Gene:

KCNJ11

potassium inwardly-rectifying channel, subfamily J, member 11

Overview

Details

Introduction

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The inwardly rectifying, ATP-sensitive potassium channel (K _ATP) was first identified in cardiac muscle, but it is also expressed in pancreatic Beta-cells, central nervous system tissue, skeletal muscle, and smooth muscle. In the pancreas, the K _ATPchannels close when intracellular glucose levels increase. The cessation of K+ efflux depolarizes the Beta-cell membrane, which activates voltage-gated calcium channels and facilitates insulin secretion. Sulfonylureas exert their hypoglycemic effect by inhibiting the K _ATP channel.

Inagaki et al. cloned the two subunits that form the K _ATPchannel, Kir6.2 (the ATP-sensor and channel pore) and the sulfonylurea receptor (SUR1), and mapped both genes to a common region on chromosome 11 [PMID: 7502040]. KCNJ11 is an intronless gene that codes for the 390 amino acid Kir6.2 subunit. KCNJ11 is approximately 3.4 kilobases in size and it lies approximately 4.5 kilobases upstream from the gene encoding SUR1 (ABCC8).

Twenty validated SNPs are present in KCNJ11, as reported in dbSNP, but the functional consequences of most are unknown. The most widely studied variant is a G to A substitution at nucleotide 635, which results in a change from a glutamate residue in position 23 to lysine (E23K). This substitution decreases the sensitivity of the potassium channel to ATP and thus affects insulin secretion [PMID: 15842514]. KCNJ11variation is implicated as a risk factor for type 2 diabetes based on the results of numerous clinical and population-based association studies [PMID:]. The literature for ABCC8 is not as consistent, although variants in the KCNJ11 and ABCC8 are tightly linked. [PMID: 12540637, 12540638, 15579791, 15842514, 12540637 15579791, 15111507, 15797964].

The primary target of sulfonylureas is the K _ATP channel, therefore KCNJ11 variation may influence the outcome of sulfonylurea treatment in type 2 diabetes [PMID: 16595597]. Additionally, patients with rare activating variants in KCNJ11 may be able to discontinue insulin after starting oral sulfonylurea therapy. [PMID: 16885550]

In-Depth Annotations ()

1. rs5219 at chr11:17366148 in KCNJ11
   May decrease sensitivity of channel to ATP by altering the charge of the ATP binding region

   Variant Name:

   KCNJ11:E23K

   Related Drugs:

   sulfonamides, urea derivatives

   Evidence:

   http://www.pharmgkb.org/.../variant.jsp
   

Curated Annotations ()

1. rs5219 at chr11:17366148 in KCNJ11
   rs5219 demonstrated association with Type 2 Diabetes in a GWAS of Finnish and Swedish patients and controls.

   Related Diseases:

   Diabetes Mellitus, Type 2

   Evidence:

   PMID:17463246
   

2. rs5219 at chr11:17366148 in KCNJ11
   In a large Finnish case-control GWAS, rs5219 was found to be associated with susceptibility to Type 2 Diabetes.

   Related Diseases:

   Diabetes Mellitus, Type 2

   Evidence:

   PMID:17463248
   

3. rs5219 at chr11:17366148 in KCNJ11
   Risk or phenotype-associated allele: G allele. Phenotype: Increased levels of fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) (p < 0.05); and post-repaglinide treatment, GA or AA genotype carries had increased levels of FPG, PPG, and glycated hemoglobin (HbA(1c)) compared with patients with the GG genotype (p < 0.05) Study size: 259 type II diabetes cases and 188 healthy controls. Study population/ethnicity: Chinese. Significance metric(s): p < 0.05. Type of association: GN; PD.

   Variant Name:

   KCNJ11: Lys23Glu

   Related Drugs:

   repaglinide

   Related Diseases:

   Diabetes Mellitus, Type 2

   Evidence:

   PMID:20054294
   

4. rs5219 at chr11:17366148 in KCNJ11
   Risk or phenotype-associated allele: G (23Glu) allele. Phenotype: Baseline clinical characteristic (fasting plasma glucose (p < 0.032)), postprandial plasma glucose (p < 0.014) levels) were significantly increased in T2DM patients with the G (23Glu) allele in a comparison of the GG, GA and AA genotypes. Study size: 259. Study population/ethnicity: Chinese type 2 Diabetes (T2DM) patients. Significance metric(s): p < 0.032. Type of association: GN.

   Variant Name:

   KCNJ11:67A>G, Lys23Glu (E23K)

   Related Diseases:

   Diabetes Mellitus, Type 2

   Evidence:

   PMID:20054294
   

5. rs5219 at chr11:17366148 in KCNJ11
   Risk or phenotype-associated allele: GG (23Glu/Glu) genotype. Phenotype: After 8-week repaglinide treatment, levels of fasting plasma glucose, postprandial plasma glucose, and percent HbA(1c) glycated hemoglobin were significantly lower in T2DM patients with the GG (23Glu/Glu) genotype (n = 18) compared to patients with the AA (23Lys/Lys) and AG (23Lys/Glu) genotypes combined (n = 22) (p < 0.036). Study Size: 40. Study population/ethnicity: Chinese type 2 Diabetes (T2DM) patients with uniform genotype with regard to SLCO1B3 (OATP1B1) T521C. Significance metric(s): p < 0.036. Type of association: GN; PD.

   Variant Name:

   KCNJ11:67A>G, Lys23Glu (E23K)

   Related Drugs:

   repaglinide

   Related Diseases:

   Diabetes Mellitus, Type 2

   Evidence:

   PMID:20054294
   

Non-Curated Annotations ()

1. rs5219 at chr11:17366148 in KCNJ11
   GWAS results: Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome wide association data. (Initial Sample Size: 1,924 cases, 2,938 controls; Replication Sample Size: 3,757 cases, 5,346 controls); (Region: 11p15.1; Reported Gene(s): KCNJ11; Risk Allele: rs5219-?); (p-value(obese) = 0.0000005).This variant is associated with Type 2 diabetes.

   Related Diseases:

   Diabetes Mellitus, Diabetes Mellitus, Type 2

   Evidence:

   PMID:19056611
   http://www.genome.gov/gwastudies/
   

2. rs5219 at chr11:17366148 in KCNJ11
   GWAS results: Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome wide association data. (Initial Sample Size: 1,924 cases, 2,938 controls; Replication Sample Size: 3,757 cases, 5,346 controls); (Region: 11p15.1; Reported Gene(s): KCNJ11; Risk Allele: rs5219-?); (p-value(non-obese)= 0.000000001).This variant is associated with Type 2 diabetes.

   Related Diseases:

   Diabetes Mellitus, Diabetes Mellitus, Type 2

   Evidence:

   PMID:19056611
   http://www.genome.gov/gwastudies/
   

Non-Curated Information

A list of non-curated publications that mention this gene along with other genes is available.

PharmGKB Curated Pathways

• Anti-diabetic drug pathway (Potassium channel inhibitors PD)
• Antiarrhythmic Drug Pathway

PID Pathways†

• FOXA2 and FOXA3 transcription factor networks - (Pathway Interaction Database NCI-Nature Curated)

Reactome Pathways†

• Glucose Regulation of Insulin Secretion - (Reactome via Pathway Interaction Database)

Curated Information

The following drugs are in curated knowledge about this gene.

	Drug Class	Relationship	Evidence
	antiarrhythmics, class i and iii	FA	Publications
	sulfonamides, urea derivatives	CO PD       GN	Publications, Variants

	Drug	Relationship	Evidence
	diazoxide	FA	Publications
	repaglinide	PD PK	Publications, Variants

Non-Curated Information

A list of non-curated publications that mention this gene along with other drugs is available.

Curated Information

The following diseases are in curated knowledge about this gene.

	Disease	Relationship	Evidence
	Diabetes Mellitus, Type 1	CO          GN	Publications
	Diabetes Mellitus, Type 2	CO PD PK    GN	Publications, Variants
	Diabetes, Permanent Neonatal (PNDM)	CO       FA GN	Publications

Non-Curated Information

A list of non-curated publications that mention this gene along with other diseases is available.

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

1. Adaptations to Climate in Candidate Genes for Common Metabolic Disorders

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LinkOuts

Common Searches

• Comparative Genomics at UCSC
• Search BioCarta and KEGG Pathways at CGAP
• Search Reactome

Non-Curated Publications

A list of non-curated publications that mention this gene is available.