Review Article KCNJ11: Genetic Polymorphisms and …downloads.hindawi.com/journals/jdr/2015/908152.pdf · Review Article KCNJ11: Genetic Polymorphisms and Risk of Diabetes Mellitus

Review ArticleKCNJ11 Genetic Polymorphisms and Risk of Diabetes Mellitus

Polin Haghvirdizadeh1 Zahurin Mohamed1 Nor Azizan Abdullah2

Pantea Haghvirdizadeh3 Monir Sadat Haerian45 and Batoul Sadat Haerian1

1Pharmacogenomics Lab Department of Pharmacology Faculty of Medicine University of Malaya 50603 Kuala Lumpur Malaysia2Department of Pharmacology Faculty of Medicine University of Malaya 50603 Kuala Lumpur Malaysia3Department of Biology Faculty of Science Azad University Tehran Iran4Shahid Beheshti University of Medical Sciences PO Box 19395-4763 Tehran Iran5Food and Drug Control Reference Labs Center (FDCRLC) Ministry of Health and Medical Education Tehran 131456-8784 Iran

Correspondence should be addressed to Batoul Sadat Haerian batoolsadatyahoocom

Received 28 June 2014 Revised 18 November 2014 Accepted 27 November 2014

Academic Editor Garth Warnock

Copyright copy 2015 Polin Haghvirdizadeh et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Diabetes mellitus (DM) is a major worldwide health problem and its prevalence has been rapidly increasing in the last centuryIt is caused by defects in insulin secretion or insulin action or both leading to hyperglycemia Of the various types of DM type2 occurs most frequently Multiple genes and their interactions are involved in the insulin secretion pathway Insulin secretion ismediated through the ATP-sensitive potassium (KATP) channel in pancreatic beta cells This channel is a heteromeric proteincomposed of four inward-rectifier potassium ion channel (Kir62) tetramers which form the pore of the KATP channel as well assulfonylurea receptor 1 subunits surrounding the pore Kir62 is encoded by the potassium inwardly rectifying channel subfamilyJ member 11 (KCNJ11) gene a member of the potassium channel genes Numerous studies have reported the involvement of singlenucleotide polymorphisms of the KCNJ11 gene and their interactions in the susceptibility to DMThis review discusses the currentevidence for the contribution of common KCNJ11 genetic variants to the development of DM Future studies should concentrateon understanding the exact role played by these risk variants in the development of DM

1 Introduction

Diabetes mellitus (DM) is a chronic disease characterized byhigh blood glucose levels caused by either insufficient insulinproduction by the pancreas or improper response of the bodycells to insulin [1] Approximately 366 million people werediagnosed with DMworldwide in 2011 and this is expected toincrease to 552 million by 2030 [2] This disease has early-and late-stage complications Early complications includehyperglycemia polyphagia polydipsia polyuria and blurredvision leading to complications manifested later such asvascular disease heart disease stroke peripheral neuropathynephropathy and predisposition to infection [3]

DM is classified into various types of which type 2(T2DM) occurs most frequently Approximately 5ndash10 ofpatients with DM are affected by type 1 (T1DM) and morethan 90 by T2DM T1DM (formerly insulin-dependent

diabetes or juvenile diabetes) results from the autoimmunedestruction of the insulin-producing beta cells in the pan-creas [4] T2DM (formerly noninsulin-dependent DM) isa metabolic disorder due to hyperglycemia in the contextof insulin resistance and relative lack of insulin This is incontrast to T1DM in which there is an absolute lack ofinsulin due to the breakdown of islet cells in the pancreas[5] Gestational DM (GDM) affects 3ndash10of pregnancies invarious populations In this disease insulin receptors do notfunction properly which results in high blood glucose levelsduring pregnancy with subsequent negative effects such asthe baby being large for gestational age being born stillbornor dying shortly after birth or themother having amiscarriageor problems with her eyes and kidneys [6 7]

DM is a multifactorial disease caused by both genetic andenvironmental factors and their complex interaction Envi-ronmental risk factors include obesity physical inactivity

Hindawi Publishing CorporationJournal of Diabetes ResearchVolume 2015 Article ID 908152 9 pageshttpdxdoiorg1011552015908152

2 Journal of Diabetes Research

hypertension abnormal cholesterol levels age and smoking[8] Pathogenic and nonpathogenic mutations in genomicDNA can also contribute to the development of diabetesSeveral single nucleotide polymorphisms (SNPs) which area type of nonpathogenic mutation have been reported to beassociated with susceptibility to different types of DM Theaim of this review is to assess the possible contribution ofSNPs of the gene known as the potassium inwardly rectifyingchannel subfamily J member 11 (KCNJ11) which formsa compartment of the ATP-sensitive potassium (KATP)channel present in beta cells of the islets in the susceptibilityto different types of DM

2 Role of Genetics in the Development of DM

People with a family history of T1DM and T2DM are sixand three times more likely respectively to develop thesediseases than are unrelated individuals [9] Multiple genesare involved in DM Those that have garnered the mostattention are the ATP-binding cassette transporter subfamilyC member 8 (ABCC8) gene the KCNJ11 gene and theperoxisome proliferator-activated receptor-gamma (PPARG)gene Most of these genes are involved in insulin actionglucose metabolism pancreatic beta cell function or othermetabolic conditions (eg energy intakeexpenditure lipidmetabolism) [10] Mutations in genes such as ABCC8 andKCNJ11 can disrupt the potentiation activity of the KATPchannel and have thus been associated with permanentneonatal DM [11] The PPARG gene is implicated in adipoge-nesis and the development of insulin resistance Deleteriousmutations in this gene impair insulin resistance and can causelack of response to insulin [12]

From recent genome-wide association studies more than60 500 and 65 loci have been identified for susceptibilityto T1DM T2DM and GDM respectively [13] SNPs are themost common type of genetic variation distributed within oroutside a gene region in the human genomeThe frequency ofSNPs is less than 1 in the genome and approximately 54of these variants are not deleterious [14] SNPs can modifythe risk of occurrence of a disease either alone or in linkagedisequilibrium in one gene or in neighborhood genes Forinstance in several studies the common Pro12Ala polymor-phism in the PPARGgene theGlu23Lys polymorphism in theKCNJ11 gene or the Ser1369Ala polymorphism in theABCC8gene was confirmed to be associated with DM [15]

3 KCNJ11 Gene and Its Product

The KCNJ11 gene a member of the potassium channel genefamily is located at 11p151 and has no intron (Figure 117385237ndash17389331) This gene encodes an inward-rectifierpotassium ion channel (Kir62) The Kir62 protein togetherwith the high-affinity sulfonylurea receptor 1 (SUR1) formsthe KATP channel SUR1 is encoded by the ABCC8 genelocated next to the KCNJ11 gene The Kir62 protein is a 390-amino acid protein with two transmembrane domains (M1and M2) and intracellular N- and C-terminals StructurallyKir62 tetramers form the pore and four high-affinity SUR1subunits surround the pore of the KATP channel located at

the plasma membrane of pancreatic beta cells This channelmodulates insulin production and secretion through glucosemetabolism [16]

31 Role of Kir62 in Insulin Secretion The Kir62 pro-tein coupled with the SUR1 protein in the KATP channelmediates insulin secretion This channel is involved in awide range of physiological responses Increased glucoseinduces higher potassium flow into the cell through theKATP channel ADP in the presence of magnesium (Mg)converts to ATP the ATP then closes the KATP channelby binding to Kir62 increasing the intracellular potassiumion concentration which depolarizes the cell membrane andsubsequently activates calcium ion (Ca2+) channel Ca2+ isa ubiquitous intracellular second messenger that is criticalfor cellular functioning These calcium channels influencethe voltage-dependent potassium channels to repolarize thecell membrane leading to closure of the voltage-dependentcalcium channels Increased intracellular free Ca2+ levelstrigger other components of the insulin secretion pathway torelease granules at or near the plasma membrane (Figure 2)Mutations in the KCNJ11 gene can cause DM because of thereduced ability of ATP to inhibit the activity of the KATPchannel and the enhanced ability of MgATP to simultane-ously stimulate the function of this channelThis is associatedwith defective insulin secretion ultimately causing DM [17]

32 KCNJ11 Common Polymorphisms Involved in DiabetesKCNJ11 has 219 SNPs six of which have been receivingmore attention for their association with diabetes Amongthese six common SNPs three are located in the codingregions and three in the noncoding regions (Table 1) Thesesix SNPs include rs5219 rs5215 rs5210 rs5218 rs886288 andrs2285676

321 KCNJ11 rs5219 This locus is located in exon 1 of theKCNJ11 gene Substitution of A to C (AAGrarrCAG) changesthe amino acid from lysine to glutamine (Lys23Gln) at theNH2-terminal tail of Kir62 Lysine has a positively chargedepsilon-amino group whereas glutamine is uncharged underall biological conditionsDespite this amino acid substitutiontheoretically it does not make a remarkable change in thestructure and function of the KCNJ11 protein [18] Studieshave shown however that the rs5219 variant may alter thecharge of the ATP-binding region and decrease channelsensitivity to ATP Twenty-four association studies and arecent meta-analysis showed a strong relationship betweenthe rs5219 polymorphism and susceptibility to T2DM [19ndash43] whereas 21 studies did not confirm this finding [44ndash64]Thismeta-analysis showed that the rs5219 polymorphismis a risk factor for developing T2DM in Caucasians and insome Asian populations Populations from East Asia weremore prone to this disease where the A allele frequency inmost patients was more common than in controlsThereforegenetic background can affect susceptibility to T2DM [65]

The rs5219 polymorphism can affect the insulin secretionpathway The A allele of this locus impairs this pathwayby reducing ATP sensitivity of the KATP channel hence

Journal of Diabetes Research 3

Table 1 Characteristics of KCNJ11 gene variants in association with diabetes mellitus

Number SNP Location MAF Allele Amino acid Diabetes Association ReferencesChromosome Gene

1 rs2285676 17386478 31015840 UTR 046 TgtC mdash T2DM Yes [30]

2 rs5210 17386704 31015840 UTR 046 GgtA mdash T2DM Yes [30 36 76]No [72 74]

3 rs5215 17387083 Exon 028 GgtA Val250IleT2DM Yes [27 30 35 36]

No [49 50 69ndash72]T1DM No [73 74]GDM No [68]

4 rs5218 17387522 Exon 027 CgtT Ala103Ala T2DM No [36]

5 rs5219 17388025 Exon 027 GgtA Lys23Gln

T1DM No [63 64]

T2DM Yes [19ndash43]No [44ndash64]

GDM Yes [38]No [66ndash68]

6 rs886288 17389616 51015840 near gene 046 TgtC mdash T2DM Yes [36]MAF minor allele frequency T1DM type 1 diabetes mellitus T2DM type 2 diabetes mellitus GDM gestational diabetes mellitus SNP single nucleotidepolymorphism UTR untranslated region

NSUR1Kir62

C N

NBD2 NBD1

A AB BC

Increased glucose metabolism increasesATP levels and thus inhibits SUR1leading to closure of KATP channel

Open Close

Chromosome 11

p151

ABCC8 geneKCNJ11 gene

Figure 1 ABCC8 and KNJ11 genes and their encoded proteins and functions The KCNJ11 and ABCC8 genes are next to each other onchromosome 11p151 KCNJ11 is a single exon (dark box) gene encoding the Kir62 protein and ABCC8 has 35 exons (dark boxes) encodingthe SUR1 protein both are subunits of the ATP-sensitive potassium (KATP) channel Metabolism of glucose can affect ATP levels and therebythe function of the KATP channel ABCC8 ATP-binding cassette transporter subfamily Cmember 8 KCNJ11 potassium inwardly-rectifyingchannel subfamily J member 11 Kir62 inward-rectifier potassium ion channel SUR1 sulfonylurea receptor 1 NBD1 nucleotide-bindingdomain 1 NBD2 nucleotide-binding domain 2 N NH2 terminal of protein C COOH terminal of protein A Walker A motif B Walker Bmotif cAMP cyclic adenosine monophosphate ATP adenosine triphosphate


SUR1Kir 62

Insulin secretion

120573 1205751205721

1205722

120574

Ca2+

K+

K+ATP

Glucose

Figure 2 Mechanism of insulin secretion by the KATP channel inpancreatic beta cells The Kir62 and SUR1 proteins in the KATPchannel mediate insulin secretion An increase in glucose levelsstimulates the KATP channel to allow the entry of potassium ionsAn increase in intracellular potassium ions depolarizes the cellmembrane and induces calcium channels to increase intracellularfree Ca2+ levels The calcium ions trigger other components ofthe insulin secretion pathway to release granules at or near theplasmamembrane KATP ATP-sensitive potassium channel Kir62inward-rectifier potassium ion channel SUR1 sulfonylurea receptor1 ATP adenosine triphosphate K+ potassium ion Ca2+ calciumionThe calcium channel is composed of 120572

1 1205722 120573 120574 and 120575 subunits

resulting in overactivity of the channel and subsequent sup-pression of insulin secretion This effect on insulin secretionis more significant in carriers of the AA genotype comparedwith carriers of the GA genotype [30] Similar results wereobserved for fasting plasma glucose and postprandial plasmaglucose levels in patients with T2DM The A allele increasedthe fasting plasma glucose and postprandial plasma glucoselevels in these patients whereas GA carriers had higher 2 hpostprandial plasma glucose levels than did GG carriers withT2DM [32 38]This allele was also associated with reductionin serum insulin levels in a postoral glucose tolerance test[39] In contrast to one study from Scandinavia on GDMrisk [37] the remaining studies did not report any associationbetween this locus and T1DM and GDM [66ndash68]

Hypertension is a main complication of T2DM Thers5219 polymorphism plays a strong role in HbA1c and bloodpressure levels in this disease The A allele carriers of rs5219had higher HbA1c levels and blood pressure than did the Gallele carriers [33 35 36 40 41] In T2DM a relationship hasbeen suggested between the A allele and increased hepatitisinsulin sensitivity [32] Pharmacogenomics studies demon-strated that A allele carriers of the rs5219 polymorphism whohave T2DM have better therapeutic response to gliclazidethan do G allele carriers In the A allele group HbA1c wasalso reduced more in patients taking glimepiride and gliben-clamide than it was in patients taking gliclazide treatment

[40] The ring-fused pyrrole moiety in these two drugs bindsto the A allele underling the inhibitory potency of thesedrugs on KATP channels [41]The rs5219 polymorphism alsoplays a role in determining the efficacy of repaglinide [33 39]Carriers of the C allele were also found to have a reducedresponse to sulfonylurea therapy [42 43]

322 KCNJ11 rs5215 The rs5215 polymorphism is locatedin exon 1 of the KCNJ11 gene It is a nonsynonymousvariant caused by a substitution of G to A (GTCrarrATC)which changes the amino acid from valine to isoleucineat residue 250 Valine is hydrophobic whereas isoleucineis one of three amino acids having branched hydrocarbonside chains Isoleucine is usually interchangeable with leucineand occasionally with valine in proteins Of 13 studies onDM 3 showed strong associations between this variant andT2DM [27 30 35] whereas the remaining studies showed noassociation with T2DM T1DM or GDM [36 49ndash51 69ndash74]In another study the rs5215 polymorphism was associatedwith blood pressure among subjects with T2DM [36]

323 KCNJ11 rs5210 Thers5210 polymorphism is located at ahighly conserved 31015840 untranslated region (UTR) of the KCNJ11gene Of four reports relevant to susceptibility to T2DM twoidentified a plausible role in development of this diseasewhereas the other studies did not confirm this relationship[30 36 72 75] A study found that this variant improvesthe clinical efficacy of gliclazide in patients with T2DM [76]This locus is a target of miR-1910 however the mechanismof action of this miRNA in the development of DM isunknown MiRNAs encompass 17 to 25 nucleotides whichposttranscriptionally regulate the expression of thousandsof genes in a broad range of organisms in both normalphysiological and disease contexts Appropriate secretionof insulin from pancreatic beta cells is a vital factor inblood glucose homeostasis andmiRNAs have been identifiedas being involved in the regulation of insulin exocytosisMiRNAs control insulin synthesis and release it in beta cellsThe G allele is a potential target for miR-1910 whereas the Aallele abolishes binding of this miRNA to this region [77 78]Further studies may reveal the role of miR-1910 in DM

324 KCNJ11 rs5218 The rs5218 polymorphism is located inthe 31015840-UTR of the KCNJ11 gene It is a synonymous variantwith a substitution of G to A (GCCrarrGCT) which encodesfor alanine at residue 103 a hydrophobic and ambivalentamino acid There is only one report of this locus in DMwhich showed no association with T2DM risk [36]

325 KCNJ11 rs886288 and rs2285676 The rs886288 poly-morphism is located in the 51015840 flank near the gene whereasthe rs2285676 polymorphism is located at the 31015840-UTR regionTwo studies revealed an association of the rs886288 andrs2285676 polymorphisms with T2DM [30 36]

33 Interaction of the KCNJ11 Gene with Other Genes Insu-lin secretion from pancreatic beta cells can be modulatedby a complex cluster of proteins encoded by related genes


ENSAPRKACG

KCN11ABCC8

CACNA1ACACNA1BCACNA1CCACNA1DCACNA1ECACNA1G

ABCC9

Genes encoding cell membrane proteins

Genes encoding intracellular proteins

Genes encoding KATP channel

Figure 3 Cross-talk between the KCNJ11 gene and the other genesinvolved in the regulation of insulin secretion in pancreatic betacells KCNJ11 interacts with many genes of which 10 are mostprominent KCNJ11 interacts with ABCC8 to produce the KATPchannel which transfers potassium ions across the beta cells TheKCNJ11 and ABCC8 genes interact with three groups of geneproducts at the cell membrane (white) and the intracellular (darkgray) levels KATP ATP-sensitive potassium channel CACNA1Acalcium channel voltage-dependent PQ type alpha 1A subunitCACNA1B calcium channel voltage-dependent N type alpha 1Bsubunit CACNA1C calcium channel voltage-dependent L typealpha 1C subunit CACNA1D calcium channel voltage-dependentL type alpha 1D subunit CACNA1E calcium channel voltage-dependent R type alpha 1E subunit CACNA1G calcium channelvoltage-dependent T type alpha 1G subunit ABCC9 ATP-bindingcassette transporter subfamily C member 9 KCNJ11 potassiuminwardly rectifying channel subfamily J member 11 ABCC8ATP-binding cassette transporter subfamily C member 8 ENSAendosulfine alpha PRKACG protein kinase catalytic subunit GRAPGEF4 rap guanine nucleotide exchange factor 4 FOXA2forkhead box A2

including KCNJ11 ABCC8 voltage-sensitive calcium chan-nels (VSCCs) ABCC9 protein kinase catalytic subunitG (PRKACG) rap guanine nucleotide exchange factor 4(RAPGEF4) forkhead box A2 (FOXA2) and endosulfinealpha (ENSA) These proteins act at the cell membrane orintracellular level (Figure 3)

331 Interactions at the Cell Membrane Level KCNJ11 andABCC8 genes encode Kir62 and Sur1 respectively in pan-creatic beta cells Both proteins form compartments in theKATP channels which allow potassium to flow into the cellrather than out of it asmediated byGproteins [17]TheKATPchannel interacts with different types of VSCCs includingL (long-lasting) N (neural) PQ (purkinje) R (residual)and T (transient) Calcium channels are generally composedof four subunits 120572

1 1205722-120575 120573 and 120574 The function of the

calcium channel is controlled by the pore-forming1205721subunit

which blocks the entry of calcium ions into the excitable cellsand by the auxiliary subunits which modulate traffickingand the biophysical properties of the 120572

1subunit The 120572

1

subunit isoforms include A B C D E and G encoded byCACNA1A CACNA1B CACNA1C CACNA1D CACNA1Eand CACNA1G genes respectively The A to E forms ofthe 1205721subunit produce various types of calcium channels

including PQ N L L R and T respectively The L N PQ

and R types of these channels belong to the high-voltageactivated (HVA) group and the T type belongs to the low-voltage activated (LVA) group BothHVA and LVA groups areinvolved in calcium-dependent processes such as neurotrans-mitter or hormone release muscle contraction cell motilitygene expression cell division and cell death [78 79] FinallyKir2 and ABCC9 can form another type of KATP channel incardiac skeletal vascular and nonvascular smooth muscleThe structure of the ABCC9 protein suggests a role as a drug-binding channel-modulating subunit of the extrapancreaticKATP channels [80]

332 Interactions at the Intracellular Level The KATP chan-nels interact with the PRKACG protein encoded by thePRKACG gene This protein is the gamma catalytic subunitof protein kinase which is involved in exocytosis throughdifferent pathways such as calcium- and hormone-mediatedsignaling This protein also activates cellular processessuch as intracellular protein kinase A [81] Kir62 interactswith RAPGEF4 FOXA2 and ENSA proteins encoded byRAPGEF4 FOXA2 ENSA and ABCC9 genes respectivelyRAPGEF4 is an exchange protein that can be activatedby cAMP FOXA2 functions as a transcription activatorfor genes such as alpha-fetoprotein albumin and tyrosineaminotransferase ENSA is an endogenous ligand for SUR1which stimulates insulin secretion [82ndash84] Defects in theKCNJ11 gene may also lead to autosomal-dominant T2DMtransient neonatal DM type 3 and permanent neonatal DM[85]

4 Concluding Remarks

DM is one of the most common diseases globally with highsocial and economic burdens Kir62 plays a potential role inthe function of the KATP channel Some active mutationsin this gene can disrupt Kir62 activity and consequentlyreduce the potential of the KATP channel leading to DMIt is evident from the literature that several variants of theKCNJ11 gene are associated with different types of DM Thisraises the question of which polymorphisms of the KCNJ11gene and their combinations play more prominent roles inthe development of DM

Most previous studies have focused on six common poly-morphisms in DM rs5210 rs5215 rs5218 rs5219 rs886288and rs2285676 Of these six loci rs5219 rs5215 and rs5210have been given most attention No evidence yet exists in theliterature for the involvement of other SNPs of the KCNJ11gene The rs5219 A allele plays an important role in insulinsecretion through reduction of ATP sensitivity of the KATPchannel and suppression of insulin secretion However themechanism of action of this locus in the insulin secretionpathway is still not completely understoodThe rs5210G alleleacts as a potential target for miR-1910 which is implicatedin T2DM however the mechanism of action of this miRNAin the development of DM is unknown MiRNAs controlinsulin synthesis and release from beta cells Future studiesare suggested to reveal the use of miR-1910 as a potential


biomarker in the diagnosis of diabetes and its plausibleapplication for treatment of DM

Regulation of insulin release is mediated by KCNJ11 inconcert with different genes such as ABCC8 ABCC9 andCACNA1A-G Diminished coexpression of these genes mayincrease the risk of DM Nevertheless the exact functionalrelationship of the network of these genes in the regulation ofinsulin release remains to be determined Future studies aresuggested to discover the exact role of KCNj11 gene variantsand their interaction with other genes in DM for the possibledevelopment of suitable therapies and the diagnosis of thiscommon disease

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This study was supported by Malaysian Grants HIR MOHEE000025-20001 UMC6251HIR161 RG 52013HTM andRG05609HTM

References

[1] T J Wilkin ldquoThe accelerator hypothesis a review of theevidence for insulin resistance as the basis for type I as well astype II diabetesrdquo International Journal of Obesity vol 33 no 7pp 716ndash726 2009

[2] D G Gardner and D M Shoback Eds Greenspanrsquos Basic ampClinical Endocrinology McGraw-Hill Medical New York NYUSA 2007

[3] P Z Zimmet D J Magliano W H Herman and J E ShawldquoDiabetes a 21st century challengerdquo The Lancet Diabetes andEndocrinology vol 2 no 1 pp 56ndash64 2014

[4] V Kumar A K Abbas N Fausto and J C Aster Robbins andCotran Pathologic Basis of Disease Professional Edition ExpertConsult-Online Elsevier Health Sciences 2009

[5] D W Cooke and L Plotnick ldquoType 1 diabetes mellitus inpediatricsrdquo Pediatrics in Review vol 29 no 11 pp 374ndash3852008

[6] E A Ryan and L Enns ldquoRole of gestational hormones inthe induction of insulin resistancerdquo The Journal of ClinicalEndocrinology amp Metabolism vol 67 no 2 pp 341ndash347 1988

[7] S Prudente B Dallapiccola F Pellegrini A Doria and VTrischitta ldquoGenetic prediction of common diseases still nohelp for the clinical diabetologistrdquo Nutrition Metabolism andCardiovascular Diseases vol 22 no 11 pp 929ndash936 2012

[8] D Sluik H Boeing K Li et al ldquoLifestyle factors and mortalityrisk in individuals with diabetes mellitus are the associationsdifferent from those in individuals without diabetesrdquo Dia-betologia vol 57 no 1 pp 63ndash72 2014

[9] J S Dorman and C H Bunker ldquoHLA-DQ locus of the humanleukocyte antigen complex and type 1 diabetesmellitus a HuGEreviewrdquo Epidemiologic Reviews vol 22 no 2 pp 218ndash227 2000

[10] R W Schwenk H Vogel and A Schurmann ldquoGenetic andepigenetic control of metabolic healthrdquo Molecular Metabolismvol 2 no 4 pp 337ndash347 2013

[11] M A Abujbara M I Liswi M S El-Khateeb S E FlanaganS Ellard and K M Ajlouni ldquoPermanent neonatal diabetesmellitus in Jordanrdquo Journal of Pediatric Endocrinology andMetabolism vol 27 no 9-10 pp 879ndash883 2014

[12] A K Pattanayak B Bankura N Balmiki T K Das SChowdhury and M Das ldquoRole of peroxisome proliferator-activated receptor gamma gene polymorphisms in type 2diabetes mellitus patients of West Bengal Indiardquo Journal ofDiabetes Investigation vol 5 no 2 pp 188ndash191 2014

[13] M-F Hivert J L Vassy and J B Meigs ldquoSusceptibility to type2 diabetes mellitusmdashfrom genes to preventionrdquoNature ReviewsEndocrinology vol 10 no 4 pp 198ndash205 2014

[14] A A Mitchell A Chakravarti and D J Cutler ldquoOn theprobability that a novel variant is a disease-causing mutationrdquoGenome Research vol 15 no 7 pp 960ndash966 2005

[15] J E Bailey-Wilson and A F Wilson ldquoLinkage analysis in thenext-generation sequencing erardquo Human Heredity vol 72 no4 pp 228ndash236 2011

[16] J S McTaggart R H Clark and F M Ashcroft ldquoThe role ofthe KATP channel in glucose homeostasis in health and diseasemore thanmeets the isletrdquo Journal of Physiology vol 588 no 17pp 3201ndash3209 2010

[17] FM Ashcroft ldquoKATP channels and insulin secretion a key rolein health and diseaserdquo Biochemical Society Transactions vol 34no 2 pp 243ndash246 2006

[18] MHarakalova J J T VanHarssel P A Terhal et al ldquoDominantmissense mutations in ABCC9 cause Cantusyndromerdquo NatureGenetics vol 44 no 7 pp 793ndash796 2012

[19] I Abdelhamid K Lasram G Meiloud et al ldquoE23K variant inKCNJ11 gene is associated with susceptibility to type 2 diabetesin the Mauritanian populationrdquo Primary Care Diabetes vol 8no 2 pp 171ndash175 2014

[20] G Chen Y Xu Y Lin et al ldquoAssociation study of geneticvariants of 17 diabetes-related genesloci and cardiovascularrisk and diabetic nephropathy in the Chinese She populationrdquoJournal of Diabetes vol 5 no 2 pp 136ndash145 2013

[21] C Hu R Zhang C Wang et al ldquoPPARG KCNJ11 CDKAL1CDKN2A-CDKN2B IDE-KIF11- HHEX IGF2BP2 andSLC30A8 are associated with type 2 diabetes in a chinesepopulationrdquo PLoS ONE vol 4 no 10 Article ID e7643 2009

[22] D Zhou D Zhang Y Liu et al ldquoThe E23K variation in theKCNJ11 gene is associated with type 2 diabetes in Chinese andEast Asian populationrdquo Journal of Human Genetics vol 54 no7 pp 433ndash435 2009

[23] Y Tabara H Osawa R Kawamoto et al ldquoReplication studyof candidate genes associated with type 2 diabetes based ongenome-wide screeningrdquo Diabetes vol 58 no 2 pp 493ndash4982009

[24] M M Sale S G Smith J C Mychaleckyj et al ldquoVariants of thetranscription factor 7-like 2 (TCF7L2) gene are associated withtype 2 diabetes in anAfrican-American population enriched fornephropathyrdquo Diabetes vol 56 no 10 pp 2638ndash2642 2007

[25] M N Weedon M I McCarthy G Hitman et al ldquoCombininginformation from common type 2 diabetes risk polymorphismsimproves disease predictionrdquo PLoS Medicine vol 3 no 10Article ID e374 2006

[26] N Mtiraoui A Turki R Nemr et al ldquoContribution of com-mon variants of ENPP1 IGF2BP2 KCNJ11 MLXIPL PPAR120574SLC30A8 and TCF7L2 to the risk of type 2 diabetes in Lebaneseand TunisianArabsrdquoDiabetes andMetabolism vol 38 no 5 pp444ndash449 2012


[27] S Chavali A Mahajan R Tabassum et al ldquoAssociation ofvariants in genes involved in pancreatic Β-cell developmentand function with type 2 diabetes in North Indiansrdquo Journal ofHuman Genetics vol 56 no 10 pp 695ndash700 2011

[28] F Wang X-Y Han Q Ren et al ldquoEffect of genetic variants inKCNJ11 ABCC8 PPARG and HNF4A loci on the susceptibilityof type 2 diabetes in Chinese Han populationrdquo Chinese MedicalJournal vol 122 no 20 pp 2477ndash2482 2009

[29] O Alsmadi K Al-Rubeaan S M Wakil et al ldquoGenetic Studyof Saudi Diabetes (GSSD)significant association of the KCNJ11E23Kpolymorphismwith type 2 diabetesrdquoDiabetesMetabolismResearch and Reviews vol 24 no 2 pp 137ndash140 2008

[30] Z Liu Y-W Zhang Q-P Feng et al ldquoAssociation analysis of30 type 2 diabetes candidate genes in Chinese Han populationrdquoActa Academiae Medicinae Sinicae vol 28 no 2 pp 124ndash1282006

[31] J Vangipurapu A Stancakova J Pihlajamaki et al ldquoAssociationof indices of liver and adipocyte insulin resistance with 19confirmed susceptibility loci for type 2 diabetes in 6733 non-diabetic finnish menrdquo Diabetologia vol 54 no 3 pp 563ndash5712011

[32] M S Gonen H Arikoglu D Erkoc Kaya et al ldquoEffects of singlenucleotide polymorphisms in KATP channel genes on type 2diabetes in a Turkish populationrdquo Archives of Medical Researchvol 43 no 4 pp 317ndash323 2012

[33] Y-Y He R Zhang X-Y Shao et al ldquoAssociation of KCNJ11 andABCC8 genetic polymorphisms with response to repaglinide inChinese diabetic patientsrdquo Acta Pharmacologica Sinica vol 29no 8 pp 983ndash989 2008

[34] D A Chistiakov V A Potapov D C Khodirev M SShamkhalova M V Shestakova and V V Nosikov ldquoGeneticvariations in the pancreatic ATP-sensitive potassium channel120573-cell dysfunction and susceptibility to type 2 diabetesrdquo ActaDiabetologica vol 46 no 1 pp 43ndash49 2009

[35] Y Sakamoto H Inoue P Keshavarz et al ldquoSNPs in the KCNJ11-ABCC8 gene locus are associatedwith type 2 diabetes and bloodpressure levels in the Japanese populationrdquo Journal of HumanGenetics vol 52 no 10 pp 781ndash793 2007

[36] B K Koo Y M Cho B L Park et al ldquoPolymorphisms ofKCNJ11 (Kir62 gene) are associated with type 2 diabetes andhypertension in the Korean populationrdquoDiabetic Medicine vol24 no 2 pp 178ndash186 2007

[37] E-M D Nielsen L Hansen B Carstensen et al ldquoThe E23Kvariant of Kir62 associates with impaired post-OGTT seruminsulin response and increased risk of type 2 diabetesrdquoDiabetesvol 52 no 2 pp 573ndash577 2003

[38] N Shaat M Ekelund A Lernmark et al ldquoAssociation ofthe E23K polymorphism in the KCNJ11 gene with gestationaldiabetes mellitusrdquo Diabetologia vol 48 no 12 pp 2544ndash25512005

[39] M Yu X-J Xu J-Y Yin et al ldquoKCNJ11 Lys23Glu and TCF7L2rs290487(CT) polymorphisms affect therapeutic efficacy ofrepaglinide in Chinese patients with type 2 diabetesrdquo ClinicalPharmacology andTherapeutics vol 87 no 3 pp 330ndash335 2010

[40] M Javorsky L Klimcakova Z Schroner et al ldquoKCNJ11 geneE23K variant and therapeutic response to sulfonylureasrdquo Euro-pean Journal of Internal Medicine vol 23 no 3 pp 245ndash2492012

[41] V Y Lang M Fatehi and P E Light ldquoPharmacogenomicanalysis of ATP-sensitive potassium channels coexpressing the

common type 2 diabetes risk variants E23K and S1369ArdquoPharmacogenetics and Genomics vol 22 no 3 pp 206ndash2142012

[42] A Holstein M Hahn M Stumvoll and P Kovacs ldquoThe E23Kvariant of KCNJ11 and the risk for severe sulfonylurea-inducedhypoglycemia in patients with type 2 diabetesrdquo Hormone andMetabolic Research vol 41 no 5 pp 387ndash390 2009

[43] A E El-sisi S K Hegazy S S Metwally A M Wafa and N ADawood ldquoEffect of genetic polymorphisms on the developmentof secondary failure to sulfonylurea in egyptian patients withtype 2 diabetesrdquo Therapeutic Advances in Endocrinology andMetabolism vol 2 no 4 pp 155ndash164 2011

[44] P Keshavarz R Habibipour M Ghasemi E Kazemnezhad MAlizadeh and M H Omami ldquoLack of genetic susceptibility ofKCNJ11 E23K polymorphism with risk of type 2 diabetes in anIranian populationrdquo Endocrine Research vol 39 no 3 pp 120ndash125 2014

[45] I Danquah T Othmer L K Frank G Bedu-Addo M BSchulze and F P Mockenhaupt ldquoThe TCF7L2 rs7903146 (T)allele is associated with type 2 diabetes in urban Ghana ahospital-based case-control studyrdquo BMC Medical Genetics vol14 article 96 2013

[46] M A Gamboa-Melendez A Huerta-Chagoya H Moreno-Macıas et al ldquoContribution of common genetic variation tothe risk of type 2 diabetes in the Mexican Mestizo populationrdquoDiabetes vol 61 no 12 pp 3314ndash3321 2012

[47] M Iwata S Maeda Y Kamura et al ldquoGenetic risk scoreconstructed using 14 susceptibility alleles for type 2 diabetesis associated with the early onset of diabetes and may predictthe future requirement of insulin injections among Japaneseindividualsrdquo Diabetes Care vol 35 no 8 pp 1763ndash1770 2012

[48] G Ragia A Tavridou I Petridis and V G Manolopou-los ldquoAssociation of KCNJ11 E23K gene polymorphism withhypoglycemia in sulfonylurea-treated type 2 diabetic patientsrdquoDiabetes Research and Clinical Practice vol 98 no 1 pp 119ndash124 2012

[49] K Hotta A Kitamoto T Kitamoto et al ldquoAssociation betweentype 2 diabetes genetic susceptibility loci and visceral andsubcutaneous fat area as determined by computed tomographyrdquoJournal of Human Genetics vol 57 no 5 pp 305ndash310 2012

[50] Z Odgerel H S Lee N Erdenebileg et al ldquoGenetic variantsin potassium channels are associated with type 2 diabetes ina Mongolian populationrdquo Journal of Diabetes vol 4 no 3 pp238ndash242 2012

[51] H J Cho S Y Lee Y G Kim et al ldquoEffect of genetic polymor-phisms on the pharmacokinetics and efficacy of glimepiride ina Korean populationrdquo Clinica Chimica Acta vol 412 no 19 pp1831ndash1834 2011

[52] R J Webster N M Warrington J P Beilby T M Fraylingand L J Palmer ldquoThe longitudinal association of commonsusceptibility variants for type 2 diabetes and obesity withfasting glucose level and BMIrdquo BMC Medical Genetics vol 11article 140 2010

[53] T E Meyer E Boerwinkle A C Morrison et al ldquoDiabetesgenes and prostate cancer in the atherosclerosis risk in commu-nities studyrdquo Cancer Epidemiology Biomarkers and Preventionvol 19 no 2 pp 558ndash565 2010

[54] N Nikolac A-M Simundic D Katalinic E Topic A Cipakand V Zjacic Rotkvic ldquoMetabolic control in type 2 diabetes isassociated with sulfonylurea receptor-1 (SUR-1) but not with


KCNJ11 polymorphismsrdquo Archives of Medical Research vol 40no 5 pp 387ndash392 2009

[55] I Ezzidi N Mtiraoui S Cauchi et al ldquoContribution of type 2diabetes associated loci in the Arabic population from Tunisiaa case-control studyrdquo BMC Medical Genetics vol 10 article 332009

[56] P M Thorsby K Midthjell N Gjerlaugsen et al ldquoComparisonof genetic risk in three candidate genes (TCF7L2 PPARGKCNJ11) with traditional risk factors for type 2 diabetes ina population-based studymdashThe HUNT studyrdquo ScandinavianJournal of Clinical and Laboratory Investigation vol 69 no 2pp 282ndash287 2009

[57] P Christopoulos G Mastorakos M Gazouli et al ldquoGeneticvariants in TCF7L2 and KCNJ11 genes in a Greek populationwith polycystic ovary syndromerdquo Gynecological Endocrinologyvol 24 no 9 pp 486ndash490 2008

[58] DK Sanghera LOrtega SHan et al ldquoImpact of nine commontype 2 diabetes risk polymorphisms in Asian Indian SikhsPPARG2 (Pro12Ala) IGF2BP2 TCF7L2 and FTO variantsconfer a significant riskrdquo BMC Medical Genetics vol 9 article59 2008

[59] S Cauchi K T Nead H Choquet et al ldquoThe genetic suscep-tibility to type 2 diabetes may be modulated by obesity statusimplications for association studiesrdquoBMCMedical Genetics vol9 article 45 2008

[60] V Lyssenko P Almgren D Anevski et al ldquoGenetic predictionof future type 2 diabetesrdquo PLoS Medicine vol 2 no 12 ArticleID e345 2005

[61] O Laukkanen J Pihlajamaki J Lindstrom et al ldquoPolymor-phisms of the SUR1 (ABCC8) and Kir62 (KCNJ11) genespredict the conversion from impaired glucose tolerance to type2 diabetes The Finnish Diabetes Prevention Studyrdquo Journal ofClinical Endocrinology andMetabolism vol 89 no 12 pp 6286ndash6290 2004

[62] R J Neuman J Wasson G Atzmon et al ldquoGene-gene interac-tions lead to higher risk for development of type 2 diabetes in anAshkenazi Jewish populationrdquo PLoS ONE vol 5 no 3 ArticleID e9903 2010

[63] J M Ko S Yang S Y Kim H S Lee J S Hwang and I THwang ldquoE23K polymorphism of the KCNJ11 gene in Koreanchildren with type 1 diabetesrdquo World Journal of Pediatrics vol8 no 2 pp 169ndash172 2012

[64] S M Raj J M Howson N M Walker et al ldquoNo association ofmultiple type 2 diabetes loci with type 1 diabetesrdquo Diabetologiavol 52 no 10 pp 2109ndash2116 2009

[65] L Qiu R Na R Xu et al ldquoQuantitative assessment of the effectof KCNJ11 gene polymorphism on the risk of type 2 diabetesrdquoPLoS ONE vol 9 no 4 Article ID e93961 2014

[66] K I Pappa M Gazouli K Economou et al ldquoGestationaldiabetes mellitus shares polymorphisms of genes associatedwith insulin resistance and type 2 diabetes in the GreekpopulationrdquoGynecological Endocrinology vol 27 no 4 pp 267ndash272 2011

[67] M Ekelund N Shaat P Almgren et al ldquoGenetic predictionof postpartum diabetes in women with gestational diabetesmellitusrdquo Diabetes Research and Clinical Practice vol 97 no 3pp 394ndash398 2012

[68] Y M Cho T H Kim S Lim et al ldquoType 2 diabetes-associatedgenetic variants discovered in the recent genome-wide associ-ation studies are related to gestational diabetes mellitus in the

Korean populationrdquo Diabetologia vol 52 no 2 pp 253ndash2612009

[69] M Kurzawski K Dziewanowski J Łapczuk A Wajda and MDrozdzik ldquoAnalysis of common type 2 diabetes mellitus geneticrisk factors in new-onset diabetes after transplantation in kid-ney transplant patients medicated with tacrolimusrdquo EuropeanJournal of Clinical Pharmacology vol 68 no 12 pp 1587ndash15942012

[70] M Heni C Ketterer C Thamer et al ldquoGlycemia determinesthe effect of type 2 diabetes risk genes on insulin secretionrdquoDiabetes vol 59 no 12 pp 3247ndash3252 2010

[71] Y Lin P Li L Cai et al ldquoAssociation study of genetic variantsin eight genesloci with type 2 diabetes in a Han Chinesepopulationrdquo BMCMedical Genetics vol 11 article 97 2010

[72] M Cruz A Valladares-Salgado J Garcia-Mena et al ldquoCandi-date gene association study conditioning on individual ancestryin patients with type 2 diabetes and metabolic syndrome fromMexico cityrdquo DiabetesMetabolism Research and Reviews vol26 no 4 pp 261ndash270 2010

[73] C Winkler J Raab H Grallert and A-G Ziegler ldquoLack ofassociation of type 2 diabetes susceptibility genotypes and bodyweight on the development of islet autoimmunity and type 1diabetesrdquo PloS ONE vol 7 no 4 Article ID e35410 2012

[74] S Sanda SWei T Rue H Shilling and C Greenbaum ldquoA SNPin G6PC2 predicts insulin secretion in type 1 diabetesrdquo ActaDiabetologica vol 50 no 3 pp 459ndash462 2013

[75] Y Feng G Mao X Ren et al ldquoSer 1369Ala variant in sul-fonylurea receptor gene ABCC8 is associated with antidiabeticefficacy of gliclazide in Chinese type 2 diabetic patientsrdquoDiabetes Care vol 31 no 10 pp 1939ndash1944 2008

[76] H Xu M Murray and A J McLachlan ldquoInfluence of geneticpolymorphisms on the pharmacokinetics and pharmacody-namics of sulfonylurea drugsrdquo Current Drug Metabolism vol10 no 6 pp 643ndash658 2009

[77] M A S Dehwah A Xu andQ Huang ldquoMicroRNAs and type 2diabetesobesityrdquo Journal of Genetics and Genomics vol 39 no1 pp 11ndash18 2012

[78] M LAlvarez and J KDiStefano ldquoThe role of non-codingRNAsin diabetic nephropathy potential applications as biomarkersfor disease development and progressionrdquo Diabetes Researchand Clinical Practice vol 99 no 1 pp 1ndash11 2013

[79] A C Dolphin ldquoA short history of voltage-gated calciumchannelsrdquo British Journal of Pharmacology vol 147 no 1 ppS56ndashS62 2006

[80] J Bryan A Munoz X Zhang et al ldquoABCC8 and ABCC9ABC transporters that regulate K+ channelsrdquo Pflugers ArchivEuropean Journal of Physiology vol 453 no 5 pp 703ndash718 2007

[81] K Soslashberg T Jahnsen T Rognes B S Skalhegg and J KLaerdahl ldquoEvolutionary paths of the cAMP-dependent proteinkinase (PKA) catalytic subunitsrdquoPLoSONE vol 8 no 4 ArticleID e60935 2013

[82] T M Olson A E Alekseev C Moreau et al ldquoKATP channelmutation confers risk for vein of Marshall adrenergic atrialfibrillationrdquo Nature Clinical Practice Cardiovascular Medicinevol 4 no 2 pp 110ndash116 2007

[83] S V Guttula A Rao G Sridhar M Chakravarthy K Nagesh-wararo and P Rao ldquoCluster analysis and phylogenetic rela-tionship in biomarker identification of type 2 diabetes andnephropathyrdquo International Journal of Diabetes in DevelopingCountries vol 30 no 1 pp 52ndash56 2010


[84] M P Fogarty M E Cannon S Vadlamudi and K J GaultonldquoIdentification of a regulatory variant that binds FOXA1 andFOXA2 at the CDC123CAMK1D type 2 diabetes GWAS locusrdquoPLoS Genetics vol 10 no 9 Article ID e1004633 2014

[85] GAlkorta-AranburuD Carmody YWCheng andVNelaku-diti ldquoPhenotypic heterogeneity inmonogenic diabetes the clin-ical and diagnostic utility of a gene panel-based next-generationsequencing approachrdquo Molecular Genetics and Metabolism2014

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

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Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



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OphthalmologyJournal of


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Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


hypertension abnormal cholesterol levels age and smoking[8] Pathogenic and nonpathogenic mutations in genomicDNA can also contribute to the development of diabetesSeveral single nucleotide polymorphisms (SNPs) which area type of nonpathogenic mutation have been reported to beassociated with susceptibility to different types of DM Theaim of this review is to assess the possible contribution ofSNPs of the gene known as the potassium inwardly rectifyingchannel subfamily J member 11 (KCNJ11) which formsa compartment of the ATP-sensitive potassium (KATP)channel present in beta cells of the islets in the susceptibilityto different types of DM

2 Role of Genetics in the Development of DM

People with a family history of T1DM and T2DM are sixand three times more likely respectively to develop thesediseases than are unrelated individuals [9] Multiple genesare involved in DM Those that have garnered the mostattention are the ATP-binding cassette transporter subfamilyC member 8 (ABCC8) gene the KCNJ11 gene and theperoxisome proliferator-activated receptor-gamma (PPARG)gene Most of these genes are involved in insulin actionglucose metabolism pancreatic beta cell function or othermetabolic conditions (eg energy intakeexpenditure lipidmetabolism) [10] Mutations in genes such as ABCC8 andKCNJ11 can disrupt the potentiation activity of the KATPchannel and have thus been associated with permanentneonatal DM [11] The PPARG gene is implicated in adipoge-nesis and the development of insulin resistance Deleteriousmutations in this gene impair insulin resistance and can causelack of response to insulin [12]

From recent genome-wide association studies more than60 500 and 65 loci have been identified for susceptibilityto T1DM T2DM and GDM respectively [13] SNPs are themost common type of genetic variation distributed within oroutside a gene region in the human genomeThe frequency ofSNPs is less than 1 in the genome and approximately 54of these variants are not deleterious [14] SNPs can modifythe risk of occurrence of a disease either alone or in linkagedisequilibrium in one gene or in neighborhood genes Forinstance in several studies the common Pro12Ala polymor-phism in the PPARGgene theGlu23Lys polymorphism in theKCNJ11 gene or the Ser1369Ala polymorphism in theABCC8gene was confirmed to be associated with DM [15]

3 KCNJ11 Gene and Its Product

The KCNJ11 gene a member of the potassium channel genefamily is located at 11p151 and has no intron (Figure 117385237ndash17389331) This gene encodes an inward-rectifierpotassium ion channel (Kir62) The Kir62 protein togetherwith the high-affinity sulfonylurea receptor 1 (SUR1) formsthe KATP channel SUR1 is encoded by the ABCC8 genelocated next to the KCNJ11 gene The Kir62 protein is a 390-amino acid protein with two transmembrane domains (M1and M2) and intracellular N- and C-terminals StructurallyKir62 tetramers form the pore and four high-affinity SUR1subunits surround the pore of the KATP channel located at

the plasma membrane of pancreatic beta cells This channelmodulates insulin production and secretion through glucosemetabolism [16]

31 Role of Kir62 in Insulin Secretion The Kir62 pro-tein coupled with the SUR1 protein in the KATP channelmediates insulin secretion This channel is involved in awide range of physiological responses Increased glucoseinduces higher potassium flow into the cell through theKATP channel ADP in the presence of magnesium (Mg)converts to ATP the ATP then closes the KATP channelby binding to Kir62 increasing the intracellular potassiumion concentration which depolarizes the cell membrane andsubsequently activates calcium ion (Ca2+) channel Ca2+ isa ubiquitous intracellular second messenger that is criticalfor cellular functioning These calcium channels influencethe voltage-dependent potassium channels to repolarize thecell membrane leading to closure of the voltage-dependentcalcium channels Increased intracellular free Ca2+ levelstrigger other components of the insulin secretion pathway torelease granules at or near the plasma membrane (Figure 2)Mutations in the KCNJ11 gene can cause DM because of thereduced ability of ATP to inhibit the activity of the KATPchannel and the enhanced ability of MgATP to simultane-ously stimulate the function of this channelThis is associatedwith defective insulin secretion ultimately causing DM [17]

32 KCNJ11 Common Polymorphisms Involved in DiabetesKCNJ11 has 219 SNPs six of which have been receivingmore attention for their association with diabetes Amongthese six common SNPs three are located in the codingregions and three in the noncoding regions (Table 1) Thesesix SNPs include rs5219 rs5215 rs5210 rs5218 rs886288 andrs2285676

321 KCNJ11 rs5219 This locus is located in exon 1 of theKCNJ11 gene Substitution of A to C (AAGrarrCAG) changesthe amino acid from lysine to glutamine (Lys23Gln) at theNH2-terminal tail of Kir62 Lysine has a positively chargedepsilon-amino group whereas glutamine is uncharged underall biological conditionsDespite this amino acid substitutiontheoretically it does not make a remarkable change in thestructure and function of the KCNJ11 protein [18] Studieshave shown however that the rs5219 variant may alter thecharge of the ATP-binding region and decrease channelsensitivity to ATP Twenty-four association studies and arecent meta-analysis showed a strong relationship betweenthe rs5219 polymorphism and susceptibility to T2DM [19ndash43] whereas 21 studies did not confirm this finding [44ndash64]Thismeta-analysis showed that the rs5219 polymorphismis a risk factor for developing T2DM in Caucasians and insome Asian populations Populations from East Asia weremore prone to this disease where the A allele frequency inmost patients was more common than in controlsThereforegenetic background can affect susceptibility to T2DM [65]

The rs5219 polymorphism can affect the insulin secretionpathway The A allele of this locus impairs this pathwayby reducing ATP sensitivity of the KATP channel hence










T1DM No [63 64]




NSUR1Kir62

C N

NBD2 NBD1

A AB BC


Open Close

Chromosome 11

p151




SUR1Kir 62

Insulin secretion

120573 1205751205721

1205722

120574

Ca2+

K+

K+ATP

Glucose


1 1205722 120573 120574 and 120575 subunits










ENSAPRKACG

KCN11ABCC8


ABCC9










1subunit The 120572

1













Acknowledgments


References

































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























T1DM No [63 64]




NSUR1Kir62

C N

NBD2 NBD1

A AB BC


Open Close

Chromosome 11

p151




SUR1Kir 62

Insulin secretion

120573 1205751205721

1205722

120574

Ca2+

K+

K+ATP

Glucose


1 1205722 120573 120574 and 120575 subunits










ENSAPRKACG

KCN11ABCC8


ABCC9










1subunit The 120572

1













Acknowledgments


References

































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















SUR1Kir 62

Insulin secretion

120573 1205751205721

1205722

120574

Ca2+

K+

K+ATP

Glucose


1 1205722 120573 120574 and 120575 subunits










ENSAPRKACG

KCN11ABCC8


ABCC9










1subunit The 120572

1













Acknowledgments


References

































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















ENSAPRKACG

KCN11ABCC8


ABCC9










1subunit The 120572

1













Acknowledgments


References

































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















Acknowledgments


References

































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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Review Article KCNJ11: Genetic Polymorphisms and …downloads.hindawi.com/journals/jdr/2015/908152.pdf · Review Article KCNJ11: Genetic Polymorphisms and Risk of Diabetes Mellitus