Masked and Overt Autoantibodies Specific to the DPD Epitope of 65-kDa Glutamate Decarboxylase (GAD65-DPD) Are Associated With Preserved β-Cell Functional Reserve in Ketosis-Prone Diabetes

Oak, Shilpa; Gaur, Lakshmi K.; Radtke, Jared; Patel, Roshni; Iyer, Dinakar; Ram, Nalini; Gaba, Ruchi; Balasubramanyam, Ashok; Hampe, Christiane S.

doi:10.1210/jc.2013-4189

Cited by 6 publications

(7 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The HLA-DRB1*1501-DQB1*0601 haplotype has been associated with either the presence or increased quantity of immunoglobulins of the IgG, IgA and IgM families both in healthy controls and in disease, including total immunoglobulins (Ferreira et al, 2010), antibodies induced by viruses such as Epstein-Barr virus (Rubicz et al, 2013), and autoantibodies in type 1 diabetes (Ishii et al, 2005) and Sjo ¨gren syndrome (Gottenberg et al, 2003) though an opposite correlation is seen for few other antibody responses (Sundqvist et al, 2014). HLA-DQA1*0301, highly correlated with SNP rs34083746, is associated with autoantibody negative disease in ketosis-prone diabetes (Oak et al, 2014). SNP rs6457617 is a major susceptibility factor in rheumatoid arthritis and systemic sclerosis, independent of classical HLA alleles (The International MHC and Autoimmunity Genetics Network, 2009;Radstake et al, 2010;Allanore et al, 2011;Orozco et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Genetic variants are major determinants of CSF antibody levels in multiple sclerosis

Goris

Pauwels

Gustavsen

et al. 2015

Brain

View full text Add to dashboard Cite

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.

show abstract

Section: Discussionmentioning

confidence: 99%

Genetic variants are major determinants of CSF antibody levels in multiple sclerosis

Goris

Pauwels

Gustavsen

et al. 2015

Brain

View full text Add to dashboard Cite

show abstract

“…The more moderate clinical course of A+ß+ KPD patients compared with A+ß- KPD patients may be related in part to epitope-specific antibodies to the 65-kDa isoform of glutamic acid decarboxylase (GAD65)[ 12 ]. Furthermore, a specific amino-terminal epitope defined by monoclonal antibody DPD is correlated with a higher beta-cell functional reserve and was associated with the milder A+ß+[ 13 ]. However, the mechanisms that create the autoantibody specificity and result in variable beta-cell functional reserve remains to be known.…”

Section: Pathophysiologymentioning

confidence: 99%

“…However, the mechanisms that create the autoantibody specificity and result in variable beta-cell functional reserve remains to be known. In healthy individuals, GAD65 antibodies (GAD65Ab) are present in the sera but are masked by anti-idiotypic antibodies[ 13 ]. Masked GAD65Ab specific for the epitope DPD is strongly associated with preserved beta-cell function among patients with KPD[ 13 ].…”

Section: Pathophysiologymentioning

confidence: 99%

Ketosis-prone diabetes mellitus: A phenotype that hospitalists need to understand

Boike¹,

Mir²,

Rauf³

et al. 2022

World J Clin Cases

View full text Add to dashboard Cite

Diabetes has been classified mainly into types 1 and 2. Some type 2 diabetes patients, when developing ketosis, have been labeled as having atypical diabetes. Lately, syndromes of ketosis-prone diabetes, primarily in patients who we previously classified as type 2 diabetics, have emerged, and calls are being made to even reclassify diabetes. This mini-review will extensively deal with the historical, molecular, phenotypical, and clinical basis of why ketosis-prone diabetes is different than the traditional principles of type 1 and 2 diabetes and should be classified as such. Clinicians, especially those who are not diabetologists or endocrinologists, as well as hospitalists, intensivists, and primary care providers, will greatly benefit from this review.

show abstract

“…For example, up to four different phenotypes have been described in KPD, depending on the presence or absence of islet cell autoantibodies (A − or A + ) and ␤ cell functional reserve (␤ − or ␤ + ). 37 This classification, based on both immunologic and ␤ cell function criteria, has the highest accuracy and predictive value in classifying patients with KPD with regard to clinical outcomes and pathophysiologic subtypes. 38 In addition, a long-term longitudinal follow-up study including KPD A − ␤ + patients has revealed that this phenotype comprises two distinct subtypes distinguished by whether T1D-associated HLA susceptibility is present or not.…”

Section: Subclassification Of Type 2 Diabetesmentioning

confidence: 99%

Precision medicine in diabetes: an opportunity for clinical translation

Merino

Florez

2018

Annals of the New York Academy of Sciences

View full text Add to dashboard Cite

Metabolic disorders present a public health challenge of staggering proportions. In diabetes, there is an urgent need to better understand disease heterogeneity, clinical trajectories, and related comorbidities. A pressing and timely question is whether we are ready for precision medicine in diabetes. Some biological insights that have emerged during the last decade have already been used to direct clinical decision making, especially in monogenic forms of diabetes. However, much work is necessary to integrate high-dimensional explorations into complex disease architectures, less penetrant biological alterations, and broader phenotypes, such as type 2 diabetes. In addition, for precision medicine to take hold in diabetes, reproducibility, interpretability, and actionability remain key guiding objectives. In this review, we examine how mounting data sets generated during the last decade to understand biological variability are now inspiring new venues to clarify diabetes nosology and ultimately translate findings into more effective prevention and treatment strategies.

show abstract

Masked and Overt Autoantibodies Specific to the DPD Epitope of 65-kDa Glutamate Decarboxylase (GAD65-DPD) Are Associated With Preserved β-Cell Functional Reserve in Ketosis-Prone Diabetes

Abstract: Masked GAD65Ab(DPD) are strongly associated with preserved β-cell functional reserve among patients with KPD. Absence of GAD65Ab(DPD) reactivity is associated with 2 HLA class II susceptibility haplotypes for autoimmune type 1 diabetes.

Cited by 6 publications

References 19 publications

Genetic variants are major determinants of CSF antibody levels in multiple sclerosis

Genetic variants are major determinants of CSF antibody levels in multiple sclerosis

Ketosis-prone diabetes mellitus: A phenotype that hospitalists need to understand

Precision medicine in diabetes: an opportunity for clinical translation

Contact Info

Product

Resources

About