Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Susceptibility to several disorders, including insulin-dependent diabetes mellitus and multiple sclerosis, has been associated with alleles of HLA class II genes and loci in the TNF cluster in the central major histocompatibility complex (MHC) region. As recombination within this region is rare, it is difficult to determine which genes are important. This will be facilitated by the identification of functional polymorphisms. Hence we are sequencing reverse transcription-polymerase chain reaction products derived from central MHC genes in well characterized and conserved ancestral haplotypes. Here we address the IKBL gene, which lies near the TNF cluster at the telomeric end of the central MHC. Although the IKBL cDNA sequence was conserved between most ancestral haplotypes, a synonymous nucleotide substitution, a 3' untranslated region substitution, and a single nonsynonymous substitution were identified. The latter (IKBL+738) was present in multiple examples of the 7.1 haplotype [HLA-A3, B7, DR2 (DR15)] and resulted in a cysteine to arginine substitution in a predicted protein kinase C phosphorylation site. This polymorphism did not occur in 18 other common haplotypes from the 10th International Histocompatibility Workshop and thus appears haplospecific. A role for IKBL+738 in the association between HLA-A3,B7,DR2(DR15) and susceptibility to multiple sclerosis is discussed.
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PMID:The central MHC gene IKBL carries a structural polymorphism that is associated with HLA-A3,B7,DR15. 1036 24

Type 1 diabetes is a multifactorial disease in which the genes of the major histocompatibility complex (MHC) play a key role. Recently, non-human leukocyte antigen (non-HLA) genes in the class III region of this complex have been presumed to be associated with type 1 diabetes by linkage analyses. We investigated the possibility of the inhibitor of kappaB-like (IKBL, also known as 'NFKBIL1') gene as one of these candidates. We carried out a case-control study of 124 patients with type 1 diabetes and 330 healthy control subjects. The haplotypes of the IKBL promoter, i.e., PA (-263A, -63T), PB (-263A, -63A), PC (-263G, -63T), were assigned by the single-nucleotide polymorphisms at positions -263 and -63 from the transcription start site. The frequency of the wild-type haplotype, PA, was elevated, while that of the variant-type haplotype, PC, was lower in patients than controls. In two-locus analyses with HLA-DRB1 alleles, the PA haplotype showed linkage disequilibrium with the DRB1*0405 allele and the PC haplotype with the DRB1*1502 allele. A notable observation was that the PC haplotype was significantly associated with protection in the DRB1*1502-negative population. Our study indicates the first evidence of a possible independent association between type 1 diabetes and polymorphisms in the promoter of the IKBL gene.
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PMID:IKBL promoter polymorphism is strongly associated with resistance to type 1 diabetes in Japanese. 1498 11

Subtypes of HLA-DR4 are associated with susceptibility or protection against type 1 diabetes (T1DM). We addressed whether this reflects linkage disequilibrium with the true susceptibility locus by studying broader MHC haplotypes marked by alleles of HLA-B, IKBL (adjacent to TNFA) and complement C4. The study used a largely Caucasian cohort from Western Australia. HLA-DRB1*0401 and HLA-DRB1*0405 marked susceptibility to T1DM. In Caucasians, DRB1*0401 occurs predominantly in the 44.1 ancestral haplotype (AH; HLA-A2,B44, DRB1*0401,DQB1*0301) and the 62.1AH (HLA-A2,B15(62),DRB1*0401,DQB1*0302). HLA-B15 marked susceptibility and HLA-B44 marked with resistance to T1DM in patients and controls preselected for HLA-DRB1*0401. A gene between TNFA and HLA-B on the 8.1AH (HLA-A1,B8,;DR3,DQ2) modifies the effects of the class II alleles. Here, alleles characteristic of the 62.1AH (C4B3, IKBL+446*T and HLA-A2,B15) were screened in donors preselected for HLA-DRB1*0401. C4B3 was associated with diabetes, consistent with a diabetes gene telomeric of MHC class II. However, increases in carriage of IKBL+446*T and HLA-A2,B15 were marginal, as too few control subjects were available with the diabetogenic alleles. However, with these tools, selection of HLA-DRB1*0401, DQB1*0302 donors who are positive and negative for C4B3 will allow bidirectional mapping of diabetes genes in the central MHC.
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PMID:Does a central MHC gene in linkage disequilibrium with HLA-DRB1*0401 affect susceptibility to type 1 diabetes? 1585 1