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CDKAL1
CDKAL1 is a gene on chromosome 6p22.3 that plays a key role in insulin secretion and beta-cell function, influencing the risk of type 2 diabetes (T2D) and gestational diabetes mellitus (GDM).
Genetic variants of CDKAL1 have been linked to impaired insulin release and metabolic dysfunction, with potential implications for personalized diabetes risk assessment and prevention strategies.
What is CDKAL1?
The CDKAL1 gene, located on chromosome 6p22.3, plays a crucial role in insulin secretion, beta-cell function, and mitochondrial function in adipose tissue, influencing the pathogenesis of gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM).
Genetic Variants and Associations
Several polymorphisms in the CDKAL1 gene have been identified as significant risk factors for GDM and T2DM.
CDKAL1 and Type 2 Diabetes Mellitus
CDKAL1 is associated with increased risk of type 2 diabetes (T2D), primarily through its role in regulating insulin secretion and beta-cell function. Variants of CDKAL1 impair insulin release, contributing to T2D risk.
However, dietary protein and fat intake may influence the risk of diabetes in individuals carrying certain CDKAL1 variants, with interactions varying by gender.
CDKAL1 and Gestational Diabetes
Two well-studied variants are rs7756992 A/G and rs7754840 G/C, which have been linked to increased susceptibility to GDM, particularly in Asian and Caucasian populations.
The C allele of rs7747752 is also associated with an elevated risk of GDM, especially when combined with high levels of palmitic acid (16:0), a saturated fatty acid linked to insulin resistance and beta-cell dysfunction.
Genetic Testing for CDKAL1
At present, CDKAL1 genetic testing is primarily used in research settings rather than routine clinical practice. While CDKAL1 variants are important for understanding the genetic basis of T2D, they are not typically included in standard diagnostic testing for the condition.
In personalized medicine or specialized research, genetic testing for CDKAL1 may be used as part of a more comprehensive risk assessment for T2D, especially when looking at how genetic predispositions intersect with environmental factors like diet and lifestyle.
However, testing for CDKAL1 variants is not generally included for routine screening in the general population.
Interpreting CDKAL1 Variants
Specific CDKAL1 genetic variants are linked to a modestly increased risk of T2D but are not known to directly impact metabolic markers like blood glucose or HbA1c, making them risk factors rather than diagnostic markers.
The absence of these variants does not guarantee immunity to T2D, as other genetic and environmental factors, such as diet, exercise, and weight management, also influence overall risk.
Clinical Implications of CDKAL1 Testing
The clinical utility of CDKAL1 testing may be limited at this time, offering no immediate insights for T2D treatment or management in routine practice. However, it can be valuable in research and personalized medicine for disease prevention.
If tested, CDKAL1 results should be considered alongside other T2D risk factors. Fasting glucose, HbA1c, and oral glucose tolerance tests remain the gold standard for diagnosing and assessing glucose metabolism.
Test Procedure and Interpretation
The following section outlines the typical test procedure and interpretation for CDKAL1 genetic testing:
Testing Procedure
Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types.
A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.
Normal Reference Ranges
Normal reference ranges for CDKAL1 genetic testing are considered to be without mutations that can alter the activity of the CDKAL1 proteins.
Clinical Implications of Positive CDKAL1 Mutations
The clinical implications of a positive CDKAL1 mutation test result will vary by individual, although CDKAL1 mutations in symptomatic patients signal an immediate need for further assessment and possibly treatment.
Patients or practitioners with questions about the clinical implications of CDKAL1 mutations should seek further assessment with a genetic counselor or expert.
Diagnostic Limitations
While CDKAL1 testing can provide valuable insights, it is important to interpret results carefully. The presence of CDKAL1 mutations should not be used in isolation for diagnosis.
Clinicians must consider other biomarkers and clinical factors when making decisions about patient care. Additionally, sample handling and patient conditions can impact test results, so ensuring proper testing procedures is essential.
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CDKAL1 CDK5 regulatory subunit associated protein 1 like 1 [Homo sapiens (human)] - Gene - NCBI. (n.d.). Www.ncbi.nlm.nih.gov. https://www.ncbi.nlm.nih.gov/gene/54901
Choi, W. J., Jin, H. S., Kim, S. S., & Shin, D. (2020). Dietary Protein and Fat Intake Affects Diabetes Risk with CDKAL1 Genetic Variants in Korean Adults. International journal of molecular sciences, 21(16), 5607. https://doi.org/10.3390/ijms21165607
Entry - *611259 - CDK5 REGULATORY SUBUNIT-ASSOCIATED PROTEIN 1-LIKE 1; CDKAL1 - OMIM. (2016). Omim.org. https://omim.org/entry/611259
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Li, Y. Y., Wang, L. S., Lu, X. Z., Yang, Z. J., Wang, X. M., Zhou, C. W., Xu, J., Qian, Y., & Chen, A. L. (2013). CDKAL1 gene rs7756992 A/G polymorphism and type 2 diabetes mellitus: a meta-analysis of 62,567 subjects. Scientific reports, 3, 3131. https://doi.org/10.1038/srep03131
Palmer, C. J., Bruckner, R. J., Paulo, J. A., Kazak, L., Long, J. Z., Mina, A. I., Deng, Z., LeClair, K. B., Hall, J. A., Hong, S., Zushin, P. H., Smith, K. L., Gygi, S. P., Hagen, S., Cohen, D. E., & Banks, A. S. (2017). Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue. Molecular metabolism, 6(10), 1212–1225. https://doi.org/10.1016/j.molmet.2017.07.013
Wang, H., Yang, W., Liu, J., Leng, J., Li, W., Yu, Z., Li, J., Ma, R. C. W., Hu, G., Fang, Z., Wang, Y., & Yang, X. (2021). Serum concentrations of SFAs and CDKAL1 single-nucleotide polymorphism rs7747752 are related to an increased risk of gestational diabetes mellitus. The American Journal of Clinical Nutrition, 114(5), 1698–1707. https://doi.org/10.1093/ajcn/nqab225
Wang, H., Li, J., Leng, J., Li, W., Liu, J., Yan, X., Yu, Z., Hu, G., Ma, R. C. W., Fang, Z., Wang, Y., & Yang, X. (2022). The CDKAL1 rs7747752-Bile Acids Interaction Increased Risk of Gestational Diabetes Mellitus: A Nested Case-Control Study. Frontiers in Endocrinology, 13. https://doi.org/10.3389/fendo.2022.808956
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