes (T2D) susceptibility loci in the European and Japanese populations. However, these SNPs have not been well evaluated in Chinese population. Here, we performed a case-control study with 2925 T2D cases and 3281 controls in a Chinese population. We used TaqMan OpenArray and Sequenom MassARRAY to genotype the four SNPs (rs4712523, rs7756992, rs4712524 and rs6931514) in CDKAL1 (cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1) at 6p22.3 and one SNP (rs9472138) near vascular endothelial growth factor A (VEGFA) at 6p21.1. All the five SNPs were significantly associated with T2D risk with overall effects (odds ratio, OR) from 1.19 to 1.29 in the additive genetic model (rs6931514: OR=1.29, 95% confidence intervals (95% CI)=1.19-1.39, P=5.6 × 10(-10); rs7756992: OR=1.23, 95% CI=1.15-1.32, P=1.2 × 10(-8); rs4712523: OR=1.25, 95% CI=1.15-1.35, P=3.8 × 10(-8); rs4712524: OR=1.24, 95% CI=1.15-1.35, P=6.8 × 10(-8); rs9472138: OR=1.19, 95% CI=1.05-1.34, P=006). Conditional analysis identified two independent signals (rs6931514 at 6p22.3 and rs9472138 at 6p21.1) that were significantly associated with T2D. Compared with the wild homozygote of rs6931514 and rs9472138, subjects with variant alleles of the two SNPs had increased risk for T2D susceptibility in a dose-response manner (P(trend)=7.4 × 10(-12)). Our findings indicated that genetic variants of CDKAL1 and VEGFA on chromosome 6 may contribute to T2D risk in Chinese population, especially for rs9472138 at 6p21.1 identified for the first time to significantly increase the T2D risk in Chinese individuals.

Association of glycosylated hemoglobin with the gene encoding CDKAL1 in the Korean Association Resource (KARE) study

Genome-wide associations with glycosylated hemoglobin, which reflects the long-term glycemia, were examined using two independent cohorts of the Korea Association Resource (KARE) consortium. We first identified sequence variants within a linkage disequilibrium block (r(2) > 0.98) in the intron 5 of cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) gene using 4,275 normoglycemic subjects of Cohort 1 (P < 2.5 × 10(-8)). The association was replicated in 3,782 normoglycemic subjects of Cohort 2. Furthermore, the sequence variants were also associated with glucose levels after oral glucose tolerance test. Especially, a strong association with 1 h glucose (P = 1.3 × 10(-11)) led us to interpreting that CDKAL1 might influence the level of glycosylated hemoglobin by affecting 1 h glucose level. Ultimately, accumulated effects on the glycosylated hemoglobin level by the genetic variation of CDKAL1 might affect susceptibility to type 2 diabetes mellitus.

Shared Genomics of Type 2 and Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy and the prevalence of GDM is increasing worldwide. Short- and long-term complications of GDM on mothers and fetuses are well-recognized. These include more than seven-fold higher risk for type 2 diabetes mellitus (T2DM) later in life in women with GDM than those without. Evidence supports that GDM shares several risk factors with T2DM, including genetic risks. This chapter reviewed studies on candidate genes shared by T2DM and GDM published from 1990 to 2011. At least 20 susceptible genes of T2DM have been studied in women with GDM in various races. Results from current association studies on T2DM susceptible genes in GDM have shown significant heterogeneity There may be primary evidence that polymorphisms of susceptible genes of T2DM such as transcription factor 7-like 2 (TCF7L2) gene, potassium channel voltage-gate KQT-like subfamily member 1 (KCNQ1) gene, and cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) gene, may increase risk of GDM. Associations between GDM and many genetic variants have led to different findings across populations. Many genetic polymorphisms related to GDM were investigated in a single study or a single population. Replication studies to verify contributions of both common and rare genetic variants for GDM and T2DM in specific racial/ethnic groups are needed.

The carriage of risk variants of CDKAL1 impairs beta-cell function in both diabetic and non-diabetic patients and reduces response to non-sulfonylurea and sulfonylurea agonists of the pancreatic KATP channel

On chromosome 6q22.3, a cluster of single-nucleotide polymorphisms located in intron 5 of the cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1 (CDKAL1) gene were shown to confer susceptibility to type 2 diabetes in multiple ethnic groups. The diabetogenic role of CDKAL1 variants is suggested to consist in lower insulin secretion probably due to the insufficient inhibition of the CDK5 activity. In this study, we assessed the association of several SNPs of CDKAL1 with T2D in 772 Russian affected patients and 773 normoglycemic controls using a Taqman-based allelic discrimination assay. We showed association of the minor allele C of rs10946398 (Odds Ratio (OR) = 1.21, 95% CI = 1.04-1.4, P = 0.016), allele C of rs7754840 (OR = 1.18, 95% CI = 1.01-1.37, P = 0.038), and allele G of rs7756992 (OR = 1.21, 95% CI = 1.04-1.42, P = 0.017) with higher diabetes risk thereby replicating the predisposing role of CDKAL1 in etiology of T2D. These alleles contribute to three haplotypes (CCA, CGG, and CCG) related to higher diabetes risk (OR = 1.48, 2.12, and 1.95). Combinations of these haplotypes between each other form the group of high-risk haplogenotypes whose carriers had decreased HOMA-β compared to other CDKAL1 variants in both diabetic (38.6 ± 19.3 vs. 48.2 ± 21.2, P(adjusted) = 0.019-0.044) and non-diabetic (91.8 ± 42.1 vs. 108 ± 47.2, P(adjusted) = 0.0054-0.01) patients. The carriage of the risk haplogenotypes of CDKAL1 was associated with reduced response to non-sulfonylurea and sulfonylurea agonists of the pancreatic KATP channel. These data suggest that CDKAL1 is involved in the pathogenesis of T2D through impaired beta-cell function.

Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender

We examined the genetic associations of previously identified sequence variants with type 2 diabetes mellitus (T2DM) and its potentially genetic heterogeneity by gender in a large-scale cohort. A total of 613 T2DM patients and 8221 control subjects from the Korea Association REsource (KARE) cohort were included in the analysis of genetic association of T2DM with 33 nucleotide polymorphic markers identified by previous studies. The association analysis was further conducted with data partitioned by gender. The association analysis resulted in five nucleotide sequence variants associated with the susceptibility of T2DM after Bonferonni correction (P < 0.0015). One was located near the gene of hematopoietically expressed homeobox (HHEX), and the others were all in the gene of cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1). Further analysis revealed that the sequence variant (rs5015480) near HHEX and two SNPs (rs7756992 and rs9465871) in CDKAL1 were associated with the susceptibility of T2DM in females (P<0.005), but not in males (P>0.005). We suggested heterogeneous genetic associations of the T2DM susceptibility with the CDKAL1 and HHEX genes by gender.

Association of CDKAL1 Genetic Polymorphism with Glycosylated Hemoglobin A1c Level among Non-Diabetic Chinese Adults

Objectives: Multiple single nucleotide polymorphisms (SNPs) have been identified as risk loci for type 2 diabetes (T2DM). This study was conducted to increase our understanding of the mechanisms through which three novel risk variants affect the risk of T2DM. Methods: 918 Chinese volunteers from Pudong New Area of Shanghai, China, were recruited in Oct-Dec, 2006. Collection of demographic and lifestyle characteristics, body measurements, bio-specimen collection and biochemistry assays were performed during the period. Genotyping of rs290487 at transcription factor 7-like 2 (TCF7L2), rs9465871 at cyclin-dependent kinase 5 regulatory subunit associated protein 1-like 1(CDKAL1) and rs1359790 at chromosome 13q31.1 were conducted using Taqman approach. Results: Genotypes of TCF7L2-rs290487, CDKAL1-rs9465871 and rs1359790 at 13q31.1 were not associated with metabolic syndrome or its components. While average levels of glycosylated hemoglobin A1c (HbA1c), fasting glucose, serum lipids and anthropometrics did not differ by genotypes of TCF7L2-rs290487 and rs1359790 at 13q31.1, HbA1c level varied significantly by genotypes of CDKAL1-rs9465871, particularly among women. After adjusting for age, women carrying C allele had a higher level of HbA1c than those bearing T allele, with each C allele linking to appropriate 0.1% increase of HbA1c level (P for trend=0.025). However, the difference was no longer significant after multiple comparison correction. Similar patterns were consistently observed regardless of levels of energy, dietary fat and average glycemic index intake (P for interaction >0.05). Conclusions: CDKAL1-rs9465871 may slightly affect glycemic phenotypes in non-diabetic Chinese women. Our results support the potential role of CDKAL1 gene in the regulation of insulin secretion.

Association of a Cyclin-Dependent Kinase 5 Regulatory Subunit-Associated Protein 1-Like 1 (CDKAL1) Polymorphism With Elevated Hemoglobin A1c Levels and the Prevalence of Metabolic Syndrome in Japanese Men: Interaction With Dietary Energy Intake

Genome-wide association studies have identified the cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) gene as a novel risk factor for type 2 diabetes mellitus. Application of this genetic marker for prevention of type 2 diabetes and metabolic syndrome (MetS) in healthy populations has not yet been evaluated. The authors examined the effects of a CDKAL1 polymorphism (rs9465871) on metabolic phenotype and of gene-lifestyle (CDKAL1-energy intake) interaction on MetS in a cohort of apparently healthy Japanese men examined in 2003. The CC genotype of the CDKAL1 variant was associated with elevated glycosylated hemoglobin A₁(c) (HbA1c) levels. The prevalence of MetS was 25.6% for CC and 16.3% for TT + CT (odds ratio = 2.18, 95% confidence interval: 1.06, 4.48; P = 0.035). When dietary energy intake was accounted for, the variant's effect on HbA1c was observed in the highest energy-intake group (mean: CC, 5.6% (standard deviation, 1.7); TT + CT, 5.0% (standard deviation, 0.5); P = 0.025). In addition, the positive association between HbA1c and energy intake was stronger in subjects with the CC genotype than in subjects with TT + CT. These results suggest that the interaction between the CDKAL1 polymorphism and dietary energy intake influences the dysglycemic phenotype leading to MetS, possibly through impaired insulin secretion. The CDKAL1 polymorphism may be a marker for MetS in the Japanese population.