HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study.

OBJECTIVES: Tissue transglutaminase autoantibodies (tTGAs) represent the first evidence of celiac disease (CD) development. Associations of HLA-DR3-DQA1*05:01-DQB1*02:01 (i.e., DR3-DQ2) and, to a lesser extent, DR4-DQA1*03:01-DQB1*03:02 (i.e., DR4-DQ8) with the risk of CD differ by country, consistent with additional genetic heterogeneity that further refines risk. Therefore, we examined human leukocyte antigen (HLA) factors other than DR3-DQ2 for their contribution to developing tTGAs. METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 infants at an increased HLA-DR-DQ risk for type 1 diabetes and CD into a 15-year prospective surveillance follow-up. Of those followed up, 21% (n=1,813) carried DR3-DQ2/DR3-DQ2, 39% (n=3,359) carried DR3-DQ2/DR4-DQ8, 20% (n=1701) carried DR4-DQ8/DR4-DQ8, and 17% (n=1,493) carried DR4-DQ8/DQ4. Within TEDDY, a nested case-control design of 248 children with CD autoimmunity (CDA) and 248 matched control children were genotyped for HLA-B, -DRB3, -DRB4, -DPA1, and -DPB1 genes, and the entire cohort was genotyped for single-nucleotide polymorphisms (SNPs) using the Illumina ImmunoChip. CDA was defined as a positive tTGA test at two consecutive clinic visits, whereas matching in those with no evidence of tTGAs was based on the presence of HLA-DQ2, country, and sex. RESULTS: After adjustment for DR3-DQ2 and restriction to allele frequency (AF) ≥5%, HLA-DPB1*04:01 was inversely associated with CDA by conditional logistic regression (AF=44%, odds ratio=0.71, 95% confidence interval (CI)=0.53-0.96, P=0.025). This association of time to CDA and HLA-DPB1*04:01 was replicated with statistical significance in the remainder of the cohort using imputation for specific HLA alleles based on SNP genotyping (hazard ratio=0.84, 95% CI=0.73-0.96, P=0.013). CONCLUSIONS: HLA-DPB1*04:01 may reduce the risk of tTGAs, an early marker of CD, among DR3-DQ2 children, confirming that additional variants in the HLA region influence the risk for CDA.

Juvenile idiopathic arthritis and HLA class I and class II interactions and age-at-onset effects.

OBJECTIVE: The aim of this study was to quantitate risk and to examine heterogeneity for HLA at high resolution in patients with the most common subtypes of juvenile idiopathic arthritis (JIA), IgM rheumatoid factor-negative polyarticular JIA and oligoarticular JIA. Use of 4-digit comprehensive HLA typing enabled great precision, and a large cohort allowed for consideration of both age at disease onset and disease subtype. METHODS: Polymerase chain reaction-based high-resolution HLA typing for class I and class II loci was accomplished for 820 patients with JIA and 273 control subjects. Specific HLA epitopes, potential interactions of alleles at specific loci and between loci (accounting for linkage disequilibrium and haplotypic associations), and an assessment of the current International League of Associations for Rheumatology classification criteria were considered. RESULTS: An HLA-DRB1/DQB1 effect was shown to be exclusively attributable to DRB1 and was similar between patients with oligoarticular JIA and a younger subgroup of patients with polyarticular JIA. Furthermore, patients with polyarticular JIA showed age-specific related effects, with disease susceptibility in the group older than age 6 years limited to an effect of the HLA-DRB1*08 haplotype, which is markedly different from the additional susceptibility haplotypes, HLA-DRB1*1103/1104, found in the group with oligoarticular JIA and the group of younger patients with polyarticular JIA. Also in contrast to findings for oligoarticular JIA, patients with polyarticular arthritis had no evidence of an HLA class I effect. Markers associated with a reduced risk of disease included DRB1*1501, DRB1*0401, and DRB1*0701. DRB1*1501 was shown to reduce risk across the whole cohort, whereas DRB1*0401 and DRB1*0701 were protective for selected JIA subtypes. Surprisingly, the disease predisposition mediated by DPB1*0201 in individuals without any disease-predisposing DRB1 alleles was great enough to overcome even the very strong protective effect observed for DRB1*1501. CONCLUSION: Inherited HLA factors in JIA show similarities overall as well as differences between JIA subtypes.

Polymorphism in the human major histocompatibility complex and early viral decline during treatment of chronic hepatitis C.

The dynamics of the viral decline immediately after the start of therapy for chronic hepatitis C virus (HCV) infection may have prognostic potential for ultimate sustained virologic response. Considerable interindividual variability in the decline has been reported, including differences by race. The human major histocompatability complex (MHC) genes encode the human leukocyte antigens, which are important in the immune response to viral infections. We examined whether carriage of specific human MHC alleles are associated with the rate of the early viral decline. Longitudinal viral level data (baseline and days 1, 2, 7, 14, and 28 of treatment), medium resolution MHC genotyping, and random coefficients models were used to examine associations between MHC class I and class II allele carriage and the dynamics of the viral decline in 180 African-Americans (AAs) and 194 Caucasian Americans (CAs) with genotype-1 HCV infection over the first 28 days of treatment with peginterferon alpha2a plus ribavirin. Baseline viral levels were similar by race, irrespective of allele carriage. However, the rate of change in the viral decline was associated with both allele and race. Among the four subgroups defined by race and specific allele, the fastest rates of decline were observed (in terms of estimated mean viral declines log(10) IU/ml during the first four weeks) in CA noncarriers for A*03 (2.75; P = 0.018), in CA carriers for Cw*03 (2.99; P = 0.046), and in CA noncarriers for DQA1*04 (2.66; P = 0.018) or DQB1*0402 (2.65; P = 0.018). MHC alleles are associated with the viral decline during the first 28 days of peginterferon therapy.

The oral splicing modifier RG7800 increases full length survival of motor neuron 2 mRNA and survival of motor neuron protein: Results from trials in healthy adults and patients with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a rare genetic and progressively debilitating neuromuscular disease. It is the leading genetic cause of death among infants. In SMA, low levels of survival of motor neuron (SMN) protein lead to motor neuron death and muscle atrophy as the SMN protein is critical to motor neuron survival. SMA is caused by mutations in, or deletion of, the SMN1 gene. A second SMN gene, SMN2, produces only low levels of functional SMN protein due to alternative splicing which excludes exon 7 from most transcripts, generating truncated, rapidly degraded SMN protein. Patients with SMA rely on limited expression of functional SMN full-length protein from the SMN2 gene, but insufficient levels are generated. RG7800 is an oral, selective SMN2 splicing modifier designed to modulate alternative splicing of SMN2 to increase the levels of functional SMN protein. In two trials, oral administration of RG7800 increased in blood full-length SMN2 mRNA expression in healthy adults and SMN protein levels in SMA patients by up to two-fold, which is expected to provide clinical benefit.

"Extended" A1, B8, DR3 haplotype shows remarkable linkage disequilibrium but is similar to nonextended haplotypes in terms of diabetes risk.

To evaluate potential differential diabetes risk of DR3 haplotypes we have evaluated class I alleles as well as two microsatellites previously associated with differential risk associated with DR3 haplotypes. We found that over one-third of patient DR3 chromosomes consisted of an extended DR3 haplotype, from DQ2 to D6S2223 (DQ2, DR3, D6S273-143, MIC-A5.1, HLA-B8, HLA-Cw7, HLA-A1, and D6S2223-177) with an identical extended haplotype in controls. The extended haplotype was present more frequently (35.1% of autoimmune-associated DR3 haplotypes, 39.4% of control DR3 haplotypes) than other haplotypes (no other haplotype >5% of DR3 haplotypes) and remarkably conserved, but it was not transmitted from parents to affected children more frequently than nonconserved DR3-bearing haplotypes. This suggests that if all alleles are truly identical for the major A1, B8, DR3 haplotype (between A1 and DR3), with different alleles on nonconserved haplotypes without differential diabetes risk, then in this region of the genome DR3-DQ2 may be the primary polymorphisms of common haplotypes contributing to diabetes risk.

Association of non-HLA genes with type 1 diabetes autoimmunity.

Approximately 50% of the genetic risk for type 1 diabetes is attributable to the HLA region. We evaluated associations between candidate genes outside the HLA region-INS, cytotoxic T-lymphocyte-associated antigen (CTLA)-4, interleukin (IL)-4, IL-4R, and IL-13 and islet autoimmunity among children participating in the Diabetes Autoimmunity Study in the Young (DAISY). Children with persistent islet autoantibody positivity (n = 102, 38 of whom have already developed diabetes) and control subjects (n = 198) were genotyped for single nucleotide polymorphisms (SNPs) in the candidate genes. The INS-23Hph1 polymorphism was significantly associated with both type 1 diabetes (OR = 0.30; 95% CI 0.13-0.69) and persistent islet autoimmunity but in the latter, only in children with the HLA-DR3/4 genotype (0.40; 0.18-0.89). CTLA-4 promoter SNP was significantly associated with type 1 diabetes (3.52; 1.22-10.17) but not with persistent islet autoimmunity. Several SNPs in the IL-4 regulatory pathway appeared to have a predisposing effect for type 1 diabetes. Associations were found between both IL-4R haplotypes and IL-4-IL-13 haplotypes and persistent islet autoimmunity and type 1 diabetes. This study confirms the association between the INS and CTLA-4 loci and type 1 diabetes. Genes involved in the IL-4 regulatory pathway (IL-4, IL-4R, IL-13) may confer susceptibility or protection to type 1 diabetes depending on individual SNPs or specific haplotypes.

Celiac disease and HLA in a Bedouin kindred.

We report the prevalence of celiac disease (CD) and its relationship with other autoimmune diseases and HLA haplotypes in a Bedouin kindred. Of 175 individuals sampled and typed for autoantibodies and HLA class II genotypes, six (3.4%) members had CD, and an additional 10 (5.7%) members tested positive for autoantibodies to transglutaminase (TgAA+). Several CD/TgAA+ relatives also had islet cell antigen or adrenal autoimmunity. Affected relatives are more closely related than expected from the pedigree relationships of all family members and were more often the offspring of consanguineous marriages. Individuals with CD or TgAA+ were enriched for DRB1*0301-DQA1*0501-DQB1*0201, a haplotype previously reported as high risk for CD. There was also an increased frequency of DQB1*0201/DQB1*0201 homozygotes among affected relatives. We found no evidence that DRB1*0701-DQA1*0201-DQB1*0201/DRB1*11-DQA1*0501-DQB1*0301 is a high-risk genotype, consistent with other studies of Arab communities. In addition, a nonparametric linkage analysis of 376 autosomal markers revealed suggestive evidence for linkage on chromosome 12p13 at marker D12S364 (NPL = 2.009, p = 0.0098). There were no other significant results, including the HLA region or any other previously reported regions. This could reflect the reduced power of family-based linkage and association analyses in isolated inbred populations.

DPB1 alleles are associated with type 1 diabetes susceptibility in multiple ethnic groups.

Genetic associations between type 1 diabetes and alleles at the HLA class II locus DPB1 have been previously reported. Observed associations could be due to variation in the DPB1 locus itself or to linkage disequilibrium (LD) between DPB1 alleles and other susceptibility loci. One measure of whether the association of an allele with a disease reflects a true effect of the locus or is simply due to LD is the observation of that association in multiple ethnic groups. Previous type 1 diabetes associations have been reported for DPB1*0301 and DPB1*0202 (predisposing) and for DPB1*0402 (protective). In this study, results are reported from testing these associations in three different sample sets: 1) Puerto Rican case and control subjects, 2) Mexican-American simplex families, and 3) high-risk (DR3/DR4) individuals with and without an affected relative. DPB1*0301 was associated in all three groups, even after accounting for LD with DRB1-DQB1. DPB1*0202 and DPB1*0402 were positively and negatively associated, respectively, in two of the three populations. These results suggest that the observed DPB1 associations, especially that of the DPB1*0301 allele, with type 1 diabetes are likely to be true associations. This supports the concept that multiple genes in the HLA region can affect type 1 diabetes susceptibility.

Biomarker for Spinal Muscular Atrophy: Expression of SMN in Peripheral Blood of SMA Patients and Healthy Controls.

Spinal muscular atrophy is caused by a functional deletion of SMN1 on Chromosome 5, which leads to a progressive loss of motor function in affected patients. SMA patients have at least one copy of a similar gene, SMN2, which produces functional SMN protein, although in reduced quantities. The severity of SMA is variable, partially due to differences in SMN2 copy numbers. Here, we report the results of a biomarker study characterizing SMA patients of varying disease severity. SMN copy number, mRNA and Protein levels in whole blood of patients were measured and compared against a cohort of healthy controls. The results show differential regulation of expression of SMN2 in peripheral blood between patients and healthy subjects.

The HLA class I A locus affects susceptibility to type 1 diabetes.

Human leukocyte antigen A (HLA-A) genotypes were determined for samples from 283 multiplex, Caucasian, type 1 diabetes families from the Human Biological Data Interchange (HBDI) using an immobilized probe assay. Distribution of HLA-A alleles transmitted to patients was significantly different from that in affected family-based controls (AFBAC) (p = 0.004). Transmission disequilibrium test (TDT) analysis revealed differential transmission of several HLA-A alleles from parents to affected offspring. HLA class II DRB1 and DQB1 loci were also typed, allowing assignment of HLA-A alleles to haplotypes and calculation of linkage disequilibrium values. Some of the apparent effects of HLA-A alleles on type 1 diabetes susceptibility were attributable to linkage disequilibrium with DR and DQ alleles, although others were not. The differences in frequencies between patients and controls of alleles A*0101, A*2402, and A*3002 could not be explained by linkage disequilibrium alone. Our results suggest an important role for class I antigens in modulating susceptibility to type 1 diabetes.

Ethnic differences in the associations between the HLA-DRB1*04 subtypes and type 1 diabetes.

The HLA genotype DRB1*03,DQB1*0201/DRB1*04,DQB1*0302 confers a 25-fold increase in the risk of type 1 diabetes. In persons with this genotype, DRB1*0405, *0402, and *0401 subtypes have been reported to further increase risk, whereas the *0403 and *0406 alleles confer a relative protection. We compared the frequencies of the DRB1*04 alleles in 193 type 1 diabetic patients with the HLA-DRB1*03,DQB1*0201/DRB1*04,DQB1*0302 genotype (140 non-Hispanic white [NHW] and 53 Hispanic) and 205 nondiabetic controls (142 NHW and 63 Hispanic). In addition, 87 NHW first-degree relatives of type 1 diabetes patients were studied: 33 positive and 54 negative for autoantibodies to insulin, GAD65, or IA-2. The HLA-DRB1 was typed using standard PCR SSOP methods. DRB1*0401 (OR, 2.19; 95% CI, 1.36-3.54) in NHW and *0405 (OR, 3.78; 95% CI, 1.43-10.0) in Hispanics were significantly associated with T1DM, whereas DRB1*0403 was protective (OR, 0.19; 95% CI, 0.04-0.89 in NHWs; OR, 0.10; 95% CI, 0.01-0.83 in Hispanics). Associations between the DRB1*04 alleles and prediabetic islet autoimmunity were generally in the same direction as those with diabetes. Among diabetic patients, the mean age of diagnosis appeared to be higher among those with the *0403 and *0407 allele compared with the others. In summary, on the DRB1*03,DQB1*0201/DRB1*04,DQB1*0302 genotypes, the *0403 allele confers relative protection from type 1 diabetes and development of islet autoantibodies in both Hispanics and NHWs and is associated with older age at diabetes diagnosis. Although the associations between diabetes and *0401 and *0405 appear to differ somewhat between Hispanics and NHWs, overall there is no significant difference between these two ethnic groups.

Do non-HLA genes influence development of persistent islet autoimmunity and type 1 diabetes in children with high-risk HLA-DR,DQ genotypes?

OBJECTIVE: Specific alleles of non-HLA genes INS, CTLA-4, and PTPN22 have been associated with type 1 diabetes. We examined whether some of these alleles influence development of islet autoimmunity or progression from persistent islet autoimmunity to type 1 diabetes in children with high-risk HLA-DR,DQ genotypes. RESEARCH DESIGN AND METHODS: Since 1993, the Diabetes Autoimmunity Study in the Young (DAISY) has followed 2,449 young children carrying HLA-DR,DQ genotypes associated with type 1 diabetes. Of those, 112 have developed islet autoimmunity (persistent autoantibodies to insulin, GAD65, and/or IA-2), and 47 of these have progressed to type 1 diabetes. The influence of polymorphisms of INS(-23Hph1), CTLA-4(T17A), and PTPN22(R620W) on development of persistent islet autoimmunity and progression to type 1 diabetes was evaluated by parametric models and by survival analyses. RESULTS: PTPN22(R620W) allele T was associated with development of persistent islet autoimmunity (hazard ratio 1.83 [95% CI 1.27-2.63]) controlling for ethnicity, presence of HLA-DR3/4,DQB1*0302, and having a first-degree relative with type 1 diabetes. Survival analyses showed a significantly (P = 0.002) higher risk of persistent islet autoimmunity by age 10 years for the TT genotype (27.3%) than for the CT or CC genotype (7.9 and 5.3%, respectively). Cumulative risk of persistent islet autoimmunity was slightly higher (P = 0.02) for the INS(-23Hph1) AA genotype (7.8%) than for the AT or TT genotype (4.2 and 6.4% risk by age 10 years, respectively). CONCLUSIONS: Whereas the HLA-DR3/4,DQB1*0302 genotype had a dramatic influence on both development of islet autoimmunity and progression to type 1 diabetes, the PTPN22(R620W) T allele significantly influences progression to persistent islet autoimmunity in the DAISY cohort.

Newborn HLA-DR,DQ genotype screening: age- and ethnicity-specific type 1 diabetes risk estimates.

OBJECTIVE: Certain human leukocyte antigen (HLA)-DR,DQ genotypes have been associated with type 1 diabetes mellitus (T1DM) risk, although it is unknown whether the association is due to alleles, haplotypes, genotypes, the formation of heterodimers, or all of the above. To characterize the role of the HLA-DR,DQ genotype and ethnicity on the onset age of T1DM, we analyzed these factors in patients with T1DM and the general population. METHODS: One thousand three hundred twenty-two well-characterized patients with T1DM were compared with 3339 children from the general population of Denver, Colorado, USA. Because of the extensive available data across age and ethnic groups, this study population is unique. RESULTS: The HLA-DR3/4,DQB1*0302, DRX/4,DQB1*0302 (where X=1, 4, 8, and 9), and HLA--DR3/3 genotypes were associated with T1DM, supporting previous research. Additionally, the DR3/9 genotype showed a positive association with T1DM, which has not previously been described in Caucasian populations. The HLA-DR3/4*0302 genotype was most strongly associated with T1DM in diabetic individuals with the youngest onset age. Genotype frequencies were similar between Hispanics and non-Hispanic whites, except for the DR3/3 genotype, which was more likely to be found in non-Hispanic whites. CONCLUSIONS: These results indicate that there are multiple alleles and genotypes associated with T1DM and that the risk associated with different genetic markers depends on the age of disease onset, suggesting that some markers may be involved in more rapid disease progression.

Homozygosity for premature stop codon of the MHC class I chain-related gene A (MIC-A) is associated with early activation of islet autoimmunity of DR3/4-DQ2/8 high risk DAISY relatives.

We hypothesized that homozygosity for the major histocompatibility complex (MHC) class I chain-related gene A (MIC-A)5.1 allele with premature stop codon would increase diabetes risk of individuals followed from infancy in the DAISY study (Diabetes Autoimmunity Study in the young). Forty five percent (10/22) of relatives (siblings and offspring cohort, SOC) who developed anti-islet autoantibodies were MIC-A5.1/5.1 homozygous. Of SOC individuals without autoantibodies, 12/58 (19%, p = 0.02) were MIC-A5.1 homozygous. By life table analysis of expression of autoantibodies, DR3-DQ2/ DR4-DQ8 more than 50% of MIC-A5.1 homozygous children became autoantibody positive by 7 years of age, compared to delayed development of autoantibodies for non-MIC-A5.1/5.1 DR3-DQ2/ DR4-DQ8 children (p = 0.005). For DR3-DQ2/DR4-DQ8 nonrelatives, the risk of activating anti-islet autoimmunity remained low even with MIC-A5.1 homozygosity suggesting that there are additional factors contributing to the marked risk of relatives compared to the general population with the DR3-DQ2/DR4-DQ8 genotype.

Association and interaction of the IL4R, IL4, and IL13 loci with type 1 diabetes among Filipinos.

In the search for genes involved in type 1 diabetes (T1D), other than the well-established risk alleles at the human leukocyte antigen loci, we have investigated the association and interaction of polymorphisms in genes involved in the IL4/IL13 pathway in a sample of 90 Filipino patients with T1D and 94 controls. Ten single-nucleotide polymorphisms (SNPs), including two promoter SNPs in the IL4R locus on chromosome 16p11, one promoter SNP in the IL4 locus on chromosome 5q31, and four SNPs--including two promoter SNPs--in the IL13 locus on chromosome 5q31 were examined for association, linkage disequilibrium, and interaction. We found that both individual SNPs (IL4R L389L; odds ratio [OR] 0.34; 95% confidence interval [CI] 0.17-0.67; P=.001) and specific haplotypes both in IL4R (OR 0.10; 95% CI 0-0.5; P=.001) and for the five linked IL4 and IL13 SNPs (OR 3.47; P=.004) were strongly associated with susceptibility to T1D. Since IL4 and IL13 both serve as ligands for a receptor composed, in part, of the IL4R alpha chain, we looked for potential epistasis between polymorphisms in the IL4R locus on chromosome 16p11 and the five SNPs in the IL4 and IL13 loci on chromosome 5q31 and found, through use of a logistic-regression model, significant gene-gene interactions (P=.045, corrected for multiple comparisons by permutation analysis). Our data suggest that the risk for T1D is determined, in part, by polymorphisms within the IL4R locus, including promoter and coding-sequence variants, and by specific combinations of genotypes at the IL4R and the IL4 and IL13 loci.

HLA-DRB1 genotype associations in 793 white patients from a rheumatoid arthritis inception cohort: frequency, severity, and treatment bias.

OBJECTIVE: The HLA-DRB1 "shared epitope" (SE) genotypes are associated with rheumatoid arthritis (RA), but it remains controversial whether the association is with incidence, severity, or both, whether there are associations in seronegative patients, and whether different DRB1 alleles that contain the SE have similar effects on RA susceptibility and/or severity. The present study was undertaken to study these issues in a large cohort of patients with RA. METHODS: White patients with RA of <6 months' duration (n = 793) were enrolled in an inception cohort. HLA-DRB1 typing was performed, and patients were categorized into 21 DRB1 genotype groups. The disability index of the Health Assessment Questionnaire was the primary outcome measure. RESULTS: DRB1 associations in seronegative RA patients closely resembled those in controls. Of seropositive patients, 21% had 2 copies of the epitope, 52% had 1 copy, and 27% had none. However, not all genotypes with 1 copy were associated with increased susceptibility; for example, frequencies of DRB1*0404/X and *01/X did not differ from those in controls. Absolute differences between seropositive RA patients and controls were greatest for DRB1*0401 homozygosity (3.8% versus 0.8%, respectively) and *0401/0404 heterozygosity (4.7% versus 1.0%). DRB1*0404 was increased in frequency in seropositive RA but, unlike *0401, an increased frequency was seen only with 2 epitope copies. The relatively rare DRB1*10 had an unexpected association with seropositive RA, being present in 1.7% of seropositive RA patients and 0.7% of controls, and also showed a trend toward association with greater disease severity. The presence of 2 epitope copies was associated with increased frequency of seropositivity and younger age at disease onset, not with disease severity. Treatment indication bias was substantial and may have accounted for some of these effects. HLA-DRB1*0401/0404 was found much more frequently in men and in patients with a lower age at disease onset, and there was a trend toward a higher frequency of *0404/0401 in women. CONCLUSION: This large inception cohort study confirms previously identified major associations and provides additional insights. Only one dominant association was found: *0401, which differs from other SE alleles in a single Lys-for-Arg substitution. The association of the rare DRB1*10 allele has not previously been postulated. Sex associations were confirmed. Associations with seronegative RA were not seen. Not all genotypes containing an SE copy showed increased susceptibility to RA. The association of SE genotypes found in this study related to disease susceptibility rather than severity.

Association of CTLA-4 variation with type I diabetes in Filipinos.

The role of non-HLA single nucleotide polymorphisms from a panel of candidate genes in genetic susceptibility to type I diabetes (TID) among Filipinos was examined by PCR/SSOP typing of 90 patients and 94 controls, previously typed for the HLA class I and class II loci. We report the association of CTLA-4 A49G variation (cytotoxic T-lymphocyte associated-4) to TID among Filipinos, consistent with some but not all previous reports in other ethnic groups. The G allele frequency (0.61 versus 0.45, P=0.003) and GG genotype frequency (0.42 versus 0.22, P=0.004) were each increased in patients compared to controls, respectively. Among Filipinos, the CTLA-4 genotypes are associated with disease only in the presence of the predisposing DR3, 4, and 9 haplotypes (P=0.012). Compared to the AA genotype, the increased risk of diabetes predisposition is greatest in genotype GG bearing the DR susceptible alleles (DR3, 4, and 9) (odds ratio=4.6, P=0.001), demonstrating that non- HLA loci, acting in concert with HLA, can play potent roles in modifying susceptibility to TID.

Millennium award recipient contribution. Identification of children with early onset and high incidence of anti-islet autoantibodies.

A total of 21,000 general population newborns (NECs) and 693 young siblings-offspring of patients with type 1A diabetes (SOCs) were class II genotyped and 293 NECs and 72 SOCs with the high-risk genotype, DR3/4, DQB1*0302 have been prospectively evaluated. Seventeen individuals who converted to persistent autoantibody positivity and two autoantibody-negative control groups (35 SOCs and 24 NECs) were typed for HLA-A class I alleles. The A1, A2 genotype was significantly increased among the autoantibody-positive subjects (47%) compared to autoantibody-negative SOCs (14%, P = 0.01) and NECs (13%, P = 0.02). Life-table analysis of DR3/4, DQB1*0302 siblings revealed a risk of 75% for development of islet autoantibodies by the age of 2 years for those with A1, A2. The HLA-A2 phenotype frequency was increased among an independent DR3/4, DQB1*0302 young diabetes cohort (64% versus 33% for autoantibody-negative NECs). These results suggest that a high incidence and early appearance of islet autoantibodies for siblings of patients with type 1A diabetes are associated with DR3/4, DQB1*0302 and potentially increased with HLA-A genotype A1, A2.

An integrated haplotype map of the human major histocompatibility complex.

Numerous studies have clearly indicated a role for the major histocompatibility complex (MHC) in susceptibility to autoimmune diseases. Such studies have focused on the genetic variation of a small number of classical human-leukocyte-antigen (HLA) genes in the region. Although these genes represent good candidates, given their immunological roles, linkage disequilibrium (LD) surrounding these genes has made it difficult to rule out neighboring genes, many with immune function, as influencing disease susceptibility. It is likely that a comprehensive analysis of the patterns of LD and variation, by using a high-density map of single-nucleotide polymorphisms (SNPs), would enable a greater understanding of the nature of the observed associations, as well as lead to the identification of causal variation. We present herein an initial analysis of this region, using 201 SNPs, nine classical HLA loci, two TAP genes, and 18 microsatellites. This analysis suggests that LD and variation in the MHC, aside from the classical HLA loci, are essentially no different from those in the rest of the genome. Furthermore, these data show that multi-SNP haplotypes will likely be a valuable means for refining association signals in this region.