Identification of two novel DQA1 alleles, DQA1*0107 and DQA1*0602, by sequence-based typing in the GoKinD population.

Two novel DQA1 alleles, DQA1*0107 and DQA1*0602, were discovered using DQA1 sequence-based typing (SBT) in participants in the Genetics of Kidneys in Diabetes (GoKinD) Study. The DQA1*0107 allele, found in three unrelated Caucasian participants, contains a novel polymorphism at codon 79 of exon 2 (CGC-->TGC), which results in an amino acid change from an arginine to a cysteine. The participants containing this novel polymorphism also had a 1-bp insertion in intron 2 that is common to the *01 alleles. The DQA1*0602 allele, found in one Caucasian participant, contains a novel polymorphism at codon 139 of exon 3 (AGC-->CGC), which results in an amino acid change from a serine to an arginine. Additionally, the *0602 allele has a base change in intron 1 that is common to the *06 alleles. Both new alleles were isolated using single-allele amplification SBT and confirmed using sequence-specific primer amplification.

Novel human leukocyte antigen class I and class II alleles identified by sequence-based typing in the Genetics of Kidneys in Diabetes (GoKinD) study population.

Nine novel HLA class I and class II alleles were identified by sequence-based typing (SBT) in Caucasian participants from the Genetics of Kidneys in Diabetes (GoKinD) study. All novel alleles were single nucleotide substitutions. Seven alleles resulted in an amino acid change and two alleles were silent substitutions. The new alleles are as follows: five HLA-A alleles (*0132, *020121, *0344, *030107, *2507), one HLA-C allele (*0619), two HLA-DQB1 alleles (*0204, *0318), and one HLA-DPB1 allele (*1802). Eight of these new alleles were identified in participants with type 1 diabetes, three of whom also had diabetic nephropathy, and one new allele was identified in an unaffected parent of a participant with type 1 diabetes. All new alleles were isolated and characterized by use of single allele amplification (SAA) SBT; the new alleles were confirmed by sequence-specific primer (SSP) amplification.

Nephropathy in type 1 diabetes is diminished in carriers of HLA-DRB1*04: the genetics of kidneys in diabetes (GoKinD) study.

OBJECTIVE: The purpose of this study was to examine whether known genetic risk factors for type 1 diabetes (HLA-DRB1, -DQA1, and -DQB1 and insulin locus) play a role in the etiology of diabetic nephropathy. RESEARCH DESIGN AND METHODS; Genetic analysis of HLA-DRB1, -DQA1, -DQB1 and the insulin gene (INS) was performed in the Genetics of Kidneys in Diabetes (GoKinD) collection of DNA (European ancestry subset), which includes case patients with type 1 diabetes and nephropathy (n = 829) and control patients with type 1 diabetes but not nephropathy (n = 904). The availability of phenotypic and genotypic data on GoKinD participants allowed a detailed analysis of the association of these genes with diabetic nephropathy. RESULTS: Diabetic probands who were homozygous for HLA-DRB1*04 were 50% less likely to have nephropathy than probands without any DRB1*04 alleles. In heterozygous carriers, a protective effect of this allele was not as clearly evident; the mode of inheritance therefore remains unclear. This association was seen in probands with both short (<28 years, P = 0.02) and long (>/=28 years, P = 0.0001) duration of diabetes. A1C, a marker of sustained hyperglycemia, was increased in control probands with normoalbuminuira, despite long-duration diabetes, from 7.2 to 7.3 to 7.7% with 0, 1, and 2 copies of the DRB1*04 allele, respectively. This result is consistent with a protective effect of DRB1*04 that may allow individuals to tolerate higher levels of hyperglycemia, as measured by A1C, without developing nephropathy. CONCLUSIONS: These data suggest that carriers of DRB1*04 are protected from some of the injurious hyperglycemic effects related to nephropathy. Interestingly, DRB1*04 appears to be both a risk allele for type 1 diabetes and a protective allele for nephropathy.