The Rising Incidence of Type 1 Diabetes Is Accounted for by Cases With Lower-Risk Human Leukocyte Antigen Genotypes

OBJECTIVE—The rising incidence of type 1 diabetes has been attributed to environment, implying a lesser role for genetic susceptibility. However, the rise could be accounted for by either more cases with classic high-risk genes or by cases with other risk genes. Separately, for any degree of genetic susceptibility, age at presentation may decrease in a permissive environment. To examine these possibilities, human leukocyte antigen (HLA) class II DRB1 genes known to confer risk for type 1 diabetes were analyzed in relation to year of birth and age at diagnosis over the last five decades

Current Evidence for a Role of the Kynurenine Pathway of Tryptophan Metabolism in Multiple Sclerosis

The kynurenine pathway (KP) is the major metabolic pathway of the essential amino acid tryptophan (TRP). Stimulation by inflammatory molecules, such as interferon-γ (IFN-γ), is the trigger for induction of the KP, driving a complex cascade of production of both neuroprotective and neurotoxic metabolites, and in turn, regulation of the immune response and responses of brain cells to the KP metabolites. Consequently, substantial evidence has accumulated over the past couple of decades that dysregulation of the KP and the production of neurotoxic metabolites are associated with many neuroinflammatory and neurodegenerative diseases, including Parkinson's disease, AIDS-related dementia, motor neurone disease, schizophrenia, Huntington's disease, and brain cancers. In the past decade, evidence of the link between the KP and multiple sclerosis (MS) has rapidly grown and has implicated the KP in MS pathogenesis. KP enzymes, indoleamine 2,3-dioxygenase (IDO-1) and tryptophan dioxygenase (highest expression in hepatic cells), are the principal enzymes triggering activation of the KP to produce kynurenine from TRP. This is in preference to other routes such as serotonin and melatonin production. In neurological disease, degradation of the blood-brain barrier, even if transient, allows the entry of blood monocytes into the brain parenchyma. Similar to microglia and macrophages, these cells are highly responsive to IFN-γ, which upregulates the expression of enzymes, including IDO-1, producing neurotoxic KP metabolites such as quinolinic acid. These metabolites circulate systemically or are released locally in the brain and can contribute to the excitotoxic death of oligodendrocytes and neurons in neurological disease principally by virtue of their agonist activity at N-methyl-d-aspartic acid receptors. The latest evidence is presented and discussed. The enzymes that control the checkpoints in the KP represent an attractive therapeutic target, and consequently several KP inhibitors are currently in clinical trials for other neurological diseases, and hence may make suitable candidates for MS patients. Underpinning these drug discovery endeavors, in recent years, several advances have been made in how KP metabolites are assayed in various biological fluids, and tremendous advancements have been made in how specimens are imaged to determine disease progression and involvement of various cell types and molecules in MS.22 page(s

HLA Class I and Genetic Susceptibility to Type 1 Diabetes: Results From the Type 1 Diabetes Genetics Consortium

OBJECTIVE-We report here genotyping data and type 1 diabetes association analyses for HLA class I loci (A, B, and C) on 1,753 multiplex pedigrees from the Type 1 Diabetes Genetics Consortium (T1DGC), a large international collaborative study. RESEARCH DESIGN AND METHODS-Complete eight-locus HLA genotyping data were generated. Expected patient class I (HLA-A, -B, and -C) allele frequencies were calculated, based on linkage disequilibrium (LD) patterns with observed HLA class II DRB1-DQA1-DQB1 haplotype frequencies. Expected frequencies were compared to observed allele frequencies in patients. RESULTS-Significant type 1 diabetes associations were observed at all class I HLA loci. After accounting for LD with HLA class II, the most significantly type 1 diabetes-associated alleles were B*5701 (odds ratio 0.19; P = 4 x 10(-11)) and B*3906 (10.31; P = 4 X 10(-10)). Other significantly type 1 diabetes-associated alleles included A*2402, A*0201, B*1801, and C*0501 (predisposing) and A*1101, A*3201, A*6601, B*0702, B*4403, B*3502, C*1601, and C*0401 (protective). Some alleles, notably B*3906, appear to modulate the risk of all DRB1-DQA1-DQB1 haplotypes on which they reside, suggesting a class I effect that is independent of class H. Other class I type 1 diabetes associations appear to be specific to individual class H haplotypes. Some apparent associations (e.g., C*1601) could be attributed to strong LD to another class I susceptibility locus (B*4403). CONCLUSIONS-These data indicate that HLA class I alleles, in addition to and independently from HLA class H alleles, are associated with type 1 diabetes. Diabetes 59:2972-2979, 201

HLA DPA1, DPB1 Alleles and Haplotypes Contribute to the Risk Associated With Type 1 Diabetes: Analysis of the Type 1 Diabetes Genetics Consortium Families

OBJECTIVE-To determine the relative risk associated with DPA1 and DPB1 alleles and haplotypes in type I diabetes. RESEARCH DESIGN AND METHODS-The frequency of DPA1 and DPB1 alleles and haplotypes in type I diabetic patients was compared to the family based control frequency in 1,771 families directly and conditional on FILA (B)-DRB1-DQA1-DQB1 linkage disequilibrium. A relative predispositional analysis (RPA) was performed in the presence or absence of the primary HLA DR-DQ associations and the contribution of DP haplotype to individual DR-DQ haplotype risks examined. RESULTS-Eight DPAI and thirty-eight DPB1 alleles forming seventy-four DPA1-DPB1 haplotypes were observed, nineteen DPB1 alleles were associated with multiple DPA1 alleles Following both analyses, type I diabetes susceptibility was significantly associated with DPB1*0301 (DPA1*0103-DPB1*0301) and protection with DPB1*0402 (DPA1*0103-DPB1*0402) and DPA1*0103-DPB1*0101 but not DPA1*0201-DPB1*0101. In addition, DPB1*0202 (DPA1*0103-DPB1*0202) and DPB1*0201 (DPA1*0103-DPB1*0201) were significantly associated with susceptibility in the presence of the high risk and protective DR-DQ haplotypes Three associations (DPB1*0301, *0402, and *0202) remained statistically significant when only the extended HLA-A1-B8-DR3 haplotype was considered, suggesting that DPB1 alone may delineate the risk associated with this otherwise conserved haplotype CONCLUSIONS-HLA DP allelic and haplotypic diversity contributes significantly to the risk for type I diabetes; DPB1*0301 (DPA1*0103-DPB1*0301) is associated with susceptibility and DPB1*0402 (DPA1*0103-DPB1*0402) and DPA1*0103-DPB1*0101 with protection Additional evidence is presented for the susceptibility association of DPB1*0202 (DPA1*0103-DPB1*0202) and for a contributory role of individual amino acids and DPA1 or a gene in linkage disequilibrium in DR3-DPB1*0101 positive haplotypes Diabetes 59:2055-2062, 201

Engineered 2D Ising interactions on a trapped-ion quantum simulator with hundreds of spins

The presence of long-range quantum spin correlations underlies a variety of physical phenomena in condensed matter systems, potentially including high-temperature superconductivity. However, many properties of exotic strongly correlated spin systems (e.g., spin liquids) have proved difficult to study, in part because calculations involving N-body entanglement become intractable for as few as N~30 particles. Feynman divined that a quantum simulator - a special-purpose "analog" processor built using quantum particles (qubits) - would be inherently adept at such problems. In the context of quantum magnetism, a number of experiments have demonstrated the feasibility of this approach. However, simulations of quantum magnetism allowing controlled, tunable interactions between spins localized on 2D and 3D lattices of more than a few 10's of qubits have yet to be demonstrated, owing in part to the technical challenge of realizing large-scale qubit arrays. Here we demonstrate a variable-range Ising-type spin-spin interaction J_ij on a naturally occurring 2D triangular crystal lattice of hundreds of spin-1/2 particles (9Be+ ions stored in a Penning trap), a computationally relevant scale more than an order of magnitude larger than existing experiments. We show that a spin-dependent optical dipole force can produce an antiferromagnetic interaction J_ij ~ 1/d_ij^a, where a is tunable over 0<a<3; d_ij is the distance between spin pairs. These power-laws correspond physically to infinite-range (a=0), Coulomb-like (a=1), monopole-dipole (a=2) and dipole-dipole (a=3) couplings. Experimentally, we demonstrate excellent agreement with theory for 0.05<a<1.4. This demonstration coupled with the high spin-count, excellent quantum control and low technical complexity of the Penning trap brings within reach simulation of interesting and otherwise computationally intractable problems in quantum magnetism.Comment: 10 pages, 10 figures; article plus Supplementary Material

Sexual orientation and symptoms of common mental disorder or low wellbeing: combined meta-analysis of 12 UK population health surveys

Background Previous studies have indicated increased risk of mental disorder symptoms, suicide and substance misuse in lesbian, gay and bisexual (LGB) adults, compared to heterosexual adults. Our aims were to determine an estimate of the association between sexual orientation identity and poor mental health and wellbeing among adults from 12 population surveys in the UK, and to consider whether effects differed for specific subgroups of the population. Methods Individual data were pooled from the British Cohort Study 2012, Health Survey for England 2011, 2012 and 2013, Scottish Health Survey 2008 to 2013, Longitudinal Study of Young People in England 2009/10 and Understanding Society 2011/12. Individual participant meta-analysis was used to pool estimates from each study, allowing for between-study variation. Results Of 94,818 participants, 1.1 % identified as lesbian/gay, 0.9 % as bisexual, 0.8 % as ‘other’ and 97.2 % as heterosexual. Adjusting for a range of covariates, adults who identified as lesbian/gay had higher prevalence of common mental disorder when compared to heterosexuals, but the association was different in different age groups: apparent for those under 35 (OR = 1.78, 95 % CI 1.40, 2.26), weaker at age 35–54.9 (OR = 1.42, 95 % CI 1.10, 1.84), but strongest at age 55+ (OR = 2.06, 95 % CI 1.29, 3.31). These effects were stronger for bisexual adults, similar for those identifying as ‘other’, and similar for 'low wellbeing'. Conclusions In the UK, LGB adults have higher prevalence of poor mental health and low wellbeing when compared to heterosexuals, particularly younger and older LGB adults. Sexual orientation identity should be measured routinely in all health studies and in administrative data in the UK in order to influence national and local policy development and service delivery. These results reiterate the need for local government, NHS providers and public health policy makers to consider how to address inequalities in mental health among these minority groups

HLA genotyping in the international Type 1 Diabetes Genetics Consortium

Background Although human leukocyte antigen (HLA) DQ and DR loci appear to confer the strongest genetic risk for type 1 diabetes, more detailed information is required for other loci within the HLA region to understand causality and stratify additional risk factors. The Type 1 Diabetes Genetics Consortium (T1DGC) study design included high-resolution genotyping of HLA-A, B, C, DRB1, DQ, and DP loci in all affected sibling pair and trio families, and cases and controls, recruited from four networks worldwide, for analysis with clinical phenotypes and immunological markers

A Polymorphism in the HLA-DPB1 Gene Is Associated with Susceptibility to Multiple Sclerosis

We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each ). All associations were significant in an independent replication cohort of 2212 cases and 2251 controls () and were highly significant in the combined dataset (). The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD) with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set , replication set , combined ). HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association