HLA typing data on 100 Type 1 (insulin-dependent) diabetic patients from central Italy show a negative association with DR5 rather than with DR2

Vela, María; Adorno, D.; Longo, Anna; Papola, F.; Maccarone, D.; Centis, Dora; Raponi, Massimo; Candela, A.; Campea, L; Orsini, M; Ferrara, G.B.

doi:10.1016/0090-1229(87)90121-8

Cited by 7 publications

(4 citation statements)

References 6 publications

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“…This indicates the superior effect of the 12-kb fragment over the 4-kb fragment as a determinant of susceptibility. Dominance of DR4 over DR3 as a risk marker has also been seen in several surveys of subjects with Type i diabetes in Northern Europe [17,18], but the situation may be different in other populations [19,20]. It is also remarkable that none of the control subjects apparently homozygous for the 12-kb fragment was positive for DR4 (data not shown).…”

Section: Discussionmentioning

confidence: 74%

HLA-DQ beta-chain restriction fragment length polymorphism as a risk marker in Type 1 (insulin-dependent) diabetes mellitus: a Finnish family study

et al. 1990

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Summary. Finnish Type l (insulin-dependent) diabeticfamilies were analysed for HLA-DQ beta-chain polymorphism using a short intron-specific probe. A simple hybridization pattern was obtained in which all fragments were associated significantly with Type i diabetes. The simultaneous presence of two different risk markers, the allelic 12-kilobase and 4-kilobase fragments were strongly associated with Type 1 diabetes since 50% of the patients had this combination compared with only 2% of the control subjects. The cosegregated 7.5/3.0 kilobase fragments, which were associated with HLA-DR2 and DRw6 were not detected among the diabetic patients but were present in 48% of the control subjects. Our results provide further support for the location of susceptibility determining factors in the HLA-DQ gene area. The clear-cut, simple restriction fragment length polymorphism pattern obtained here, which bears a resemblance to a two allelic system, therefore makes this method applicable for estimating the risk of Type i diabetes at the population level.Key words: Type 1 (insulin-dependent) diabetes, restriction fragment length polymorphism, HLA-DQ, prediction of Type i diabetes, genetics.There is a strong relationship between HLA and Type 1 (insulin-dependent) diabetes mellitus, in that individuals having the HLA-DR3 and/or 4 antigen type run an increased risk of developing the disease. Determination of the Type i diabetes risk was previously based on serological and/or cellular HLA typing, but recent major breakthroughs in molecular biology have provided new tools for evaluation at the genomic level. Restriction fragment length polymorphism (RFLP) analysis in the HLA gene area has revealed several diabetes-associated polymorphisms [1, 2], suggesting that the susceptibility genes are located in the HLA-DQ region rather than the DR region. More recently it has been suggested that the amino acid at position 57 in the HLA-DQ beta-chain may play a critical role in determining predisposition to Type I diabetes. The presence of aspartic acid (Asp) in this position seems to provide protection against the development of the disease [3]. There are also results suggesting that Type i diabetes may be associated with an extended susceptibility haplotype [4,5] or with a combination of DR/DQ alleles [6,7] rather than with an isolated allele.The RFLP method was used here in order to detect polymorphisms implicated as genetic elements predisposing subjects to Type i diabetes. Use of an HLA-DQ betachain gene intron-specific probe revealed a hybridization pattern simple enough to be employed in screening surveys to identify subjects at risk of developing Type 1 diabetes.Our results support the role of the BamHI-12-kilobase and 4-kb fragments as susceptibility conferring markers for the disease [1,8] and show a striking difference between the diabetic patients and the control subjects in the frequency of 7.5/3.0-kb fragments reflecting a resistance to Type 1 diabetes. Furthermore, the trans-allelic genotypes indicate that the highest risk based...

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Section: Discussionmentioning

confidence: 74%

HLA-DQ beta-chain restriction fragment length polymorphism as a risk marker in Type 1 (insulin-dependent) diabetes mellitus: a Finnish family study

et al. 1990

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“…There is a significant increase in DR3, and a DRS frequency of 44%. Control typing details are not available, but a recent paper gives a frequency of DR5 in 406 Italian controls as 44.8% (Vela et al 1987). Therefore, as in our group of patients, DR5 is not decreased despite a tripling of the DR3 frequency.…”

Section: I S C~o Amentioning

confidence: 53%

A DQA1 allele is strongly associated with idiopathic membranous nephropathy

1989

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The high molecular weight genomic DNA from 31 patients with idiopathic membranous nephropathy (IMN) has been digested with a restriction endonuclease Taq I, electrophoresed, blotted and hybridised with probes to the HLA-DRB, -DQA, -DQB, -DPA and -DPB genes. The restriction endonuclease Msp I was also used with the HLA-DPA and -DPB probes. The resulting restriction fragment length polymorphism (RFLP) has been analysed and compared with 55 controls treated in the same way. There was a significant increase in the DRB restriction fragments associated with HLA-DR3 (Fisher's p = 0.011), in particular with a sub-division of DR3 (Fisher's p = 0.0038). These results confirm at the DNA level serological correlations observed for IMN. A 4.5 Kb DQA RFLP was significantly raised in IMN patients (Fisher's p = 0.002) and is proposed as a major disease susceptibility factor.

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“…Because the DQB1 allele most frequently represented in DR2 haplotypes, DQB1*0602, possesses an Asp 57 , this also has been considered strong supporting evidence of the importance of this amino acid residue in susceptibility to IDDM. However, a comprehensive study performed on patients from central Italy could not confirm the negative association between DR2 and IDDM previously established in other white populations (8). This represented a serious challenge to the Asp 57 hypothesis unless a different explanation could be found.…”

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confidence: 81%

“…Ten patients were selected from a previous study (8), and nine were selected subsequently. IDDM diagnosis was made according to National Diabetes Data Group criteria.…”

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confidence: 99%

An Explanation for the Neutral Effect of DR2 on IDDM Susceptibility in Central Italy

et al. 1992

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Susceptibility to IDDM is strongly associated with HLA. Some HLA allelic combinations (haplotypes) can be found in most patients, whereas other haplotypes are encountered only rarely. It has been proposed that this difference in susceptibility depends on the absence (in the DR3 and DR4 haplotypes) or the presence (in the DR2 haplotype) of Asp57 in the DQ beta-chain. Data on southern European populations challenge this hypothesis because the DR2 haplotype has not been associated negatively with IDDM, as reported in northern European populations. This study on a selected panel of DR2-positive Italian IDDM patients shows that 19 of 21 (90.5%) DR2 haplotypes possess a non-Asp57 DQB allele. Moreover, the same non-Asp57 subtype has a comparatively high frequency (9/28, or 32.1%, DR2 haplotypes) also in the DR2-positive healthy Italian population. The difference between patients and control subjects is significant (P less than 0.0001). This is the largest series of DR2-positive patients analyzed so far. Comparison with cumulated data in various white populations shows a distinct northern European-to-southern European gradient. Toward southern Europe, the relative frequency of the non-Asp57 DR2 subtype increases. Concomitantly, the apparent protective effect of the DR2 haplotype disappears. Therefore, the observed differences in DR2-IDDM association in white populations can be explained adequately by the Asp57 hypothesis, which this study's data strongly support.

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HLA typing data on 100 Type 1 (insulin-dependent) diabetic patients from central Italy show a negative association with DR5 rather than with DR2

Cited by 7 publications

References 6 publications

HLA-DQ beta-chain restriction fragment length polymorphism as a risk marker in Type 1 (insulin-dependent) diabetes mellitus: a Finnish family study

HLA-DQ beta-chain restriction fragment length polymorphism as a risk marker in Type 1 (insulin-dependent) diabetes mellitus: a Finnish family study

A DQA1 allele is strongly associated with idiopathic membranous nephropathy

An Explanation for the Neutral Effect of DR2 on IDDM Susceptibility in Central Italy

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