|This SNP has been associated with an increased risk for type 1 and type 2 diabetes|
Diabetes is a disease that affects how the body metabolizes glucose, and is characterized by high levels of glucose in the blood. Overtime, this can cause serious health problems in the eyes, kidneys, heart, nerves and teeth. Meanwhile, insulin is a hormone that helps the cells to uptake glucose for energy. There are two types of diabetes: type 1 and type 2. In type 1 diabetes, the pancreas does not produce insulin. The main factors contributing to the development of this type of diabetes are genetics and exposure to certain viruses [PMID 21248163]. In type 2 diabetes, the pancreas does not make insulin or the body does not use it efficiently, leading to high blood sugar levels. The factors contributing to higher risk for type 2 diabetes are obesity, lack of physical activity, age and family history [PMID 23071876].
CTBR1 and CTBR2 genes encode chymotrypsin, a digestive enzyme implicated in the regulation of the incretin pathway and development of diabetes [PMID 23674605]. Incretins are hormones important for the regulation of glucose levels in the body. These hormones stimulate the release of insulin by the pancreas. BCAR1 encodes a docking protein important in the regulation of tyrosine-kinase signaling.
In 2009, a meta-analysis of GWAS by Barret, J. C., et al indicated that the G allele of rs7202877 is strongly associated with increased risk for type 1 diabetes. First, a GWAS was done testing 841,622 SNPs using 3,983 cases and 3,999 controls from Great Britain. This meta-analysis included data from two previous GWAS done to identify risk factors for type 1 diabetes. The total sample size included 7,514 cases and 9,045 controls. From this meta-analysis, 25 SNPs were identified for further analysis (replication study). This replication study was done using a sample size of 4,267 cases, 4,670 controls and 4,342 trios. From this replication study, 18 new SNPs were associated with increased risk for type 1 diabetes including rs7202877. The frequency for rs7202877 minor allele was 0.096. The p-value for the GWA study was 3.9x10-6, the p-value for the first meta-analysis was 5.7x10-11, the p-value for the replication study was 1.2x10-6, and the combined p-value was 3.1x10-15. From the replication study, the odds ratio (OR) was 1.28 with a 95% CI of 1.17-1.41 [PMID 19430480].
In a separate 3-stage meta-analysis including 34,840 cases and 114,981 controls of European ethnicity by Morris et al., rs7202877 was associated with susceptibility for type 2 diabetes. 10 new SNPs associated with increased risk for type 2 diabetes were identified. The authors found that rs7202877 major allele T (frequency = 0.89) was the risk allele with a p-value of 3.5x10-8, an OR of 1.12 and 95% CI of 1.07-1.16. In this study, rs7202877 was associated with the BCAR1 locus that also includes CTBR1 and CTBR2 genes [PMID 22885922]. Six of the ten SNPs identified by Morris et al., were validated in another study by Harder M., et al. in 1,885 cases and 6,598 controls of European ethnicity. This study characterized the influence of diabetes risk-associated SNPs on pre-diabetic traits. These SNPs included rs7202877: p-value = 0.02 and odds ratio (95% CI) = 1.20 (1.04 -1.38). This study also attempted to characterize the physiology of rs7202877 for type 2 diabetes by measuring quantitative traits. However, the data only suggested that the rs7202877-T variant was associated with impairment of insulin release [PMID 23457408].
A recent study that tested 60,000 SNPs to further understand how the CTBR1/2 locus affects susceptibility for type 2 diabetes and investigate the possible treatment of this disease by targeting the incretin pathway, tested the rs7202877-G allele for association with type 2 diabetes. The G allele was identified as protective for type 2 diabetes by testing different parameters: GLP-1 stimulated insulin secretion, gene expression in pancreas islets and chymotrypsin activity. GLP-1 is an incretin hormone that stimulates glucose-dependent insulin secretion by the pancreas (incretin effect). For the GLP-1 test, the sample size included 232 healthy individuals. In this test, subjects carrying the G allele showed a 33% increase in GLP-1 stimulated insulin secretion (P = 1.9x10−6). Next, rs7202877 was examined to determine whether it could act as an expression quantitative trait locus (eQTL) by measuring RNA expression from whole pancreas and pancreatic islets (samples size = 80). It was found that the minor allele G increased expression of CTRB1 and CTRB2 (p-valuepancreas = 0.01 and p-valueislets ≤ 0.05) but not BCAR1. Finally, the G allele was associated with an increase in chymotrypsin activity (sample size = 40 G-carries and 40 non-G carries, p-value = 0.023). This study showed associations of the rs7202877 with several parameters associated with type 2 diabetes; however, the samples sizes are small. Therefore, further studies need to be done in order to validate the findings [PMID 23674605].
In conclusion, the rs7202877 major and minor alleles have been shown to be associated with an increased risk for type 1 and type 2 diabetes. The minor allele G is associated with both increased risk for type 1 diabetes and decreased risk for type 2 diabetes. Moreover, the major allele T is associated with increased risk for type 2 diabetes. To conciliate the fact that the same SNP variant is associated with two different outcomes further studies need to be done.
[PMID 19430480] Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes.
[PMID 22885922] Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes.
[PMID 21248163] Type 1 diabetes: etiology, immunology, and therapeutic strategies.
[PMID 23071876] Type 2 diabetes mellitus: a review of current trends.
|Trait||Type 1 diabetes|
|Title||Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes|
|Odds Ratio||1.28 [1.17-1.41]|
|qualified_impact||Insufficiently evaluated pathogenic|
[PMID 23457408] Type 2 diabetes risk alleles near BCAR1 and in ANK1 associate with decreased beta-cell function whereas risk alleles near ANKRD55 and GRB14 associate with decreased insulin sensitivity in the Danish Inter99 cohort.
[PMID 23674605] The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway.
[PMID 25951451] Replication Study in a Japanese Population to Evaluate the Association between 10 SNP Loci, Identified in European Genome-Wide Association Studies, and Type 2 Diabetes