MICA Polymorphism Is Associated With Type 1 Diabetes in the Korean Population

Park, Yong Soo; Lee, Hong-Kyu; Sanjeevi, Carani B.; Eisenbarth, George S.

doi:10.2337/diacare.24.1.33

Cited by 128 publications

(64 citation statements)

References 29 publications

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“…We observed a slightly negative association of MGA and a more pronounced negative association of PGA with MIC A6, but results were not statistically significant after correction for multiple testing. In comparison, a lowered frequency of MIC A6 has also previously been reported for patients with DM and Addison's disease (12,15).…”

Section: Micasupporting

confidence: 63%

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Early onset of polyglandular failure is associated with HLA-DRB1*03.

Dittmar

Ide²,

Wurm³

et al. 2008

European Journal of Endocrinology

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Objectives: Polyglandular failure or autoimmunity (PGA) involves at least two endocrine diseases. Several genes may play a role in its etiology. This study analyzed 1) whether HLA-DRB1, HLA-DQB1, and MHC class I chain-related gene A (MICA) polymorphisms are associated in PGA and 2) whether PGA patients display stronger associations with these immune genes than patients with monoglandular autoimmunity (MGA). Design: Association study. Methods: HLA-DRB1, HLA-DQB1, and MICA alleles were analyzed in 73 patients with PGA, 283 with MGA, and 206 healthy controls. The HLA-DRB1 and HLA-DQB1 polymorphisms were determined with PCR-amplified DNA being hybridized with PCR-sequence-specific oligonucleotide probes. MICA microsatellites were typed by PCR amplification and fragment size analysis on a DNA sequencer. Results: HLA-DRB1*03 was strongly increased in patients with PGA (50.7%) versus both controls (21.8%, P c !0.0001; RRZ2.32, 95% CIZ1.62-3.33) and MGA (11.4%, P c !0.0001). HLA-DRB1*03 was highly prevalent in PGA patients with early versus late disease onset (P!0.05, logistic regression analysis). HLA-DRB1*04 allele carriers were more present in PGA versus controls (53.4% vs 22.4%, P c !0.0001, RRZ2.38, 95% CIZ1.68-3.38). Further, HLA-DQB1*02 was increased in PGA versus controls (P c !0.01), whereas HLA-DQB1*06 was decreased (P c !0.001). Patients with PGA showed more MIC A5.1 and less MIC A6 allele carriers than controls (NS). Presence of the MIC A5.1 allele was not associated with the HLA-DRB1*03 or HLA-DQB1 alleles. Conclusions: HLA-DRB1*03 is a stronger genetic marker in PGA than in MGA, foremost in those with early disease onset.European Journal of Endocrinology 159 55-60

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Section: Micasupporting

confidence: 63%

“…In the vicinity of the HLA genes on chromosome 6, the MHC class I chain-related gene A (MICA) is situated. It is a putative susceptibility gene and has been shown to be associated with DM and AITD (12)(13)(14)(15)(16)(17). The MICA gene has a trinucleotide (GCT) repeat microsatellite in the exon 5 encoding alanine residues.…”

Section: Introductionmentioning

confidence: 99%

Early onset of polyglandular failure is associated with HLA-DRB1*03.

Dittmar

Ide²,

Wurm³

et al. 2008

European Journal of Endocrinology

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“…A microsatellite allele consisting of six repetitions of GCT-AGC (A6) and an allele with four repetitions (A4) were analysed. The A6 polymorphism was transmitted at a lower than expected frequency and the A4 polymorphism was transmitted at a higher than expected frequency [67].…”

Section: Mechanisms Of Diabetogenicity Of Hla Moleculesmentioning

confidence: 75%

Genetic control of autoimmunity in Type I diabetes and associated disorders

2002

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Type I (insulin-dependent) diabetes mellitus is a heterogeneous disease with major subdivisions termed Type 1A (immune-mediated) and Type 1B. Immunemediated diabetes is also heterogeneous with ªmono-genicº, oligogenic, and polygenic forms present in humans and in animal models. Single-gene mutations of two transcription factors have been recently identified in rare syndromes of autoimmunity with type 1A diabetes: autoimmune polyendocrine syndrome type 1 (APS-1) and X-linked polyendocrinopathy, immune dysfunction and diarrhoea (XPID). For more common forms of diabetes, susceptibility loci within the major histocompatibility complex and at the insulin locus have been identified. Both DQ* and DR* alleles provide susceptibility and certain alleles dominant protection. In the Diabetes Autoimmunity Study of the Young approximately 50 % of the siblings studied with the highest-risk HLA genotype develop anti-islet autoantibodies by age 3. Insulin could be a crucial autoantigen related to genetic susceptibility. The crystal structure of the high-risk allele, HLA-DQ8, complexed with an insulin peptide has just been reported. Insulin production by macrophage-dendritic cells within the thymus and lymphoid organs could underlie insulin gene polymorphisms influencing the risk of diabetes. Genome-wide scans for linkage in animal models and in humans have not conclusively identified other susceptibility genes though many loci have been implicated. We favour the hypothesis that HLA is a major determinant of susceptibility in animal models and in most families, and that the search for diabetogenes should concentrate on unique families to decrease heterogeneity and favour the eventual discovery of genes influencing risk. [Diabetologia (2002) 45:605±622]

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“…HLA-linked microsatellite markers D6S273, MIC-A, and D6S2223 were determined with a fluorescence-based method as reported previously (17,18). Analysis of family members allowed determination of haplotypes.…”

Section: Methodsmentioning

confidence: 99%

“…Analysis of family members allowed determination of haplotypes. The primers for the microsatellites were used as previously (17,18). D6S2223 is located ϳ4 Mb telomeric from DQB1.…”

Section: Methodsmentioning

confidence: 99%

“Extended” A1, B8, DR3 Haplotype Shows Remarkable Linkage Disequilibrium but Is Similar to Nonextended Haplotypes in Terms of Diabetes Risk

et al. 2005

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To evaluate potential differential diabetes risk of DR3 haplotypes we have evaluated class I alleles as well as two microsatellites previously associated with differential risk associated with DR3 haplotypes. We found that over one-third of patient DR3 chromosomes consisted of an extended DR3 haplotype, from DQ2 to D6S2223 (DQ2, DR3, D6S273-143, MIC-A5.1, HLA-B8, HLA-Cw7, HLA-A1, and D6S2223-177) with an identical extended haplotype in controls. The extended haplotype was present more frequently (35.1% of autoimmune-associated DR3 haplotypes, 39.4% of control DR3 haplotypes) than other haplotypes (no other haplotype >5% of DR3 haplotypes) and remarkably conserved, but it was not transmitted from parents to affected children more frequently than nonconserved DR3-bearing haplotypes. This suggests that if all alleles are truly identical for the major A1, B8, DR3 haplotype (between A1 and DR3), with different alleles on nonconserved haplotypes without differential diabetes risk, then in this region of the genome DR3-DQ2 may be the primary polymorphisms of common haplotypes contributing to diabetes risk. Diabetes 54: 1879 -1883, 2005 A number of studies are now evaluating the development of anti-islet autoantibodies in both children from the general population and first-degree relatives of patients with type 1 diabetes (1-3). It is clear from these studies that anti-islet autoantibodies can develop either in the 1st year of life or, subsequently, that anti-insulin autoantibodies are frequently the first autoantibody expressed, and that the presence of multiple anti-islet autoantibodies and persistent autoantibodies are associated with a high risk of progression to type 1 diabetes in both the general population and in relatives. Many of the current studies have evaluated risk based upon HLA class II alleles (4 -7). The highest-risk genotype for early-onset type 1 diabetes and expression of anti-islet autoantibodies consists of DR3-DQ2 (DQA1*0501-DQB1*0201) on one chromosome and DR4-DQ8 (DQA1*0301-DQB1*0302) on the second chromosome (7). Most studies currently evaluate children for the expression of autoantibodies reacting with GAD65, insulinoma-associated protein 2 (ICA512), and insulin autoantibodies. The risk for children with the DR3-DQ2/DR4-DQ8 genotype in general population is Ͻ5% for the development of persistent anti-islet autoimmunity by age 5 years versus Ͼ20% for offspring and perhaps as high as 40% for siblings (of a patient with type 1 diabetes) with the same DR/DQ genotype (8). Such a remarkably high risk for anti-islet autoimmunity among relatives with DR3/DR4 suggests that other alleles within the major histocompatibility complex (MHC) may be contributing risk, in addition to the class II alleles, in that most often siblings of probands with diabetes who are DR3/DR4 are HLA identical to the proband (two identical haplotypes). It is also likely that non-MHC alleles contribute to this increased risk, but by specifying HLA genotype, only this chromosomal region is "fixed" to usually be identical to the ...

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MICA Polymorphism Is Associated With Type 1 Diabetes in the Korean Population

Cited by 128 publications

References 29 publications

Early onset of polyglandular failure is associated with HLA-DRB1*03.

Early onset of polyglandular failure is associated with HLA-DRB1*03.

Genetic control of autoimmunity in Type I diabetes and associated disorders

“Extended” A1, B8, DR3 Haplotype Shows Remarkable Linkage Disequilibrium but Is Similar to Nonextended Haplotypes in Terms of Diabetes Risk

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