Vol 39 # 2 June 2007 - Kma.org.kw

June 2007KUWAIT MEDICAL JOURNAL 109on DNAsequencing, the HLA-DQ locus was foundto be the most strongly associated with diabetessusceptibility [33] . The precise mechanism throughwhich HLA-DQ determines disease susceptibility isstill not clear [39] . This locus encodes for severalvariants of the HLA-DQ molecule, a heterodimerconsisting of two glycoprotein chains (α and β)involved in immune recognition and antigenpresentation to CD4 T-cells [33] . In Caucasians, theHLA-DQ heterodimers (the α-chains are labeledDQA1 and the β-chains DQB1) encoded byDQA1*0301, DQB1*0302 and DQA1*0501, DQB1*0201alleles have the strongest association withd i a b e t e s [ 3 1 , 3 3 ] . These alleles are in linkage disequilibriumwith the HLA-DR4 and DR3 alleles [40] .It has also been noted that DQB1*0302 differsfrom DQB1*0301 at position 57, where it lacks anaspartic acid residue [33] . The DQB1*0201 allele alsolacks aspartic acid at position 57, and it has beenproposed that this residue may be involved in themolecular mechanism underlying T1D-encodedsusceptibility [40,41] . In fact, the amino acid residue atposition 57 of the DQ- β chain appears to be criticalfor peptide binding and re c o g n i t i o n [ 4 2 ] . Otherresidues of the DQ- β chain may influence peptidebinding and diabetes susceptibility, and inparticular the combined variation of residues atposition 57 and 70 seem to more strongly correlatewith diabetes risk [ 4 3 , 4 4 ] . An arginine residue atposition 52 of the DQ-α chain also correlates withdiabetes susceptibility [ 4 5 ] . However, some DQB1including DQB1*0302/DQB1*0201 (DR7),DQB1* 0 2 0 1 ( D R 3 ) / D Q B 1 * 0 2 0 1 ( D R 3 ) a n d D Q B 1 * 0 2 0 1 ( D R 3 )/DQB1*0201 (DR7) are low risk [31] .Certain haplotypes of class II HLAgenes exert ap rotective action against the development ofdiabetes. HLA -alleles have also been associatedwith protection from T1D, the haplotypeDQA1*0102/DQB1*0602/DRB1*1501 being knownto confer protection. Evidence suggest that suchp rotection may be mostly encoded by theDQB1*0602 allele and even the first degree relativeswith islet cell antibodies have a low diabetic risk ifthey carry DQB1*0602. However, this protectiveeffect is not absolute [12,34,46,47] .Other loci in the class II region have beenassociated with T1D besides HLA-DQ and DR [27] .HLA-DPB1*0101, DPB1*0301, and DPB1*0202 werereported to be positively and DPB1*0402 negativelyassociated [48-50] .To summarize, some HLA haplotypes areassociated with high, moderate or low risk ofdeveloping T1D whereas some even conferprotection against T1D (Table 1).The HLA class I Region:-A number of observations indicate that class IIgenes cannot explain all of HLA association withTable 1: HLAhaplotypes and type 1 diabetesHigh Risk HaplotypesDR 3 DQA1*0501 DQB1*0201 DRB1*0301DR 4 DQA1*0301 DQB1*0302 DRB1*0401DR 4 DQA1*0301 DQB1*0302 DRB1*0405Predisposing HaplotypesDR2 DQA1*0102 DQB1*0502 DRB1*1601DR4 DQA1*0301 DQB1*0302 DRB1*0402DR4 DQA1*0301 DQB1*0302 DRB1*0404Protective HaplotypesDR2 DQA1*0102 DQB1*0602 DRB1*1501DR6 DQA1*0101 DQB1*0503 DRB1*1401DR7 DQA1*0201 DQB1*0303 DRB1*0701T1D [33] . There is evidence that several alleles at theclass I HLA B and C loci may influencesusceptibility as well as the age of onset [51] and therate of β-cells destruction [52] . In addition, the class Ichain -related MIC-A and MIC-B genes locatedbetween the HLA-B and TNF α genes may alsoeffect T1D susceptibility [33] .The HLA class III Region:The TNF (Tumour Necrosis Factor) gene is astrong candidate from class III, since this genepolymorphisms may affect the production of TNFα,a potent cytokine, thus affecting the immuneresponse potential [33] . It has been reported that TNFα polymorphisms are associated with age of onsetand influence the inflammatory process leading tothe destruction and pancreatic β-cell anddevelopment of T1D [53] .Apart from determining T1D risk, HLA genescan also modulate clinical features of the disease,such as age of onset or outcome of active cellularautoimmunity [54] . Thus, the combination of the DR3and DR4 haplotypes not only predisposes stronglyto T1D but also accelerated disease onset [ 5 4 ] .Conversely, the rare individuals contracting T1Ddespite the presence of the protective DQB1*0602allele generally show a very late onset of disease [55] .In conclusion, the HLA associations with T1Dare complex, with many haplotypes influencingdisease risk [56] .IDDM2: The Insulin Gene:Insulin is composed of two distinct polypeptidechains, chain A and chain B, which are linked bydisulfide bonds. Many proteins that containsubunits, such as hemoglobin, are the products ofseveral genes. However, insulin is the product ofone gene, INS [57] . The research done by Nakayama etal has strongly shown that insulin is a primaryautoantigen in the beginning stages of diabetes.Also, supporting this evidence is the presence ofinsulin antibodies in the blood of prediabetic anddiabetic patients [58] .The insulin gene is the second well establishedsusceptibility locus in T1D on chromosome 11p