Genome-wide search for genes affecting the age at diagnosis of type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease affecting individuals in the early years of life. Although previous studies have identified genetic loci influencing T1D diagnosis age, these studies did not investigate the genome with high resolution. OBJECTIVE AND METHODS: We performed a genome-wide meta-analysis for age at diagnosis with cohorts from Finland (Finnish Diabetic Nephropathy Study), the United Kingdom (UK Genetic Resource Investigating Diabetes) and Sardinia. Through SNP associations, transcriptome-wide association analysis linked T1D diagnosis age and gene expression. RESULTS: We identified two chromosomal regions associated with T1D diagnosis age: multiple independent variants in the HLA region on chromosome 6 and a locus on chromosome 17q12. We performed gene-level association tests with transcriptome prediction models from two whole blood datasets, lymphocyte cell line, spleen, pancreas and small intestine tissues. Of the non-HLA genes, lower PNMT expression in whole blood, and higher IKZF3 and ZPBP2, and lower ORMDL3 and GSDMB transcription levels in multiple tissues were associated with lower T1D diagnosis age (FDR = 0.05). These genes lie on chr17q12 which is associated with T1D, other autoimmune diseases, and childhood asthma. Additionally, higher expression of PHF20L1, a gene not previously implicated in T1D, was associated with lower diagnosis age in lymphocytes, pancreas, and spleen. Altogether, the non-HLA associations were enriched in open chromatin in various blood cells, blood vessel tissues and foetal thymus tissue. CONCLUSION: Multiple genes on chr17q12 and PHF20L1 on chr8 were associated with T1D diagnosis age and only further studies may elucidate the role of these genes for immunity and T1D onset.

Population structure of modern-day Italians reveals patterns of ancient and archaic ancestries in Southern Europe.

European populations display low genetic differentiation as the result of long-term blending of their ancient founding ancestries. However, it is unclear how the combination of ancient ancestries related to early foragers, Neolithic farmers, and Bronze Age nomadic pastoralists can explain the distribution of genetic variation across Europe. Populations in natural crossroads like the Italian peninsula are expected to recapitulate the continental diversity, but have been systematically understudied. Here, we characterize the ancestry profiles of Italian populations using a genome-wide dataset representative of modern and ancient samples from across Italy, Europe, and the rest of the world. Italian genomes capture several ancient signatures, including a non-steppe contribution derived ultimately from the Caucasus. Differences in ancestry composition, as the result of migration and admixture, have generated in Italy the largest degree of population structure detected so far in the continent, as well as shaping the amount of Neanderthal DNA in modern-day populations.

Novel NALCN biallelic truncating mutations in siblings with IHPRF1 syndrome.

Infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1) is a severe autosomal recessive neurologic disorder with onset at birth or in early infancy. It is caused by mutations in the NALCN gene that encodes a voltage-independent, cation channel permeable to NM, K+ and Ca2+ and forms a channel complex with UNCSO and UNC79. So far, only 4 homozygous mutations have been found in 11 cases belonging to 4 independent consanguineous families. We studied a Sardinian family with 2 siblings presenting dysmorphic facies, hypotonia, psychomotor retardation, epilepsy, absent speech, sleep disturbance, hyperkinetic movement disorder, cachexia and chronic constipation. Polymorphic generalized seizures started at 4 and 6 years, respectively. Anti-epileptic drugs (AEDs) therapy was efficient for female proband's epilepsy, but the male still has weekly seizures. Whole exome sequencing identified 2 novel truncating mutations in NALCN allowing to assess the clinical phenotype to IHPRF1. This is the fifth family reported worldwide, and these are the first European cases with IHPRF1 syndrome with biallelic truncating mutations of NALCN.

Somatic, positive and negative domains of the Center for Epidemiological Studies Depression (CES-D) scale: a meta-analysis of genome-wide association studies.

BACKGROUND: Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains. METHOD: We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons). RESULTS: One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (p discovery = 3.82 × 10-8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (p discovery+replication = 1.10 × 10-6) with evidence of heterogeneity. CONCLUSIONS: Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.

No evidence of association between subclinical thyroid disorders and common carotid intima medial thickness or atherosclerotic plaque.

BACKGROUND AND AIMS: Increased carotid artery intima-media thickness (IMT) and the presence of plaques have been shown to be predictors of cardiovascular disease. The cardiovascular risk in patients with overt thyroid diseases is related to increased risk of atherosclerosis, but there has been no clear evidence about subclinical disorders. We have assessed whether subclinical thyroid dysfunction is associated with arterial thickening and plaque. METHODS AND RESULTS: The SardiNIA study is a population-based survey on the Italian island of Sardinia. We reviewed data from 5815 subjects (aged 14-102 years), none of whom had overt hyperthyroidism or hypothyroidism or was taking thyroid medication. Serum thyrotropin (TSH), free thyroxine, together with carotid ultrasound IMT and the presence of common carotid plaques were analysed in all subjects. Possible association of IMT and carotid plaques with thyroid parameters was evaluated by univariate and multivariate analyses. IMT was significantly associated with age, sex, smoking, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol, pulse pressure (PP), history of arterial hypertension, diabetes, and previous cardiovascular events (p = 0.001 or lower, R(2) = 0.47). Carotid plaques were predicted by age, sex, LDL, PP, history of diabetes, previous cardiovascular events, and the use of statins (p = 0.029 or lower). Thyroid hormone was not predictive of carotid atherosclerosis when adjusted for confounders. CONCLUSION: Thyroid hormone is not associated with increased IMT or with the presence of carotid artery plaque. Our data do not support the idea that treating subclinical disorders might help to prevent arterial remodelling or carotid atherosclerosis.

Differential activation of accumbens shell and core dopamine by sucrose reinforcement with nose poking and with lever pressing.

In order to investigate the role of modus operandi in the changes of nucleus accumbens (NAc) dopamine (DA) transmission in sucrose reinforcement, extracellular DA was monitored by microdialysis in the NAc shell and core of rats trained on a fixed-ratio 1 schedule to respond for sucrose pellets by nose poking and lever pressing respectively. After training, rats were tested on three different sessions: sucrose reinforcement, extinction and passive sucrose presentation. In rats responding by nose poking dialysate DA increased in the shell but not in the core under reinforced as well as under extinction sessions. In contrast, in rats responding by lever pressing dialysate DA increased both in the accumbens shell and core under reinforced and extinction sessions. Response non-contingent sucrose presentation increased dialysate DA in the shell and core of rats trained to respond for sucrose by nose poking as well as in those trained by lever pressing. In rats trained to respond for sucrose by nose poking on a FR5 schedule dialysate DA also increased selectively in the NAc shell during reinforced responding and in both the shell and core under passive sucrose presentation. These findings, while provide an explanation for the discrepancies existing in the literature over the responsiveness of shell and core DA in rats responding for food, are consistent with the notion that NAc shell and core DA encode different aspects of reinforcement.

Nucleus accumbens shell and core dopamine responsiveness to sucrose in rats: role of response contingency and discriminative/conditioned cues.

This study investigated by microdialysis the role of response contingency and food-associated cues in the responsiveness of dopamine transmission in the nucleus accumbens shell and core to sucrose feeding. In naive rats, single-trial non-contingent presentation and feeding of sucrose pellets increased dialysate shell dopamine and induced full habituation of dopamine responsiveness to sucrose feeding 24 and 48 h later. In rats trained to respond for sucrose pellets on a fixed ratio 1 (FR1) schedule, dialysate dopamine increased in the shell but not in the core during active responding as well as under extinction in the presence of sucrose cues. In rats yoked to the operant rats, the presentation of sucrose cues also increased dialysate dopamine selectively in the shell. In contrast, non-contingent sucrose presentation and feeding in FR1-trained and in yoked rats increased dialysate dopamine to a similar extent in the shell and core. It is concluded that, whereas non-contingent sucrose feeding activated dopamine transmission in the shell and core, response-contingent feeding activated, without habituation, dopamine transmission selectively in the shell as a result of the action of sucrose conditioned cues. These observations are consistent with a critical role of conditioned cues acquired during training and differential activation of shell vs. core dopamine for response-contingent sucrose feeding.

A trans-specific polymorphism in ZC3HAV1 is maintained by long-standing balancing selection and may confer susceptibility to multiple sclerosis.

The human ZC3HAV1 gene encodes an antiviral protein. The longest splicing isoform of ZC3HAV1 contains a C-terminal PARP-like domain, which has evolved under positive selection in primates. We analyzed the evolutionary history of this same domain in humans and in Pan troglodytes. We identified two variants that segregate in both humans and chimpanzees; one of them (rs3735007) does not occur at a hypermutable site and accounts for a nonsynonymous substitution (Thr851Ile). The probability that the two trans-specific polymorphisms have occurred independently in the two lineages was estimated to be low (P = 0.0054), suggesting that at least one of them has arisen before speciation and has been maintained by selection. Population genetic analyses in humans indicated that the region surrounding the shared variants displays strong evidences of long-standing balancing selection. Selection signatures were also observed in a chimpanzee population sample. Inspection of 1000 Genomes data confirmed these findings but indicated that search for selection signatures using low-coverage whole-genome data may need masking of repetitive sequences. A case-control study of more than 1,000 individuals from mainland Italy indicated that the Thr851Ile SNP is significantly associated with susceptibility to multiple sclerosis (MS) (odds ratio [OR] = 1.47, 95% confidence intervals [CI]: 1.08-1.99, P = 0.011). This finding was confirmed in a larger sample of 4,416 Sardinians cases/controls (OR = 1.18, 95% CI: 1.037-1.344, P = 0.011), but not in a population from Belgium. We provide one of the first instances of human/chimpanzee trans-specific coding variant located outside the major histocompatibility complex region. The selective pressure is likely to be virus driven; in modern populations, this variant associates with susceptibility to MS, possibly via the interaction with environmental factors.

Meta-analysis of genome-wide association studies identifies common variants in CTNNA2 associated with excitement-seeking.

The tendency to seek stimulating activities and intense sensations define excitement-seeking, a personality trait akin to some aspects of sensation-seeking. This trait is a central feature of extraversion and is a component of the multifaceted impulsivity construct. Those who score high on measures of excitement-seeking are more likely to smoke, use other drugs, gamble, drive recklessly, have unsafe/unprotected sex and engage in other risky behaviors of clinical and social relevance. To identify common genetic variants associated with the Excitement-Seeking scale of the Revised NEO Personality Inventory, we performed genome-wide association studies in six samples of European ancestry (N=7860), and combined the results in a meta-analysis. We identified a genome-wide significant association between the Excitement-Seeking scale and rs7600563 (P=2 × 10(-8)). This single-nucleotide polymorphism maps within the catenin cadherin-associated protein, alpha 2 (CTNNA2) gene, which encodes for a brain-expressed α-catenin critical for synaptic contact. The effect of rs7600563 was in the same direction in all six samples, but did not replicate in additional samples (N=5105). The results provide insight into the genetics of excitement-seeking and risk-taking, and are relevant to hyperactivity, substance use, antisocial and bipolar disorders.

Number of autoantibodies and HLA genotype, more than high titers of glutamic acid decarboxylase autoantibodies, predict insulin dependence in latent autoimmune diabetes of adults.

OBJECTIVE: In latent autoimmune diabetes of adults (LADA), the progression into insulin-dependent diabetes is usually faster than in type 2 diabetes (T2D) but the factors influencing this progression are not completely known. In this study, we searched for sensitive markers associated with early development of insulin dependence. DESIGN: The screening of 5568 T2D patients for glutamic acid decarboxylase autoantibodies (GAD65Ab) identified 276 LADA patients (M=131; F=145) and in 251 of them, tyrosine phosphatase-2 (IA-2Ab) and thyroperoxidase autoantibodies (TPOAbs), some clinical features and genotype variation of the main type 1 diabetes (T1D) disease susceptibility loci (HLA-DRB1 and HLA-DQB1) were analyzed. RESULTS: Four years after the diagnosis of diabetes, high GAD65Ab titer was not significantly associated with faster progression toward insulin deficiency (P=0.104). Patients with GAD65Ab and TPOAb or IA-2Ab or triple positivity for both islet and TPOAbs (GAD65Ab/IA-2Ab/TPOAb) showed a significantly faster disease progression (P=0.002). Among 104 TPOAb-positive LADA patients, 10 received replacement therapy (l-thyroxine), 43 showed high TSH levels (62.7% developed insulin dependence), and 3 had hyperthyroidism treated with methimazole. Multivariate analysis revealed a significant effect on disease progression only for TPOAb (P=0.022), female gender (P=0.036), low body mass index (BMI; P=0.001), and T1D high/intermediate risk HLA-DRB1/DQB1 genotypes grouped (P=0.020). CONCLUSIONS: High GAD65Ab titers per se are not a major risk factor for disease progression in LADA, while the number of positive autoantibodies and HLA DRB1-DQB1 genotypes at high risk for T1D are significant predictors. Moreover, clinical characteristics such as low BMI and female gender are more likely to identify patients who will require insulin therapy within 4 years of diagnosis.

Variation within the CLEC16A gene shows consistent disease association with both multiple sclerosis and type 1 diabetes in Sardinia.

Variation within intron 19 of the CLEC16A (KIAA0350) gene region was recently found to be unequivocally associated with type 1 diabetes (T1D) in genome-wide association (GWA) studies in Northern European populations. A variant in intron 22 that is nearly independent of the intron 19 variant showed suggestive evidence of association with multiple sclerosis (MS). Here, we genotyped the rs725613 polymorphism, representative of the earlier reported associations with T1D within CLEC16A, in 1037 T1D cases, 1498 MS cases and 1706 matched controls, all from the founder, autoimmunity-prone Sardinian population. In these Sardinian samples, allele A of rs725613 is positively associated not only with T1D (odds ratio=1.15, P one-tail=5.1 x 10(-3)) but also, and with a comparable effect size, with MS (odds ratio=1.21, P one-tail 6.7 x 10(-5)). Taken together these data provide evidence of joint disease association in T1D and MS within CLEC16A and underline a shared disease pathway.

Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis.

The direct involvement of the human leukocyte antigen class II DR-DQ genes in type 1 diabetes (T1D) is well established, and these genes display a complex hierarchy of risk effects at the genotype and haplotype levels. We investigated, using data from 38 studies, whether the DR-DQ haplotypes and genotypes show the same relative predispositional effects across populations and ethnic groups. Significant differences in risk within a population were considered, as well as comparisons across populations using the patient/control (P/C) ratio. Within a population, the ratio of the P/C ratios for two different genotypes or haplotypes is a function only of the absolute penetrance values, allowing ranking of risk effects. Categories of consistent predisposing, intermediate ('neutral'), and protective haplotypes were identified and found to correlate with disease prevalence and the marked ethnic differences in DRB1-DQB1 frequencies. Specific effects were identified, for example for predisposing haplotypes, there was a statistically significant and consistent hierarchy for DR4 DQB1*0302s: DRB1*0405 =*0401 =*0402 > *0404 > *0403, with DRB1*0301 DQB1*0200 (DR3) being significantly less predisposing than DRB1*0402 and more than DRB1*0404. The predisposing DRB1*0401 DQB1*0302 haplotype was relatively increased compared with the protective haplotype DRB1*0401 DQB1*0301 in heterozygotes with DR3 compared with heterozygotes with DRB1*0101 DQB1*0501 (DR1). Our results show that meta-analyses and use of the P/C ratio and rankings thereof can be valuable in determining T1D risk factors at the haplotype and amino acid residue levels.

Genetic testing improves the diagnosis of adult type hypolactasia in the Mediterranean population of Sardinia.

OBJECTIVE: Recently, the C/T-13910 polymorphism on chromosome 2q21 in North-European populations has been found completely associated with lactase activity and its genetic typing proposed as first-stage screening test for adult hypolactasia. However, the C/T-13910 variant in some sub-Saharan African groups is not a predictor of lactase persistence. In this work, we wanted to verify if in the Mediterranean island of Sardinia, located in Southern Europe, the C/T-13910 polymorphism may be useful or not for the diagnosis of adult type hypolactasia. DESIGN: Validation study of a genetic testing for adult type hypolactasia in Sardinians. SETTING: Brotzu Hospital and Microcitemico Hospital, Cagliari, Italy. SUBJECTS: The sample consisted in 84 Sardinian individuals (63 women and 21 men; range 20-73 years) selected from a group of 832 patients. METHODS: Genetic testing was compared to an improved test obtained by a combination of different breath hydrogen tests and clinical assessment. RESULTS: We found that all 49 individuals with lactose malabsorption, demonstrated by a combination of different breath hydrogen tests and clinical assessment, carried the C/C-13910 genotype associated with lactase non-persistence, 23 individuals with lactose normal absorption carried the C/T-13910 genotype associated with lactase persistence and only one person with the above phenotype showed a discordant C/C-13910 genotype. The genetic testing showed very high sensitivity, specificity, positive and negative predictive values of 100, 95.8, 98 and 100%, respectively. CONCLUSIONS: Sardinians, unlike some ethnic groups in sub-Saharan Africa, show the same genetic association of hypolactasia with the C/T-13910 variant as other North-European populations. The genetic testing for the C/T-13910 variant may contribute to improving the diagnosis of adult type hypolactasia.

Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease.

Alleles of HLA class II genes DQB1, DQA1, and DRB1 in the MHC region are major determinants of genetic predisposition to type 1 diabetes (T1D). Several alleles of each of these three loci are associated with susceptibility or protection from disease. In addition, relative risks for some DR-DQ genotypes are not simply the sum or product of the single haplotype relative risks. For example, the risk of the DRB1*03-DQB1*02/DRB1*0401-DQB1*0302 genotype is often found to be higher than for the individual DRB1*03-DQB1*02 and DRB1*0401-DQB1*0302 homozygous genotypes. It has been hypothesized that this synergy or epistasis occurs through formation of highly susceptible trans-encoded HLA-DQ(alpha 1, beta 1) heterodimers. Here, we evaluated this hypothesis by estimating the disease associations of the range of DR-DQ genotypes and their inferred dimers in a large collection of nuclear families. We determined whether the risk of haplotypes in DRB1*0401-DQB1*0302-positive genotypes relative to the DRB1*03-DQB1*02-positive genotypes is different from that of DRB1*01-DQB1*0501, which we used as a baseline reference. Several haplotypes showed a different risk compared to DRB1*01-DQB1*0501, which correlated with their ability to form certain trans-encoded DQ dimers. This result provides new evidence for the potential importance of trans-encoded HLA DQ molecules in the determination of HLA-associated risk in T1D.

Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene.

Variations in the interleukin 4 receptor A (IL4RA) gene have been reported to be associated with atopy, asthma, and allergy, which may occur less frequently in subjects with type 1 diabetes (T1D). Since atopy shows a humoral immune reactivity pattern, and T1D results from a cellular (T lymphocyte) response, we hypothesised that alleles predisposing to atopy could be protective for T1D and transmitted less often than the expected 50% from heterozygous parents to offspring with T1D. We genotyped seven exonic single nucleotide polymorphisms (SNPs) and the -3223 C>T SNP in the putative promoter region of IL4RA in up to 3475 T1D families, including 1244 Finnish T1D families. Only the -3223 C>T SNP showed evidence of negative association (P=0.014). There was some evidence for an interaction between -3233 C>T and the T1D locus IDDM2 in the insulin gene region (P=0.001 in the combined and P=0.02 in the Finnish data set). We, therefore, cannot rule out a genetic effect of IL4RA in T1D, but it is not a major one.

[Correlation between major histocompatibility complex (MHC)-class II and type 1 diabetes]. / Correlazione fra MHC di classe II e diabete mellito di tipo 1.

The autoimmune disease type 1 diabetes (T1D) results from a T lymphocyte-dependent, selective destruction of the insulin-producing pancreatic beta-cells and subsequent irreversible insulin deficiency. The disease is caused by a combination of genetic and environmental factors. Numerous genetic, structural and biological studies have provided a convincing case that in human T1D and in its murine model, the non obese diabetes (NOD) mouse, the major histocompatibility complex (MHC) class II molecules, HLA-DQB1 and -DRB1 and their murine orthologues, IA and IE, are the major genetic determinants. The two loci act as a complex superlocus, with both haplotype- and genotype-specific effects. In humans the HLA class II molecule-association with the disease is constituted by a two-sided gradient from positively associated-high risk to negatively associated-low risk molecules. Very low risk corresponds to dominant protection from the disease. The protein structure of DQ/IA and DR/IE molecules have been established. Molecular modeling work revealed that there are marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules show conserved similarities that differ with the shared structural patterns observed between the protective molecules. The available data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall these observations suggest shared pathways in human and murine T1D.

Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia.

Several studies have indicated that multiple sclerosis (MS) is associated and linked to the major histocompatibility complex (MHC)/human leukocyte antigen (HLA) region of chromosome 6p21.3, but the exact location and nature of the primarily associated locus within the HLA complex is still controversial and largely presumptive. By linkage disequilibrium mapping, we have systematically investigated this chromosome region in the founder population of Sardinia to determine the relative associations of the various loci with MS. An overall 11.4 Mb region, which encompasses the whole HLA complex, was scanned with 19 microsatellite markers and with single nucleotide polymorphisms within 12 functional candidate genes and assessed for MS association using the extended transmission disequilibrium test (ETDT). A peak of association represented by the three adjacent DRB1, -DQA1 and -DQB1 loci was detected in the class II region. Two additional less significant areas of association were detected, respectively, in the centromeric side of the class II region at the DPB1 locus and, telomeric of the classically defined class I loci, at the D6S1683 microsatellite. Conditional ETDT analysis indicated that these regions of association could be independent of each other. Within the main peak of association, DRB1 and DQB1 contribute to the disease association independently of each other whereas DQA1 had no detectable primary genetic effects. We evaluated the haplotype distribution at the region showing the strongest association and found five DQB1-DRB1 haplotypes positively associated with MS in Sardinia. These consistently included all the haplotypes previously found associated with MS in the various human populations, thus supporting a primary effect of the products of these loci in MS. Overall these results are consistent with a multilocus model of the MHC encoded susceptibility to MS.

A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins.

In human type 1 diabetes (T1D) and in its murine model, the major histocompatibility complex (MHC) class II molecules, human leukocyte antigens (HLA)-DQ and -DR and their murine orthologues, IA and IE, are the major genetic determinants. In this report, we have ranked HLA class II molecule-associated T1D risk in a two-sided gradient from very high to very low. Very low risk corresponded to dominant protection from T1D. We predicted the protein structure of DQ by using the published crystal structures of different allotypes of the murine orthologue of DQ, IA. We discovered marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules showed conserved similarities that contrasted with the shared patterns observed between the protective molecules. We also found striking inter-isotypic conservation between protective DQ, IA allotypes and protective DR4 subtypes. The data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall, these results suggest shared epitope(s) in the target autoantigen(s), and common pathways in human and murine T1D.

No evidence for SEL1L as a candidate gene for IDDM11-conferred susceptibility.

BACKGROUND: The SEL1L gene is located on human chromosome 14q24.3-31 close to D14S67 which has been previously proposed to be a type 1 diabetes mellitus locus (IDDM11). Sel-1 is a negative regulator of the Notch signalling pathway and SEL1L is selectively expressed in adult pancreas and islets of Langerhans. This suggests that SEL1L may be a candidate gene for IDDM11. METHODS: We have analysed two newly identified CA-repeat polymorphisms within the genomic sequence of the SEL1L locus for association with type 1 diabetes mellitus (T1DM) in 152 Danish T1DM-affected sib-pair families and in 240 Sardinian families (229 simplex and 11 sib-pair families). RESULTS: No evidence for association of the two SEL1L markers with T1DM was observed in either the Danish or the Sardinian families. We have also used allelic sharing methods to analyse linkage with T1DM in the IDDM11 region using the same markers and the Danish collection of affected sib-pair families. No evidence of linkage was observed (Z(max)=0.86). CONCLUSION: Although several lines of evidence suggest that SEL1L might be a candidate for IDDM11-conferred susceptibility to T1DM the present study does not support this hypothesis.

The HLA-DPB1--associated component of the IDDM1 and its relationship to the major loci HLA-DQB1, -DQA1, and -DRB1.

The major histocompatibility complex (MHC) HLA region on chromosome 6p21 contains the major locus of type 1 diabetes (IDDM1). Common allelic variants at the class II HLA-DRB1, -DQA1, and -DQB1 loci account for the major part of IDDM1. Previous studies suggested that other MHC loci are likely to contribute to IDDM1, but determination of their relative contributions and identities is difficult because of strong linkage disequilibrium between MHC loci. One prime candidate is the polymorphic HLA-DPB1 locus, which (with the DPA1 locus) encodes the third class II antigen-presenting molecule. However, the results obtained in previous studies appear to be contradictory. Therefore, we have analyzed 408 white European families (200 from Sardinia and 208 from the U.K.) using a combination of association tests designed to directly compare the effect of DPB1 variation on the relative predisposition of DR-DQ haplotypes, taking into account linkage disequilibrium between DPB1 and the DRB1, DQA1, and DQB1 loci. In these populations, the overall contribution of DPB1 to IDDM1 is small. The main component of the DPB1 contribution to IDDM1 in these populations appears to be the protection associated with DPB1*0402 on DR4-negative haplotypes. We suggest that the HLA-DP molecule itself contributes to IDDM1.