D6S265*15 marks a DRB1*15, DQB1*0602 haplotype associated with attenuated protection from type 1 diabetes mellitus

Valdes, Ana M.; Thomson, Glenys; Graham, Jinko; Zarghami, M.; McNeney, Brad; Kockum, Ingrid; Smith, Anajane G.; Lathrop, Mark; Steenkiste, Ann R.; Dorman, Janice S.; Noble, Janelle A.; Hansen, John A.; Pugliese, Alberto; Lernmark, Åke

doi:10.1007/s00125-005-0011-8

Cited by 21 publications

(18 citation statements)

References 10 publications

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“…Our HLA typing of this patient identified the HLA-I A2 and HLA-II DQB1*0602 alleles with no evidence of a previously characterized HLA risk allele for T1D. HLA-II DQB1*0602 is associated with one of the most protective haplotypes for developing T1D with an OR of 0.03, though this protective effect seems to be restricted to childhood [38, 39]. We conclude that the HLA typing for this patient is not consistent with an immunologic predisposition to the development of T1D.…”

Section: Discussionmentioning

confidence: 92%

Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy

Lowe

Perry

Salama

et al. 2016

j. immunotherapy cancer

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BackgroundCheckpoint inhibitor immunotherapy is becoming an effective treatment modality for an increasing number of malignancies. As a result, autoinflammatory side-effects are also being observed more commonly in the clinic. We are currently unable to predict which patients will develop more severe toxicities associated with these treatment regimens.Case presentationWe present a patient with stage IV melanoma that developed rapid onset autoimmune type 1 diabetes (T1D) in response to combination ipilimumab and nivolumab immunotherapy. At the time of the patient’s presentation with diabetes ketoacidosis, a confirmed anti-GAD antibody seroconversion was noted. Longer-term follow-up of this patient has demonstrated a durable complete response based on PET CT imaging along with a persistently undetectable C-peptide level. Single nucleotide polymorphism gene sequencing and HLA risk allele analysis has revealed the patient to lack any established genetic predisposition to the development of autoimmune T1D.ConclusionsWhile larger studies are necessary to better understand the role of genetic risk factors for the development of autoimmune toxicities in those patients undergoing checkpoint inhibitor immunotherapy, these results suggest that pre-screening patients for known T1D risk alleles may not be indicated. Additional investigation is needed to determine whether an approach such as T cell receptor clonotypic analysis to identify the presence of autoreactive T cell clones may be an effective approach for predicting which patients are at risk for the development of autoinflammatory toxicities while undergoing checkpoint inhibitor immunotherapy.

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Section: Discussionmentioning

confidence: 92%

Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy

Lowe

Perry

Salama

et al. 2016

j. immunotherapy cancer

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“…Future studies could investigate whether these relatives have DRB1*15:01-DQA1*01:02-DQB1*06:02 with mutations or alleles that weaken the protective effect. For example, we previously reported that DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotypes carrying allele 15 at the microsatellite D6S265 (109 kb centromeric of HLA-A) confer reduced protection from T1D; this effect was observed in patients from Sweden who tended to develop disease at an older age (37). It should also be noted that among the 0602+ relatives who developed T1D in our study, the one with single GADA positivity was much older than most PTP participants.…”

Section: Discussionmentioning

confidence: 99%

HLA-DRB115:01-DQA101:02-DQB1*06:02 Haplotype Protects Autoantibody-Positive Relatives From Type 1 Diabetes Throughout the Stages of Disease Progression

Pugliese

Boulware

et al. 2016

Diabetes

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The HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from the development of type 1 diabetes (T1D). However, it is not known at which stages in the natural history of T1D development this haplotype affords protection. We examined a cohort of 3,358 autoantibody-positive relatives of T1D patients in the Pathway to Prevention (PTP) Study of the Type 1 Diabetes TrialNet. The PTP study examines risk factors for T1D and disease progression in relatives. HLA typing revealed that 155 relatives carried this protective haplotype. A comparison with 60 autoantibody-negative relatives suggested protection from autoantibody development. Moreover, the relatives with DRB1*15:01-DQA1*01:02-DQB1*06:02 less frequently expressed autoantibodies associated with higher T1D risk, were less likely to have multiple autoantibodies at baseline, and rarely converted from single to multiple autoantibody positivity on follow-up. These relatives also had lower frequencies of metabolic abnormalities at baseline and exhibited no overall metabolic worsening on follow-up. Ultimately, they had a very low 5-year cumulative incidence of T1D. In conclusion, the protective influence of DRB1*15:01-DQA1*01:02-DQB1*06:02 spans from autoantibody development through all stages of progression, and relatives with this allele only rarely develop T1D.

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“…The most notable example is DRB1 *15:01- DQA1 *01:02- DQB1 *06:02, which is the most common DR-DQ haplotype in Caucasians. Protection from T1D conferred by this haplotype, in a dominant fashion, is almost complete, although some studies suggest that the protection is modified by other loci within the HLA region [25]. Other haplotypes strongly associated with protection in Caucasians include DRB1 *11:04- DQA1 *05:01- DQB1 *03:01, DRB1 *07:01- DQA1 *02:01- DQB1 *03:03, and DRB1 *14:01- DQA1 *01:01- DQB1 *05:03 (Table 1).…”

Section: Drb1-dqa1-dqb1mentioning

confidence: 99%

Genetics of the HLA Region in the Prediction of Type 1 Diabetes

Noble¹,

2011

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Type 1 diabetes (T1D) is one of the most widely studied complex genetic disorders, and the genes in HLA are reported to account for approximately 40% to 50% of the familial aggregation of T1D. The major genetic determinants of this disease are polymorphisms of class II HLA genes encoding DQ and DR. The DR-DQ haplotypes conferring the highest risk are DRB1*03:01-DQA1*05:01-DQB1*02:01 (abbreviated “DR3”) and DRB1*04:01/02/04/05/08-DQA1*03:01-DQB1*03:02/04 (or DQB1*02; abbreviated “DR4”). The risk is much higher for the heterozygote formed by these two haplotypes (OR = 16.59; 95% CI, 13.7–20.1) than for either of the homozygotes (DR3/DR3, OR = 6.32; 95% CI, 5.12–7.80; DR4/DR4, OR = 5.68; 95% CI, 3.91). In addition, some haplotypes confer strong protection from disease, such as DRB1*15:01-DQA1*01:02-DQB1*06:02 (abbreviated “DR2”; OR = 0.03; 95% CI, 0.01–0.07). After adjusting for the genetic correlation with DR and DQ, significant associations can be seen for HLA class II DPB1 alleles, in particular, DPB1*04:02, DPB1*03:01, and DPB1*02:02. Outside of the class II region, the strongest susceptibility is conferred by allele B*39:06 (OR =10.31; 95% CI, 4.21–25.1) and other HLA-B alleles. In addition, several loci in the class III region are reported to be associated with T1D, as are some loci telomeric to class I. Not surprisingly, current approaches for the prediction of T1D in screening studies take advantage of genotyping HLA-DR and HLA-DQ loci, which is then combined with family history and screening for autoantibodies directed against islet-cell antigens. Inclusion of additional moderate HLA risk haplotypes may help identify the majority of children with T1D before the onset of the disease.

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D6S26515 marks a DRB115, DQB1*0602 haplotype associated with attenuated protection from type 1 diabetes mellitus

Cited by 21 publications

References 10 publications

Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy

Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy

HLA-DRB115:01-DQA101:02-DQB1*06:02 Haplotype Protects Autoantibody-Positive Relatives From Type 1 Diabetes Throughout the Stages of Disease Progression

Genetics of the HLA Region in the Prediction of Type 1 Diabetes

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D6S265*15 marks a DRB1*15, DQB1*0602 haplotype associated with attenuated protection from type 1 diabetes mellitus

Cited by 21 publications

References 10 publications

Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy

Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy

HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 Haplotype Protects Autoantibody-Positive Relatives From Type 1 Diabetes Throughout the Stages of Disease Progression

Genetics of the HLA Region in the Prediction of Type 1 Diabetes

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Product

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D6S26515 marks a DRB115, DQB1*0602 haplotype associated with attenuated protection from type 1 diabetes mellitus

HLA-DRB115:01-DQA101:02-DQB1*06:02 Haplotype Protects Autoantibody-Positive Relatives From Type 1 Diabetes Throughout the Stages of Disease Progression