title: MICA marks additional risk factors for Type 1 diabetes on extended HLA haplotypes: an association and meta-analysis.
abstract: The association of the HLA complex on chromosome 6 does not explain total linkage of the HLA region to Type 1 Diabetes (T1D), leading to the hypothesis that there may be additional causal genes in the HLA region for immune-related disorders. Reports on the MHC Class I chain-related A (MICA) gene as candidate for association with T1D are contradicting. We investigated whether variation in MICA is associated to T1D in a cohort of 350 unrelated individuals with juvenile-onset T1D and 540 control subjects, followed by a meta-analysis of 14 studies. We also investigated an HLA-independent association for MICA with T1D. In our case-control study, we found that the MICA*A5 variant was significantly associated with an increased risk for T1D, while MICA*A6 was significantly associated with a decreased risk that was confirmed by our meta-analysis. However, the meta-analysis did not show an association of MICA*A5 T1D. Analysis of MICA alleles conditional on T1D-associated high-risk MHC class II haplotypes revealed that MICA*A6 was associated with an increased risk for T1D when this marker co-occurred with HLA DQ2DR17 T1D-risk-haplotypes. In contrast, MICA*A6 reduced the risk from the HLA DQ8DR4 T1D-risk haplotype. Moreover, MICA*A9 showed a significant association to increased risk for T1D on DQ8DR4 haplotypes. Co-inheritance of MICA*A6 with the HLA DQ2DR17 haplotype in T1D indicates this haplotype may carry the additional genetic factors for T1D, but our study does not support an independent association between MICA variants and T1D.
authors.affiliation: Complex Genetic Section, Department of Medical Genetics, University Medical Center Utrecht, P.O. Box 85060, 3508 AB Utrecht, The Netherlands.
authors.forename: Behrooz Z
authors.initials: BZ
authors.lastname: Alizadeh
authors.forename: Peter
authors.initials: P
authors.lastname: Eerligh
authors.forename: Arno R
authors.initials: AR
authors.lastname: van der Slik
authors.forename: Arun
authors.initials: A
authors.lastname: Shastry
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.forename: Gustavo
authors.initials: G
authors.lastname: Valdigem
authors.forename: Jan G
authors.initials: JG
authors.lastname: Bruining
authors.forename: Carani B
authors.initials: CB
authors.lastname: Sanjeevi
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Bart O
authors.initials: BO
authors.lastname: Roep
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
mesh_terms: D000293:Adolescent; D000483:Alleles; D015415:Biomarkers; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D005805:Genes, MHC Class I; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A