KCNJ11 K23E - GET-Evidence

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Currentness:

KCNJ11 K23E

(KCNJ11 Lys23Glu)


Short summary

This variant is associated with decreased risk of type 2 diabetes. It is unclear whether this variant has additive effects, or acts in a dominant or recessive manner. Assuming diabetes has a lifetime risk of 36%, we estimate a decreased risk of around 1-2% per copy of this variant.

Variant evidence
Computational 1

Other variants in this gene are associated with hyperinsulinism

Functional -
Case/Control 5

Very high significance findings

See 17463246, Scott LJ et al. 2007 (17463248).

Familial
 
Clinical importance
Severity 3
Treatability 4
Penetrance 2

Attributable decreased risk of 1.56% (per chromosome rather than per individual estimate)

See 17463246, Scott LJ et al. 2007 (17463248), unpublished research (below).

 

Impact

Low clinical importance, Likely protective

(The "low clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

An OR of 1.15 implies a variant frequency in the cases of 50.5%, based on 47% risk allele frequency in controls
(Solve: (n / (1 – n)) / (0.47 / 0.53) = 1.15)

According to http://www.cdc.gov/diabetes/news/docs/lifetime.htm the lifetime risk of type 2 diabetes is around 36% (averaging risk of males and females). Using this and mock case/control numbers based on the above we used the PGP calculator (counting chromosomes) to estimate absolute increased risk (absolute quantities only affect p-values, not attributable risk calculation). Note that this is an estimate based on per chromosome analysis rather than per individual analysis.

Note that this nonreference allele is the protective allele, the reference allele is the risk allele, so to mock these numbers we use the reverse: case+: 495, case-: 505, cont+: 530, cont-: 470. This estimates the risk of any given chromosome with this variant to have a lifetime risk of type 2 diabetes is 34.44% — an attributable decreased risk of 1.56%.

Allele frequency

  • C @ chr11:17409572: 73.8% (7941/10758) in EVS
  • C @ chr11:17366147: 71.1% (91/128) in GET-Evidence
  • Frequency shown in summary reports: 73.8% (7941/10758)

Publications
 

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PubMed PMID: 17463246

The GWAS data from this study gives an OR of 1.15 with p = 10-7 for this variant.

Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, Erdos MR, Stringham HM, Chines PS, Jackson AU, Prokunina-Olsson L, Ding CJ, Swift AJ, Narisu N, Hu T, Pruim R, Xiao R, Li XY, Conneely KN, Riebow NL, Sprau AG, Tong M, White PP, Hetrick KN, Barnhart MW, Bark CW, Goldstein JL, Watkins L, Xiang F, Saramies J, Buchanan TA, Watanabe RM, Valle TT, Kinnunen L, Abecasis GR, Pugh EW, Doheny KF, Bergman RN, Tuomilehto J, Collins FS, Boehnke M. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007 Jun 1;316(5829):1341-5. Epub 2007 Apr 26. PubMed PMID: 17463248.

This study also shows OR’s around 1.11 or 1.15 from combined data with very high significance scores.

Yu M, Xu XJ, Yin JY, Wu J, Chen X, Gong ZC, Ren HY, Huang Q, Sheng FF, Zhou HH, Liu ZQ. KCNJ11 Lys23Glu and TCF7L2 rs290487(C/T) polymorphisms affect therapeutic efficacy of repaglinide in Chinese patients with type 2 diabetes. Clin Pharmacol Ther. 2010 Mar;87(3):330-5. Epub 2010 Jan 6. PubMed PMID: 20054294.

 

Genomes
 

hu011C57 - CGI sample GS01669-DNA_B05 from PGP sample 86486261
het C @ chr11:17409572

 

hu025CEA - CGI sample GS01669-DNA_D02 from PGP sample 27316983
hom C @ chr11:17409572

 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
het C @ chr11:17409572

 

hu0E64A1 - CGI sample GS01173-DNA_B02 from PGP sample 94378523
hom C @ chr11:17409572

 

hu241DEA - CGI sample GS01175-DNA_D05 from PGP sample 1205491
het C @ chr11:17409572

 

hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
hom C @ chr11:17409572

 

hu2DBF2D - CGI sample GS01173-DNA_G02 from PGP sample 67180598
het C @ chr11:17409572

 

 

hu342A08 - CGI sample GS01175-DNA_B05 from PGP sample 83494370
hom C @ chr11:17409572

 

 

hu38168C - CGI sample GS01173-DNA_H06 from PGP sample 91708424
hom C @ chr11:17409572

 

hu3CAB43 - CGI sample GS01175-DNA_D03 from PGP sample 27486199
het C @ chr11:17409572

 

hu4040B8 - CGI sample GS01175-DNA_D01 from PGP sample 31286272
hom C @ chr11:17409572

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
hom C @ chr11:17409572

 

hu44DCFF - CGI sample GS01669-DNA_C07 from PGP sample 74521372
het C @ chr11:17409572

 

hu4CA5B9 - CGI sample GS01669-DNA_B03 from PGP sample 14427241
het C @ chr11:17409572

 

hu604D39 - CGI sample GS00253-DNA_B02_200_37
hom C @ chr11:17409572

 

 

hu72A81D - CGI sample GS01173-DNA_C02 from PGP sample 10366372
het C @ chr11:17409572

 

hu7A4AD1 - CGI sample GS01669-DNA_C05 from PGP sample 42408046
het C @ chr11:17409572

 

hu8229AE - CGI sample GS01173-DNA_A07 from PGP sample 96240009
hom C @ chr11:17409572

 

hu92FD55 - CGI sample GS01669-DNA_A04 from PGP sample 08188426
hom C @ chr11:17409572

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
hom C @ chr11:17409572

 

huA0E089 - CGI sample GS01175-DNA_B04 from PGP sample 88590671
het C @ chr11:17409572

 

 

huAE4A11 - CGI sample GS01669-DNA_F02 from PGP sample 40767107
het C @ chr11:17409572

 

huAE6220 - CGI sample GS00253-DNA_H01_200_37
het C @ chr11:17409572

 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
hom C @ chr11:17409572

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het C @ chr11:17409572

 

huCA017E - CGI sample GS01175-DNA_B01 from PGP sample 86206034
hom C @ chr11:17409572

 

huD81F3D - CGI sample GS01173-DNA_D06 from PGP sample 69488604
hom C @ chr11:17409572

 

huE80E3D - CGI sample GS00253-DNA_D01_200_37
hom C @ chr11:17409572

 

huFAF983 - CGI sample GS01175-DNA_F02 from PGP sample 95788191
het C @ chr11:17409572

 

GS06985 - var-GS06985-1100-36-ASM
het C @ chr11:17366148

 

GS06994 - var-GS06994-1100-36-ASM
hom C @ chr11:17366148

 

GS07357 - var-GS07357-1100-36-ASM
hom C @ chr11:17366148

 

GS10851 - var-GS10851-1100-36-ASM
het C @ chr11:17366148

 

GS12004 - var-GS12004-1100-36-ASM
het C @ chr11:17366148

 

GS18501 - var-GS18501-1100-36-ASM
hom C @ chr11:17366148

 

GS18502 - var-GS18502-1100-36-ASM
hom C @ chr11:17366148

 

GS18504 - var-GS18504-1100-36-ASM
hom C @ chr11:17366148

 

GS18505 - var-GS18505-1100-36-ASM
hom C @ chr11:17366148

 

GS18508 - var-GS18508-1100-36-ASM
hom C @ chr11:17366148

 

GS18517 - var-GS18517-1100-36-ASM
hom C @ chr11:17366148

 

GS18526 - var-GS18526-1100-36-ASM
het C @ chr11:17366148

 

GS18558 - var-GS18558-1100-36-ASM
het C @ chr11:17366148

 

GS18940 - var-GS18940-1100-36-ASM
het C @ chr11:17366148

 

GS18942 - var-GS18942-1100-36-ASM
hom C @ chr11:17366148

 

GS18947 - var-GS18947-1100-36-ASM
het C @ chr11:17366148

 

GS18956 - var-GS18956-1100-36-ASM
het C @ chr11:17366148

 

GS19017 - var-GS19017-1100-36-ASM
hom C @ chr11:17366148

 

GS19020 - var-GS19020-1100-36-ASM
hom C @ chr11:17366148

 

GS19025 - var-GS19025-1100-36-ASM
hom C @ chr11:17366148

 

GS19026 - var-GS19026-1100-36-ASM
hom C @ chr11:17366148

 

GS19129 - var-GS19129-1100-36-ASM
hom C @ chr11:17366148

 

GS19238 - var-GS19238-1100-36-ASM
hom C @ chr11:17366148

 

GS19239 - var-GS19239-1100-36-ASM
hom C @ chr11:17366148

 

GS19240 - var-GS19240-1100-36-ASM
hom C @ chr11:17366148

 

GS19648 - var-GS19648-1100-36-ASM
het C @ chr11:17366148

 

GS19669 - var-GS19669-1100-36-ASM
het C @ chr11:17366148

 

GS19670 - var-GS19670-1100-36-ASM
het C @ chr11:17366148

 

GS19700 - var-GS19700-1100-36-ASM
hom C @ chr11:17366148

 

GS19701 - var-GS19701-1100-36-ASM
hom C @ chr11:17366148

 

GS19703 - var-GS19703-1100-36-ASM
hom C @ chr11:17366148

 

GS19704 - var-GS19704-1100-36-ASM
hom C @ chr11:17366148

 

GS19735 - var-GS19735-1100-36-ASM
hom C @ chr11:17366148

 

GS19834 - var-GS19834-1100-36-ASM
hom C @ chr11:17366148

 

GS20502 - var-GS20502-1100-36-ASM
het C @ chr11:17366148

 

GS20509 - var-GS20509-1100-36-ASM
hom C @ chr11:17366148

 

GS21767 - var-GS21767-1100-36-ASM
hom C @ chr11:17366148

 

Other external references
 

    dbSNP
  • rs5219
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the KCNJ11 gene
    Familial Hyperinsulinism
    Permanent Neonatal Diabetes Mellitus
    Diabetes Mellitus, KCNJ11-Related Transient Neonatal
    KCNJ11-Related Hyperinsulinism
    KCNJ11-Related Permanent Neonatal Diabetes Mellitus
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/KCNJ11
    GWAS
  • Type 2 diabetes (rs5219-?)
    Timpson 3-Dec-08 in Diabetes
    OR or beta: 1.19 [1.11-1.27]
    p-value: 5.00E-07 (obese)
    Initial sample: 1,924 cases, 2,938 controls
    Replication sample: 3,757 cases, 5,346 controls
    www.ncbi.nlm.nih.gov/pubmed/19056611
  • Type 2 diabetes (rs5219-?)
    Timpson 3-Dec-08 in Diabetes
    OR or beta: 1.25 [1.16-1.34]
    p-value: 1.00E-09 (non-obese)
    Initial sample: 1,924 cases, 2,938 controls
    Replication sample: 3,757 cases, 5,346 controls
    www.ncbi.nlm.nih.gov/pubmed/19056611
  • Type 2 diabetes (rs5219-T)
    Saxena 26-Apr-07 in Science
    OR or beta: 1.15 [1.09-1.21]
    Risk allele frequency: 0.47
    p-value: 1.00E-07
    Initial sample: 1,464 cases, 1,467 controls
    Replication sample: 5,065 cases, 5,785 controls (also includes meta-analysis from DGI+FUSION+WTCCC)
    www.ncbi.nlm.nih.gov/pubmed/17463246
  • Type 2 diabetes (rs5219-T)
    Scott 26-Apr-07 in Science
    OR or beta: 1.14 [1.10-1.19]
    Risk allele frequency: 0.46
    p-value: 7.00E-11 (DGI+FUSION+WTCCC)
    Initial sample: 1,161 cases, 1,174 controls
    Replication sample: 1,215 cases, 1,258 controls (also includes meta-analysis from DGI+FUSION+WTCCC)
    www.ncbi.nlm.nih.gov/pubmed/17463248
    PharmGKB
  • [Diabetes Mellitus, Type 2]
    [repaglinide]
    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.
    www.ncbi.nlm.nih.gov/pubmed/20054294
  • [Diabetes Mellitus, Type 2]
    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.
    www.ncbi.nlm.nih.gov/pubmed/20054294
  • [Diabetes Mellitus, Type 2]
    [repaglinide]
    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.
    www.ncbi.nlm.nih.gov/pubmed/20054294
  • [Diabetes Mellitus, Type 2]
    rs5219 demonstrated association with Type 2 Diabetes in a GWAS of Finnish and Swedish patients and controls.
    www.ncbi.nlm.nih.gov/pubmed/17463246
  • [Diabetes Mellitus, Type 2]
    In a large Finnish case-control GWAS, rs5219 was found to be associated with susceptibility to Type 2 Diabetes.
    www.ncbi.nlm.nih.gov/pubmed/17463248
  • [Diabetes Mellitus; Diabetes Mellitus, Type 2]
    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.
    www.ncbi.nlm.nih.gov/pubmed/19056611; Web Resource:http://www.genome.gov/gwastudie
  • [Diabetes Mellitus; Diabetes Mellitus, Type 2]
    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.
    www.ncbi.nlm.nih.gov/pubmed/19056611; Web Resource:http://www.genome.gov/gwastudie
    Web search results (11 hits -- see all)
  • Table 1 Text
    ... 0.02 123 "by cluster,freq" 8p22 lipoprotein lipase 2 rs328 LPL 4023 8 19864004 ... 1458 0.14 123 "by cluster,freq" 8p22 lipoprotein lipase 3 rs328 LPL 4023 8 ...
    icr.ac.uk/research/research_sections/.../2841.txt
  • The effect of transforming growth factor beta1 gene ...
    ... We identified a total of six known polymorphisms (K23E, A190A, L267V, L270V, I337V, and K281K) and two new ... SCD was not related to polymorphisms in the KCNJ11 gene.14872030 ...
    ibi.imim.es/OSIRIScorpusv01.xml
  • KCNJ11 polymorphisms and sudden cardiac death in patients ...
    KCNJ11 polymorphisms and sudden cardiac death in patients with acute myocardial ... of six known polymorphisms (K23E, A190A, L267V, L270V, I337V, and ...
    www.medscape.com/medline/abstract/14871556?prt=true
  • pedigree-ion channel citations
    analysis of Kir6.2/KCNJ11 gene was performed in a pedigree of sudden cardiac ... analyzed, a common polymorphism K23E (A>G) was noticed in this pedigree and the ...
    www.ionchannels.org/showcitationlist.php?keyword=pedigree
  • Susceptibility genes and modifiers for cardiac arrhythmias ...
    Table 3 Non-synonymous polymorphisms (SNPs) in human arrhythmia genes ... KCNJ11. K23E. 0.63/0.37. Caucasians with MI (n = 86) Allele frequencies for all variants: MI ...
    cardiovascres.oxfordjournals.org/cgi/content/full/.../TBL3
  • Susceptibility genes and modifiers for cardiac arrhythmias
    KCNJ11. K23E. L270V. I337V. 0.63 / 0.37. 0.97 / 0.03. 0.63 / 0.37. Caucasians with MI (n = 86) ... Schunkert H, et al. KCNJ11 polymorphisms and sudden cardiac ...
    cardiovascres.oxfordjournals.org/cgi/reprint/67/3/397.pdf

Other in silico analyses
 

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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