Clinical Annotations
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Variant Annotations
PharmGKB variant annotations provide information about variant-drug pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.
Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.
There are 8 annotations for this variant. Register or sign in to see them.
There are 7 disease-related annotations for this variant. Register or sign in to see them.
VIP Variant in KCNJ11
Note: The KCNJ11 gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand; therefore the alleles within our variant annotations will differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.
Two subunits form the ATP-sensitive potassium channel - the sulfonylurea receptor (SUR1) and the Kir6.2 subunit (Kir6.2). KCNJ11 encodes the Kir6.2 subunit. The nonsynonymous E23K variant in the NH2-terminal of Kir6.2 may alter pancreatic Beta-cell sensitivity to adenosine tri-phosphate (ATP) [Article:11872696]. ATP, a byproduct of glucose metabolism, activates the pancreatic potassium channel causing it to depolarize the cell and ultimately release insulin. The E23K variant may alter the charge of the ATP-binding region, decreasing the sensitivity of the channel to ATP, thereby increasing the open probability [Articles:15565284, 12198096, 12475776].
The E23K variant is common, with minor allele frequencies reported in dbSNP and in the literature as follows: African American 8%, Caucasian 34-48%, Chinese 24%, and Japanese 30%. Several large association studies, including a meta-analysis, provide strong evidence that the E23K variant is associated with type 2 diabetes [Articles:12540638, 12540637, 15111507, 12605956, 15855351, 15842514, 15579791]. Recent investigations demonstrated that the E23K variant impairs insulin secretion, whereas another describes a functional effect through abnormal glucagon secretion [Articles:12540638, 15111507, 12351459, 12196481].
Sulfonylureas target the pancreatic ATP-sensitive potassium channel, specifically the sulfonylurea receptor subunit. Consequently, the E23K variant could affect the response to sulfonylureas. In UKPDS, the change in glucose following sulfonylurea therapy and failure of sulfonylurea therapy did not differ by E23K genotype (or ABCC8 polymorphisms) [Article:11318841]. However, another study demonstrated that secondary sulfonylurea failure was more likely in those who carried the K allele [Article:16595597]. In vitro, the variant did not affect tolbutamide responsiveness[Article:8897013]. Linkage with ABCC8 variants could be responsible for the pharmacogenetic association, as one study suggested that exonic and intronic variants in ABCC8 decreased tolbutamide response [Article:9568693].
| Drugs / Other Molecules | |
|---|---|
| Diseases | Diabetes Mellitus, Type 2 9 10 11 12 13 14 15 16 17 18 Diabetes, Permanent Neonatal (PNDM) 19 20 21 Persistent Hyperinsulinemia Hypoglycemia of Infancy 22 23 |
Appendix
| Genomic Variant & GenBank ID: | 16196813 T>C on NT_009237 |
|---|---|
| mRNA Variant & GenBank ID: | 635 A>G on NM_000525(note: this mRNA sequence encodes KCNJ11:E23K, so the A at position 635 represents the variant, and the G represents reference KCNJ11) |
| Protein Variant & GenBank ID: | Lys23Glu on NP_000516 (note: this protein sequence is for KCNJ11:E23K, so the change from the variant to the reference KCNJ11 becomes Lys23Glu) |
Connected Diseases
Publications related to rs5219 at chr11:17409572: 4
| Robust replication of genotype-phenotype associations across multiple diseases in an electronic medical record. American journal of human genetics. 2010. Ritchie Marylyn D, et al. [Article:20362271@PubMed] | |
| KCNJ11 Lys23Glu and TCF7L2 rs290487(C/T) polymorphisms affect therapeutic efficacy of repaglinide in Chinese patients with type 2 diabetes. Clinical pharmacology and therapeutics. 2010. Yu M, et al. [Article:20054294@PubMed] | |
| Association studies of variants in promoter and coding regions of beta-cell ATP-sensitive K-channel genes SUR1 and Kir6.2 with Type 2 diabetes mellitus (UKPDS 53). Diabetic medicine : a journal of the British Diabetic Association. 2001. Gloyn A L, et al. [Article:11318841@PubMed] | |
| Sequence variations in the human Kir6.2 gene, a subunit of the beta-cell ATP-sensitive K-channel: no association with NIDDM in while Caucasian subjects or evidence of abnormal function when expressed in vitro. Diabetologia. 1996. Sakura H, et al. [Article:8897013@PubMed] |
Cross-References
- UCSC Golden Path:
- chr11:17409572
- dbSNP:
- rs5219
Platform Availability
- Illumina