Sunanda Babu | University of Colorado Denver (original) (raw)

Papers by Sunanda Babu

may be altered in chronic T1D. However, it is still unclear if this immune phenotypic variation i... more may be altered in chronic T1D. However, it is still unclear if this immune phenotypic variation is a cause or effect of T1D. Using polychromatic flow cytometry to analyze whole blood, we have extended to pediatric T1D patients the findings by others that adult T1D cases have increased expression of CD11b on monocytes as compared to apparently healthy non-T1D adults. We examined 37 T1D patients (age 9.2-18.3 years, median 14.4 years; median time past diagnosis for non-newly diagnosed cases = 4.3 years) and 63 healthy volunteers (age 9.9-60 years, median 34 years). CD11b expression (MFI) in HLA-DR+ monocyte subsets were as follows: on CD16+ monocytes, 265 ± 20 vs. 218 ± 10 (pediatric T1D cases vs. non-T1D adults); CD16+ CD14+ monocytes, 1108 ± 51 vs. 840 ± 27; CD14++ 'inflammatory' monocytes, 1479 ± 38 vs. 1146 ± 54. Expression levels of CCR2 on CD14++ monocytes were lower in T1D patients than in healthy volunteers (MFI 62 ± 2 vs. 75 ± 2), consistent with an activated monocyte phenotype. CD11b and CCR2 expression differences were independent of ages at diagnosis or at immunophenotyping. In order to help distinguish between cause and effect and begin to explore the possibility that extremes of these phenotypes may be precursors to disease, we will analyze age-matched subjects and unaffected siblings, and test the association of alleles of known T1D susceptibility genes (e.g., HLA haplotypes, INS, PTPN22, CD25, IFIH1, CTLA4) with monocyte-subset phenotypes.

Diabetes, Mar 1, 2008

OBJECTIVE-HLA-DRB1*03-DQB1*0201/DRB1*04-DQB1*0302 (DR3/4-DQ8) siblings who share both major histo... more OBJECTIVE-HLA-DRB1*03-DQB1*0201/DRB1*04-DQB1*0302 (DR3/4-DQ8) siblings who share both major histocompatibility complex (MHC) haplotypes identical-by-descent with their proband siblings have a higher risk for type 1A diabetes than DR3/4-DQ8 siblings who do not share both MHC haplotypes identical-bydescent. Our goal was to search for non-DR/DQ MHC genetic determinants that cause the additional risk in the DR3/4-DQ8 siblings who share both MHC haplotypes. RESEARCH DESIGN AND METHODS-We completed an extensive single nucleotide polymorphism (SNP) analysis of the extended MHC in 237 families with type 1A diabetes from the U.S. and 1,240 families from the Type 1 Diabetes Genetics Consortium. RESULTS-We found evidence for an association with type 1A diabetes (rs1233478, P ϭ 1.6 ϫ 10 Ϫ23 , allelic odds ratio 2.0) in the UBD/MAS1L region, telomeric of the classic MHC. We also observed over 99% conservation for up to 9 million nucleotides between chromosomes containing a common haplotype with the HLA-DRB1*03, HLA-B*08, and HLA-A*01 alleles, termed the "8.1 haplotype." The diabetes association in the UBD/MAS1L region remained significant both after chromosomes with the 8.1 haplotype were removed (rs1233478, P ϭ 1.4 ϫ 10 Ϫ12) and after adjustment for known HLA risk factors HLA-DRB1, HLA-DQB1, HLA-B, and HLA-A (P ϭ 0.01). CONCLUSIONS-Polymorphisms in the region of the UBD/ MAS1L genes are associated with type 1A diabetes independent of HLA class II and I alleles.

The Indian Journal of Medical Research

There is great interest in expanding the use of solid state detectors (SSD) in the field of parti... more There is great interest in expanding the use of solid state detectors (SSD) in the field of particle detection. For instance, extending the sensitivity of the detectors to lower energy particles could allow for simpler and thus smaller instrument designs. Several new technologies have been introduced recently in the region of semiconductor material for SSDs. This work will compare some of the more promising technologies to SSD material currently being used. In particular recent results from several laboratories make it possible to compare the properties of "100% internal quantum efficiency silicon photodiode", delta doped silicon, and silicon carbide (SiC) detectors and to compare these new technologies to pure silicon and germanium SSDs. The properties of interest are the detectors gain, ability to withstand the temperature extremes of space environments, radiation hardness, and responses to incident particles mass and energy particularly at low energies.

Progress in Photovoltaics: Research and Applications, 2011

Annals of the New York Academy of Sciences, 2004

T1DM is a disease that affects pancreatic beta cells and results in severe insulin depletion. T1D... more T1DM is a disease that affects pancreatic beta cells and results in severe insulin depletion. T1DM is a multigenic disease, and the strongest genetic association with this disease is shown by the genes in MHC class II, namely, DQA1 and DQB1. The other gene that has been implicated in susceptibility to T1DM is the MICA gene that lies within the MHC class I region. This gene has been investigated in many autoimmune diseases, including T1DM, in case-control as well as in family studies. The aim of our study was to test the transmission of MICA microsatellite alleles from unaffected parents to T1DM- affected offspring in HBDI multiplex nuclear families. We also looked at the transmission of MICA alleles together with high-risk DQA1-DQB1 haplotypes to determine the independent transmission of MICA alleles. We observed that MICA6 and MICA9 are transmitted to affected offspring less frequently than expected, and MICA5.1 was more frequently transmitted. DQA1 and DQB1 high-risk haplotypes were transmitted more frequently than expected and DQ6, which is a protective haplotype, was less frequently transmitted to affected offspring. Analysis of MICA-DQA1-DQB1 transmission showed that certain MICA alleles are preferably transmitted as a part of high-risk haplotypes, which might indicate that MICA together with high-risk HLA is associated with T1DM in this family material. However, this latter analysis should be repeated on a larger family sample.

Annals of the New York Academy of Sciences, 2006

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by autoimmune destruction ... more Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by autoimmune destruction of pancreatic β β β β cells. Genetic and environmental factors contribute in this disease. There is evidence that MHC class I chain-related gene (MIC-A) plays a role in the susceptibility to this and other autoimmune diseases. There are five alleles of the MIC-A gene, which consist of different repetitions of GCT. In particular, MIC-A alleles 5 and 5.1 (the former with five repetitions of GCT, the latter with five repetitions and one additional insertion of nucleotide G) have been found to be associated with susceptibility to and age at onset of T1DM. The aim of our study was to analyze the transmission of these MIC-A alleles to T1DM-affected offsprings in HBDI families. These are multiplex families with affected offsprings and unaffected parents. DNA samples were amplified for MIC-A using fluorescence-labeled primers and analyzed on an ABI prism DNA sequencer. The transmission of alleles was then analyzed using pedigrees of families also obtained from HBDI. We analyzed 78 families and found that MIC-A alleles 5 and 5.1 are present and transmitted more frequently than expected. Heterozygotic parents for MIC-A alleles 5 and 5.1 were excluded from the study. Our results suggest that MIC-A alleles 5 and 5.1 are associated with susceptibility to T1DM in family studies.

J Clin Endocrinol Metab, 2006

A significant percentage of nonautoimmune forms of diabetes presents among children in all age gr... more A significant percentage of nonautoimmune forms of diabetes presents among children in all age groups, with a remarkable increase with age. From October 1992 to October 2004, a total of 859 children less than 18 yr of age were newly diagnosed with diabetes at the Barbara Davis Center for Childhood Diabetes and had blood samples obtained within 2 wk of disease onset for analysis of antiislet autoantibodies to glutamic acid decarboxylase-65, insulinoma-associated antigen-2, insulin, and islet cell autoantibodies. The relationship of autoantibody positivity with human leukocyte antigen (HLA) class II, body mass index (BMI), glycosylated hemoglobin, age, and ethnicity was analyzed. Overall 19% (159 of 859) of these children with newly diagnosed diabetes were negative for all autoantibodies, and autoantibody negativity was significantly increased with age (P < 0.01). The Hispanic and Black subjects had significantly increased autoantibody negativity among older children with higher BMI than White subjects. The patients with the highest risk HLA genotype, DR3-DQ2/DR4-DQ8, were significantly less autoantibody negative (P = 0.001), whereas the HLA-protective allele, DQB1*0602, was significantly increased among the autoantibody-negative patients (P < 0.0001). Insulin autoantibodies were dramatically age dependent and were inversely correlated with age in both prevalence (P < 0.0001) and levels (P < 0.0001). Autoantibody positivity was inversely correlated with both BMI and age using multivariate analysis (P < 0.0001 and P = 0.0078, respectively). A significant percentage of children newly diagnosed with diabetes are negative for all antiislet autoantibodies with a marked increase in obesity-associated autoantibody-negative diabetes after age 10, suggesting diabetes heterogeneity at all ages.

Pediatric diabetes, Jan 8, 2016

Minnesota is home to the largest Somali population in USA, and pediatric diabetes teams are seein... more Minnesota is home to the largest Somali population in USA, and pediatric diabetes teams are seeing increasing numbers of Somali children with diabetes. To assess the immune basis of diabetes in Somali children in the Twin Cities, Minnesota. A total of 31 Somali children ≤19 yr were treated for type 1 diabetes (T1D) at the University of Minnesota Masonic Children's Hospital and Children's Hospitals and Clinics of Minnesota underwent analysis of human leukocyte antigen (HLA) alleles (n = 30) and diabetes autoantibodies [glutamic acid decarboxylase (GAD65), islet antigen 2 (IA-2), zinc transporter 8 (ZnT8); n = 31]. HLA alleles were analyzed in 49 Somalis without diabetes (controls). Anti-transglutaminase autoantibodies (TGA) for celiac disease were also measured. In Somali children with T1D aged 13.5 ± 5 yr (35% female, disease duration 6.5 ± 3.6 yr), the most common HLA allele was DRB1*03:01 (93%, compared with 45% of Somali controls), followed by DRB1*13:02 (27%). There was ...

The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013

There is controversy as to whether type 2 diabetes genetic susceptibility contributes to type 1 d... more There is controversy as to whether type 2 diabetes genetic susceptibility contributes to type 1 diabetes, and it is not known what proportion of islet autoantibody-negative new onset subjects have type 2 diabetes risk alleles. We designed this study to evaluate whether two type 2 diabetes-associated single nucleotide polymorphisms (SNPs) of transcription factor 7-like 2 (TCF7L2) gene are associated with the development of islet autoantibody-negative diabetes vs. islet autoantibody-positive diabetes in young patients and whether these SNPs are associated with specific clinical phenotypes. Autoantibody against glutamic acid decarboxylase 65, islet cell antibody 512bdc (form of IA-2), insulin, ZnT8 transporter, and cytoplasmic islet cell antibody were assayed in patients with new onset diabetes seen at the Barbara Davis Center using sera obtained within 2 wk of diagnosis. We genotyped two noncoding variants in the TCF7L2 gene, rs12255372 and rs7903146, in diabetic subjects and normal controls. A total of 140 patients (15.7%) were negative for all islet autoantibodies among 893 subjects less than age 25 at the onset of diabetes. The allele and genotype frequencies of two SNPs showed that these are associated (odds ratio up to 4) with the development of diabetes in the autoantibody-negative diabetic cohort, but not in the autoantibody-positive diabetic cohort. TCF7L2 type 2 diabetes susceptibility alleles are associated with islet autoantibody-negative but not autoantibody-positive new onset diabetes in young patients.

The Journal of Clinical Endocrinology and Metabolism, Jun 1, 2006

Context: Human leukocyte antigen (HLA) DQ haplotypes have the strongest genetic association with ... more Context: Human leukocyte antigen (HLA) DQ haplotypes have the strongest genetic association with type 1 diabetes (T1DM) risk.

Diabetes, Jan 28, 2016

The HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from development of ty... more The HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from 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 HLA-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 abnorma...

Journal of Clinical Endocrinology &amp Metabolism

Islet cell antigen (ICA) 512 also termed IA-2 is a novel autoantigen of type 1 diabetes, which ha... more Islet cell antigen (ICA) 512 also termed IA-2 is a novel autoantigen of type 1 diabetes, which has a tyrosine phosphatase-like domain. We have assessed autoantibody RIAs using a series of ICA512/IA-2 constructs to produce in vitro synthesized 35S-methionine-labeled proteins. Levels of ICA512/IA-2 (256-979, truncated aminoterminus) autoantibodies were strongly correlated with those of the full-length ICA512/IA-2 (1-979) autoantibodies (r = 0.96, P < 0.0001) and ICA512/IA-2 (687-979) autoantibodies (r = 0.98, P < 0.0001). RIAs using these 3 constructs had increased sensitivity relative to our initially reported ICA512 autoantibody RIA (amino acids 389-948, truncated carboxy- and aminoterminus). Only 2 of 38 sera examined in this study reacted with an aminoterminus ICA512/IA-2 (1-577) construct. The mean SD score (SD score = (index of unknown sample-mean index of controls)/SD of controls) using the ICA512/IA-2 (256-979) construct was significantly higher than the SD score obtained with other ICA512/IA-2 constructs (P < 0.001). Amongst patients with new-onset diabetes and prediabetic relatives, using RIAs for autoantibodies reacting with ICA512/IA-2 (256-979), insulin, and glutamic acid decarboxylase 65, 98% expressed one or more of these autoantibodies and 78% expressed two or more, whereas no control (n = 208) expressed more than a single autoantibody. A combined ICA512/IA-2 (256-979), glutamic acid decarboxylase 65 autoantibody RIA with differential autoantigen labeling (35S-methionine, 3H-leucine) has been developed that uses 96-well plate membrane filtration and Top Counter beta counting. Concordance between results of dual and single RIAs was greater than 90%. This simple combined autoantibody assay should facilitate large-scale autoantibody screening.

Type 1 diabetes and celiac disease are both immunologic disorders where specific HLA alleles are ... more Type 1 diabetes and celiac disease are both immunologic disorders where specific HLA alleles are associated with disease risk. We have developed a radioassay for autoantibodies to tissue transglutaminase (tTG) following the report that this enzyme is 'the' endomysial autoantigen (EMA) of celiac disease. The radioassay for transglutaminase autoantibodies is similar to that utilized for detecting anti-islet autoantibodies. The 'cut-off' for the IgA autoantibody assay was established as 3×100th percentile of 184 healthy control subjects at an index of 0.05. Ninety-eight of 847 patients with type 1 diabetes (11.6%) had tissue transglutaminase autoantibodies (tTG). All EMApositive patients were positive (49/49) for transglutaminase autoantibodies, as were 49/540 EMA-negative patients. Twenty transglutaminase-positive patients consented to intestinal biopsy and 15 biopsies were positive for celiac disease. All patients with a transglutaminase level greater than 0.70 (13/13) had a positive biopsy, while none (0/3) with a level <0.3 had a positive biopsy. The prevalence of transglutaminase autoantibodies was higher in diabetic patients with HLA DQ2 or DQ8. One third of DQ2 homozygous patients (22/68) expressed transglutaminase autoantibodies vs. less than 2% of patients lacking DQ2 or DQ8. A simple radioassay for IgA transglutaminase autoantibodies detects all endomysial antibody positive patients and detects transglutaminase autoantibodies in 5% of endomysial autoantibody negative patients. The prevalence of transglutaminase autoantibodies is associated with DQ2 and DQ8 and in particular DQ2 homozygosity. Autoimmunity to transglutaminase is remarkably prevalent amongst patients with type 1 diabetes expressing certain class II HLA alleles.

Endocrine Abstracts, 2014

Journal of Diabetes, 2011

Background: Measurement of anti-islet autoantibodies at the time of disease onset contributes gre... more Background: Measurement of anti-islet autoantibodies at the time of disease onset contributes greatly to the differentiation of Type 1A diabetes with HLA Class II subtyping also contributing. Methods: Blood samples were obtained from 900 patients with age from 1 month to 25 years (median age 11.1 years) within 2 weeks of diabetes onset to test anti-islet autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), insulinoma antigen (IA-2AA), the zinc transporter-8 (ZnT8AA), and islet-cell antibodies (ICA). Polymorphisms of the HLA Class II gene were typed in 547 randomly selected patients. Results: Of the 900 subjects analyzed, 145 (16.1%) were negative for all five anti-islet autoantibodies, and autoantibody negativity significantly increased with age: 10.2% (38 ⁄ 372) among children <10 years of age, 14.2% (46 ⁄ 325) in those 10-14 years of age, and 30.1% (61 ⁄ 203) in those >14 years of age (P < 0.001). The prevalence of IA-2AA was the highest among young children. The prevalence of GADA increased with age while the prevalence of IAA was inversely correlated with age. At diagnosis, the subjects with negative antibodies had a higher body mass index (P < 0.001) and less high risk HLA genotype DR3-DQ2 ⁄ DR4-DQ8 (P < 0.01). Conclusion: A large percentage of children and youths negative for all anti-islet autoantibodies at the onset of diabetes are likely to have the non-immune form, especially those without DR3 ⁄ DR4 and obese patients. Among autoantibody-positive Type 1A patients, IAA and GADA showed a reciprocal prevalence, suggesting differential disease pathogenesis.

Novartis Foundation symposium, 2008

A wealth of data in animal models indicates that type 1A diabetes results from T cell-mediated sp... more A wealth of data in animal models indicates that type 1A diabetes results from T cell-mediated specific destruction of islet beta cells. There is evidence for the NOD mouse model that insulin is the primary autoantigen and a specific insulin peptide B:9-23 is central to pathogenesis. It is also now possible to predict the development of type 1A (immune mediated) diabetes for the great majority of individuals with a combination of genetic, immunological and metabolic parameters. Such prediction is possible because of the chronic nature of the autoimmunity and loss of beta cell function that precedes the disease. Given the ability to predict type 1A diabetes trials at all stages of the disorder to prevent beta cell destruction are now possible.

may be altered in chronic T1D. However, it is still unclear if this immune phenotypic variation i... more may be altered in chronic T1D. However, it is still unclear if this immune phenotypic variation is a cause or effect of T1D. Using polychromatic flow cytometry to analyze whole blood, we have extended to pediatric T1D patients the findings by others that adult T1D cases have increased expression of CD11b on monocytes as compared to apparently healthy non-T1D adults. We examined 37 T1D patients (age 9.2-18.3 years, median 14.4 years; median time past diagnosis for non-newly diagnosed cases = 4.3 years) and 63 healthy volunteers (age 9.9-60 years, median 34 years). CD11b expression (MFI) in HLA-DR+ monocyte subsets were as follows: on CD16+ monocytes, 265 ± 20 vs. 218 ± 10 (pediatric T1D cases vs. non-T1D adults); CD16+ CD14+ monocytes, 1108 ± 51 vs. 840 ± 27; CD14++ 'inflammatory' monocytes, 1479 ± 38 vs. 1146 ± 54. Expression levels of CCR2 on CD14++ monocytes were lower in T1D patients than in healthy volunteers (MFI 62 ± 2 vs. 75 ± 2), consistent with an activated monocyte phenotype. CD11b and CCR2 expression differences were independent of ages at diagnosis or at immunophenotyping. In order to help distinguish between cause and effect and begin to explore the possibility that extremes of these phenotypes may be precursors to disease, we will analyze age-matched subjects and unaffected siblings, and test the association of alleles of known T1D susceptibility genes (e.g., HLA haplotypes, INS, PTPN22, CD25, IFIH1, CTLA4) with monocyte-subset phenotypes.

Diabetes, Mar 1, 2008

OBJECTIVE-HLA-DRB1*03-DQB1*0201/DRB1*04-DQB1*0302 (DR3/4-DQ8) siblings who share both major histo... more OBJECTIVE-HLA-DRB1*03-DQB1*0201/DRB1*04-DQB1*0302 (DR3/4-DQ8) siblings who share both major histocompatibility complex (MHC) haplotypes identical-by-descent with their proband siblings have a higher risk for type 1A diabetes than DR3/4-DQ8 siblings who do not share both MHC haplotypes identical-bydescent. Our goal was to search for non-DR/DQ MHC genetic determinants that cause the additional risk in the DR3/4-DQ8 siblings who share both MHC haplotypes. RESEARCH DESIGN AND METHODS-We completed an extensive single nucleotide polymorphism (SNP) analysis of the extended MHC in 237 families with type 1A diabetes from the U.S. and 1,240 families from the Type 1 Diabetes Genetics Consortium. RESULTS-We found evidence for an association with type 1A diabetes (rs1233478, P ϭ 1.6 ϫ 10 Ϫ23 , allelic odds ratio 2.0) in the UBD/MAS1L region, telomeric of the classic MHC. We also observed over 99% conservation for up to 9 million nucleotides between chromosomes containing a common haplotype with the HLA-DRB1*03, HLA-B*08, and HLA-A*01 alleles, termed the "8.1 haplotype." The diabetes association in the UBD/MAS1L region remained significant both after chromosomes with the 8.1 haplotype were removed (rs1233478, P ϭ 1.4 ϫ 10 Ϫ12) and after adjustment for known HLA risk factors HLA-DRB1, HLA-DQB1, HLA-B, and HLA-A (P ϭ 0.01). CONCLUSIONS-Polymorphisms in the region of the UBD/ MAS1L genes are associated with type 1A diabetes independent of HLA class II and I alleles.

The Indian Journal of Medical Research

There is great interest in expanding the use of solid state detectors (SSD) in the field of parti... more There is great interest in expanding the use of solid state detectors (SSD) in the field of particle detection. For instance, extending the sensitivity of the detectors to lower energy particles could allow for simpler and thus smaller instrument designs. Several new technologies have been introduced recently in the region of semiconductor material for SSDs. This work will compare some of the more promising technologies to SSD material currently being used. In particular recent results from several laboratories make it possible to compare the properties of "100% internal quantum efficiency silicon photodiode", delta doped silicon, and silicon carbide (SiC) detectors and to compare these new technologies to pure silicon and germanium SSDs. The properties of interest are the detectors gain, ability to withstand the temperature extremes of space environments, radiation hardness, and responses to incident particles mass and energy particularly at low energies.

Progress in Photovoltaics: Research and Applications, 2011

Annals of the New York Academy of Sciences, 2004

T1DM is a disease that affects pancreatic beta cells and results in severe insulin depletion. T1D... more T1DM is a disease that affects pancreatic beta cells and results in severe insulin depletion. T1DM is a multigenic disease, and the strongest genetic association with this disease is shown by the genes in MHC class II, namely, DQA1 and DQB1. The other gene that has been implicated in susceptibility to T1DM is the MICA gene that lies within the MHC class I region. This gene has been investigated in many autoimmune diseases, including T1DM, in case-control as well as in family studies. The aim of our study was to test the transmission of MICA microsatellite alleles from unaffected parents to T1DM- affected offspring in HBDI multiplex nuclear families. We also looked at the transmission of MICA alleles together with high-risk DQA1-DQB1 haplotypes to determine the independent transmission of MICA alleles. We observed that MICA6 and MICA9 are transmitted to affected offspring less frequently than expected, and MICA5.1 was more frequently transmitted. DQA1 and DQB1 high-risk haplotypes were transmitted more frequently than expected and DQ6, which is a protective haplotype, was less frequently transmitted to affected offspring. Analysis of MICA-DQA1-DQB1 transmission showed that certain MICA alleles are preferably transmitted as a part of high-risk haplotypes, which might indicate that MICA together with high-risk HLA is associated with T1DM in this family material. However, this latter analysis should be repeated on a larger family sample.

Annals of the New York Academy of Sciences, 2006

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by autoimmune destruction ... more Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by autoimmune destruction of pancreatic β β β β cells. Genetic and environmental factors contribute in this disease. There is evidence that MHC class I chain-related gene (MIC-A) plays a role in the susceptibility to this and other autoimmune diseases. There are five alleles of the MIC-A gene, which consist of different repetitions of GCT. In particular, MIC-A alleles 5 and 5.1 (the former with five repetitions of GCT, the latter with five repetitions and one additional insertion of nucleotide G) have been found to be associated with susceptibility to and age at onset of T1DM. The aim of our study was to analyze the transmission of these MIC-A alleles to T1DM-affected offsprings in HBDI families. These are multiplex families with affected offsprings and unaffected parents. DNA samples were amplified for MIC-A using fluorescence-labeled primers and analyzed on an ABI prism DNA sequencer. The transmission of alleles was then analyzed using pedigrees of families also obtained from HBDI. We analyzed 78 families and found that MIC-A alleles 5 and 5.1 are present and transmitted more frequently than expected. Heterozygotic parents for MIC-A alleles 5 and 5.1 were excluded from the study. Our results suggest that MIC-A alleles 5 and 5.1 are associated with susceptibility to T1DM in family studies.

J Clin Endocrinol Metab, 2006

A significant percentage of nonautoimmune forms of diabetes presents among children in all age gr... more A significant percentage of nonautoimmune forms of diabetes presents among children in all age groups, with a remarkable increase with age. From October 1992 to October 2004, a total of 859 children less than 18 yr of age were newly diagnosed with diabetes at the Barbara Davis Center for Childhood Diabetes and had blood samples obtained within 2 wk of disease onset for analysis of antiislet autoantibodies to glutamic acid decarboxylase-65, insulinoma-associated antigen-2, insulin, and islet cell autoantibodies. The relationship of autoantibody positivity with human leukocyte antigen (HLA) class II, body mass index (BMI), glycosylated hemoglobin, age, and ethnicity was analyzed. Overall 19% (159 of 859) of these children with newly diagnosed diabetes were negative for all autoantibodies, and autoantibody negativity was significantly increased with age (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). The Hispanic and Black subjects had significantly increased autoantibody negativity among older children with higher BMI than White subjects. The patients with the highest risk HLA genotype, DR3-DQ2/DR4-DQ8, were significantly less autoantibody negative (P = 0.001), whereas the HLA-protective allele, DQB1*0602, was significantly increased among the autoantibody-negative patients (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). Insulin autoantibodies were dramatically age dependent and were inversely correlated with age in both prevalence (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) and levels (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). Autoantibody positivity was inversely correlated with both BMI and age using multivariate analysis (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001 and P = 0.0078, respectively). A significant percentage of children newly diagnosed with diabetes are negative for all antiislet autoantibodies with a marked increase in obesity-associated autoantibody-negative diabetes after age 10, suggesting diabetes heterogeneity at all ages.

Pediatric diabetes, Jan 8, 2016

Minnesota is home to the largest Somali population in USA, and pediatric diabetes teams are seein... more Minnesota is home to the largest Somali population in USA, and pediatric diabetes teams are seeing increasing numbers of Somali children with diabetes. To assess the immune basis of diabetes in Somali children in the Twin Cities, Minnesota. A total of 31 Somali children ≤19 yr were treated for type 1 diabetes (T1D) at the University of Minnesota Masonic Children's Hospital and Children's Hospitals and Clinics of Minnesota underwent analysis of human leukocyte antigen (HLA) alleles (n = 30) and diabetes autoantibodies [glutamic acid decarboxylase (GAD65), islet antigen 2 (IA-2), zinc transporter 8 (ZnT8); n = 31]. HLA alleles were analyzed in 49 Somalis without diabetes (controls). Anti-transglutaminase autoantibodies (TGA) for celiac disease were also measured. In Somali children with T1D aged 13.5 ± 5 yr (35% female, disease duration 6.5 ± 3.6 yr), the most common HLA allele was DRB1*03:01 (93%, compared with 45% of Somali controls), followed by DRB1*13:02 (27%). There was ...

The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013

There is controversy as to whether type 2 diabetes genetic susceptibility contributes to type 1 d... more There is controversy as to whether type 2 diabetes genetic susceptibility contributes to type 1 diabetes, and it is not known what proportion of islet autoantibody-negative new onset subjects have type 2 diabetes risk alleles. We designed this study to evaluate whether two type 2 diabetes-associated single nucleotide polymorphisms (SNPs) of transcription factor 7-like 2 (TCF7L2) gene are associated with the development of islet autoantibody-negative diabetes vs. islet autoantibody-positive diabetes in young patients and whether these SNPs are associated with specific clinical phenotypes. Autoantibody against glutamic acid decarboxylase 65, islet cell antibody 512bdc (form of IA-2), insulin, ZnT8 transporter, and cytoplasmic islet cell antibody were assayed in patients with new onset diabetes seen at the Barbara Davis Center using sera obtained within 2 wk of diagnosis. We genotyped two noncoding variants in the TCF7L2 gene, rs12255372 and rs7903146, in diabetic subjects and normal controls. A total of 140 patients (15.7%) were negative for all islet autoantibodies among 893 subjects less than age 25 at the onset of diabetes. The allele and genotype frequencies of two SNPs showed that these are associated (odds ratio up to 4) with the development of diabetes in the autoantibody-negative diabetic cohort, but not in the autoantibody-positive diabetic cohort. TCF7L2 type 2 diabetes susceptibility alleles are associated with islet autoantibody-negative but not autoantibody-positive new onset diabetes in young patients.

The Journal of Clinical Endocrinology and Metabolism, Jun 1, 2006

Context: Human leukocyte antigen (HLA) DQ haplotypes have the strongest genetic association with ... more Context: Human leukocyte antigen (HLA) DQ haplotypes have the strongest genetic association with type 1 diabetes (T1DM) risk.

Diabetes, Jan 28, 2016

The HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from development of ty... more The HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from 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 HLA-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 abnorma...

Journal of Clinical Endocrinology &amp Metabolism

Islet cell antigen (ICA) 512 also termed IA-2 is a novel autoantigen of type 1 diabetes, which ha... more Islet cell antigen (ICA) 512 also termed IA-2 is a novel autoantigen of type 1 diabetes, which has a tyrosine phosphatase-like domain. We have assessed autoantibody RIAs using a series of ICA512/IA-2 constructs to produce in vitro synthesized 35S-methionine-labeled proteins. Levels of ICA512/IA-2 (256-979, truncated aminoterminus) autoantibodies were strongly correlated with those of the full-length ICA512/IA-2 (1-979) autoantibodies (r = 0.96, P &amp;amp;lt; 0.0001) and ICA512/IA-2 (687-979) autoantibodies (r = 0.98, P &amp;amp;lt; 0.0001). RIAs using these 3 constructs had increased sensitivity relative to our initially reported ICA512 autoantibody RIA (amino acids 389-948, truncated carboxy- and aminoterminus). Only 2 of 38 sera examined in this study reacted with an aminoterminus ICA512/IA-2 (1-577) construct. The mean SD score (SD score = (index of unknown sample-mean index of controls)/SD of controls) using the ICA512/IA-2 (256-979) construct was significantly higher than the SD score obtained with other ICA512/IA-2 constructs (P &amp;amp;lt; 0.001). Amongst patients with new-onset diabetes and prediabetic relatives, using RIAs for autoantibodies reacting with ICA512/IA-2 (256-979), insulin, and glutamic acid decarboxylase 65, 98% expressed one or more of these autoantibodies and 78% expressed two or more, whereas no control (n = 208) expressed more than a single autoantibody. A combined ICA512/IA-2 (256-979), glutamic acid decarboxylase 65 autoantibody RIA with differential autoantigen labeling (35S-methionine, 3H-leucine) has been developed that uses 96-well plate membrane filtration and Top Counter beta counting. Concordance between results of dual and single RIAs was greater than 90%. This simple combined autoantibody assay should facilitate large-scale autoantibody screening.

Type 1 diabetes and celiac disease are both immunologic disorders where specific HLA alleles are ... more Type 1 diabetes and celiac disease are both immunologic disorders where specific HLA alleles are associated with disease risk. We have developed a radioassay for autoantibodies to tissue transglutaminase (tTG) following the report that this enzyme is 'the' endomysial autoantigen (EMA) of celiac disease. The radioassay for transglutaminase autoantibodies is similar to that utilized for detecting anti-islet autoantibodies. The 'cut-off' for the IgA autoantibody assay was established as 3×100th percentile of 184 healthy control subjects at an index of 0.05. Ninety-eight of 847 patients with type 1 diabetes (11.6%) had tissue transglutaminase autoantibodies (tTG). All EMApositive patients were positive (49/49) for transglutaminase autoantibodies, as were 49/540 EMA-negative patients. Twenty transglutaminase-positive patients consented to intestinal biopsy and 15 biopsies were positive for celiac disease. All patients with a transglutaminase level greater than 0.70 (13/13) had a positive biopsy, while none (0/3) with a level <0.3 had a positive biopsy. The prevalence of transglutaminase autoantibodies was higher in diabetic patients with HLA DQ2 or DQ8. One third of DQ2 homozygous patients (22/68) expressed transglutaminase autoantibodies vs. less than 2% of patients lacking DQ2 or DQ8. A simple radioassay for IgA transglutaminase autoantibodies detects all endomysial antibody positive patients and detects transglutaminase autoantibodies in 5% of endomysial autoantibody negative patients. The prevalence of transglutaminase autoantibodies is associated with DQ2 and DQ8 and in particular DQ2 homozygosity. Autoimmunity to transglutaminase is remarkably prevalent amongst patients with type 1 diabetes expressing certain class II HLA alleles.

Endocrine Abstracts, 2014

Journal of Diabetes, 2011

Background: Measurement of anti-islet autoantibodies at the time of disease onset contributes gre... more Background: Measurement of anti-islet autoantibodies at the time of disease onset contributes greatly to the differentiation of Type 1A diabetes with HLA Class II subtyping also contributing. Methods: Blood samples were obtained from 900 patients with age from 1 month to 25 years (median age 11.1 years) within 2 weeks of diabetes onset to test anti-islet autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), insulinoma antigen (IA-2AA), the zinc transporter-8 (ZnT8AA), and islet-cell antibodies (ICA). Polymorphisms of the HLA Class II gene were typed in 547 randomly selected patients. Results: Of the 900 subjects analyzed, 145 (16.1%) were negative for all five anti-islet autoantibodies, and autoantibody negativity significantly increased with age: 10.2% (38 ⁄ 372) among children <10 years of age, 14.2% (46 ⁄ 325) in those 10-14 years of age, and 30.1% (61 ⁄ 203) in those >14 years of age (P < 0.001). The prevalence of IA-2AA was the highest among young children. The prevalence of GADA increased with age while the prevalence of IAA was inversely correlated with age. At diagnosis, the subjects with negative antibodies had a higher body mass index (P < 0.001) and less high risk HLA genotype DR3-DQ2 ⁄ DR4-DQ8 (P < 0.01). Conclusion: A large percentage of children and youths negative for all anti-islet autoantibodies at the onset of diabetes are likely to have the non-immune form, especially those without DR3 ⁄ DR4 and obese patients. Among autoantibody-positive Type 1A patients, IAA and GADA showed a reciprocal prevalence, suggesting differential disease pathogenesis.

Novartis Foundation symposium, 2008

A wealth of data in animal models indicates that type 1A diabetes results from T cell-mediated sp... more A wealth of data in animal models indicates that type 1A diabetes results from T cell-mediated specific destruction of islet beta cells. There is evidence for the NOD mouse model that insulin is the primary autoantigen and a specific insulin peptide B:9-23 is central to pathogenesis. It is also now possible to predict the development of type 1A (immune mediated) diabetes for the great majority of individuals with a combination of genetic, immunological and metabolic parameters. Such prediction is possible because of the chronic nature of the autoimmunity and loss of beta cell function that precedes the disease. Given the ability to predict type 1A diabetes trials at all stages of the disorder to prevent beta cell destruction are now possible.