Can This Gene Protect You From Obesity (CDKAL1)?

The CDKAL1 gene encodes the ‘CDK5 regulatory subunit-associated protein 1-like 1’ protein, so called because it’s very similar to the regulatory subunit of CDK5 [R]. 

CDK5 is a messenger protein with multiple functions, including the inhibition of insulin production in the pancreas. The regulator protein similar to CDKAL1 (CDK5RAP1) blocks CDK5 activation and allows insulin production, thus preventing the development of type 2 diabetes from excess sugar [R, R, R].

CDKAL1 is highly expressed in the muscles, brain, and pancreas. The CDKAL1 protein activates the expression of the proinsulin gene and mice lacking CDKAL1 had reduced insulin production and secretion in response to glucose. In line with this, CDKAL1 variants have been associated with reduced pancreatic function and higher diabetes risk [R, R, R, R, R, R, R].

The CDKAL1 gene encodes a protein similar to CDK5RAP1 and involved in insulin production and secretion.

The major ‘C’ variant of rs2206734 has been associated with increased BMI and obesity rates in East Asian and Canadian adults, as well as in Chinese children. Conversely, this variant protected East Asian adults and Greek children from type 2 diabetes and insulin resistance [R, R, R, R, R, R].

Another major variant, ‘T’ at rs9356744, has also been associated with increased BMI in East Asians. Again, this allele reduced the risk of developing type 2 diabetes in Chinese adults and insulin resistance in Greek children [R, R, R].

The major ‘A’ variant of rs4712523 was also associated with increased BMI in Japanese and reduced risk of type 2 diabetes in Chinese populations [R, R, R].

The minor ‘C’ variant of rs7754840 is most well-known for its association with increased risk of gestational and type 2 diabetes, reduced insulin secretion, and better response to antidiabetic treatment. Chinese carriers of the ‘C’ variant had higher waist circumference and waist-to-hip ratio, but a Dutch study found this allele unrelated to BMI [R, R, R, R, R, R].

The rs7756992 polymorphism has also been most widely investigated concerning its link to diabetes. In addition to increased risk of type 2 and gestational diabetes, its minor ‘G’ variant is associated with leanness in diabetics and reduced birth weight [R, R, R, R, R, R].

How It Works

Although none of the studies tested the effects of the variants on CDKAL1 expression or activity, some risk alleles for diabetes have been shown to reduce insulin production and secretion. Based on the general mechanism of the protein, we can speculate that variants associated with diabetes have a reduced CDKAL1 activity [R, R].

In most cases, there was an association between reduced risk of diabetes and increased BMI. Insulin reduces blood glucose levels by promoting its uptake into the cells. Variants reducing its production may cause diabetes because the excess of blood sugar damages the pancreas. Alternatively, they may reduce weight gain by preventing sugar from being transformed into storage fats in the cells [R, R].

Notably, the minor variant of rs7754840 was associated with both diabetes and increased belly fat in Chinese. The fact that this polymorphism had no effect on BMI in a Dutch study suggests that its effect is probably dependent on the ethnicity. Moreover, the different CDKAL1 variants are often inherited together and could influence the overall effects observed [R, R].

However, the effects of the different variants may be partly counteracted by the activity of CDKAL1 on fatty tissues. Studies in engineered mice showed that CDKAL1 blocks the development of fat cells and promotes calorie-burning by brown fat [R, R].

CDKAL1 variants with reduced activity and insulin production are generally associated with both increased diabetes risk and reduced BMI.

SNP Summary and Table

Primary SNP:

CDKAL1 rs2206734

• ‘C’ = associated with increased BMI and obesity rates. Reduced risk of type 2 diabetes.
• ‘T’ = associated with reduced BMI and obesity rates. Increased risk of type 2 diabetes.
• 56% of the world population carries two copies of the major ‘C’ allele.
• The ‘T’ variant is especially rare in European descendants (only 4% of ‘TT’).

Other Important SNPs:

CDKAL1 rs9356744 

• ‘T’ = associated with increased obesity rates. Reduced risk of type 2 diabetes.
• ‘C’ = associated with reduced obesity rates. Increased risk of type 2 diabetes.
• The ‘C’ variant is only slightly less common than ‘T’ and the most common situation is to carry one copy of each one.
• The ‘C’ variant is least common in people of European ancestry (only 8% of ‘CC’).

CDKAL1 rs4712523

• ‘A’ = associated with increased obesity rates. Reduced risk of type 2 diabetes.
• ‘G’ = associated with reduced obesity rates. Increased risk of type 2 diabetes.
• The genotype distribution is very similar to that of rs9356744 for all ethnicities.

CDKAL1 rs7754840 

• ‘G’ = not associated with obesity or diabetes.
• ‘C’ = associated with increased risk of type 2 and gestational diabetes. Higher waist circumference and waist-to-hip ratio in Chinese.
• The genotype distribution is very similar to that of rs9356744 and rs4712523 for all ethnicities.

CDKAL1 rs7756992 

• ‘A’ = not associated with obesity or diabetes.
• ‘G’ = associated with increased risk of type 2 and gestational diabetes. Reduced weight in diabetics and newborns.
• The ‘G’ variant is only slightly less common than ‘A’ and the most common situation is to carry one copy of each one.
• The ‘A’ variant is most common in European and South Asian descendants.