The Major Histocompatibility Complex (MHC) is a highly polymorphic region on chromosome 6 encompassing the human leucocyte antigen (HLA)-DQ/DR loci most predictive of susceptibility to type 1 diabetes (T1D). To assess the contribution of other MHC genes, in this exploratory analysis of Type 1 Diabetes Genetics Consortium (T1DGC) family data we characterize association between susceptibility and MHC single nucleotide polymorphism (SNP) genotype, with an emphasis on effects of genetic variation additional to carriage of predisposing or protective MHC haplotypes.We use Cox regression analyses of age of onset, stratified by family, to jointly test both linkage and association. Analysis is restricted to children from families having both affected and unaffected siblings and is conducted with and without adjustment for known HLA class I and II effects. Model fits provide scores for each individual that are based on estimates of the probability of being affected by the age of 35, given the individual's SNP genotype. The mean within-family variation in these scores provides a measure that closely reflects the relative size of the likelihood ratio test statistics, and their covariation provides a means of mapping patterns of association that incorporate both effect size and commonality of effect that is attributable to the strong linkage disequilibrium (LD) extending across the region.Univariate analyses yielded strong associations with T1D susceptibility that are dominated by SNPs in the class II HLA-DR/DQ region but extend across the MHC. Similar effects are frequently observed across SNPs within multiple genes, sometimes spanning hundreds of kilobases. SNPs within a region at the telomeric end of the class II gene HLA-DRA yielded significant associations with and without adjustment for carriage of the predictive DR3, DR4, DR2 and DR7 HLA haplotypes, and remained highly prominent in a secondary analysis that was restricted to 66 families in whom at least one of the affected siblings carried neither the DR3 nor DR4 haplotype.While many of the associations can be attributed to LD between the SNPs and the dominant HLA-DRB/DQA/DQB loci, there is also evidence of additional modifying effects.
<p>Figure 1 Mean ({plus minus}SD) serum lumretuzumab profiles following multiple ascending doses from 100 mg up to 2000 mg Figure 2 Percentage change in standardized uptake value maximum from baseline as assessed by FDG-PET at (a) Cycle 1 Day 14 and (b) Cycle 4 Day 14 Table 1 Summary of baseline and change in HER3 expression measured by IHC in skin and tumor biopsy samples pre and post treatment with lumretuzumab Table 2 Summary of change in expression of HER3, HER2, EGFR and cMET in fresh tumor biopsies compared to primary archival samples Table 3 Peripheral blood immunophenotyping (T, B and NK cells and NK subsets) from patients dosed with 2000 mg lumretuzumab Table 4 Ex-vivo activation potential of peripheral NK lymphocytes for all patients at ba seline and following exposure to lumretuzumab in the 2000 mg dose cohort Table 5 Summary of tumor immune effector cell infiltration Table 6 Tumor response to treatment (RECIST)</p>
Currently, 1.1 million individuals in the United States are living with HIV-1 infection. Although this is a relatively small proportion of the global pandemic, the remarkable mix of ancestries in the United States, drawn together over the past two centuries of continuous population migrations, provides an important and unique perspective on adaptive interactions between HIV-1 and human genetic diversity. HIV-1 is a rapidly adaptable organism and mutates within or near immune epitopes that are determined by the HLA class I genotype of the infected host. We characterized HLA-associated polymorphisms across the full HIV-1 proteome in a large, ethnically diverse national United States cohort of HIV-1-infected individuals. We found a striking divergence in the immunoselection patterns associated with HLA variants that have very similar or identical peptide-binding specificities but are differentially distributed among racial/ethnic groups. Although their similarity in peptide binding functionally clusters these HLA variants into supertypes, their differences at sites within the peptide-binding groove contribute to race-specific selection effects on circulating HIV-1 viruses. This suggests that the interactions between the HLA/HIV peptide complex and the TCR vary significantly within HLA supertype groups, which, in turn, influences HIV-1 evolution.
No data are available on the incidence of breast cancer for the whole of Australia. Review of published incidence data from 1972 to 1978 from New South Wales, South Australia, and Tasmania shows that the incidence of breast cancer in women aged 25 years and over ranged between 91.8/100000 and 106.5/100000 of these women. These rates are similar to those in other countries with high rates. Comparison of mortality rates in Australian States between 1968 and 1978 for women aged 25 years and over showed rates from 28.3/100000 in the Northern Territory to 42.3/100000 in Victoria and 44.1/100000 in the Australian Capital Territory. The rates for Victoria and the Australian Capital Territory were significantly higher than those in the other States. Trends in mortality in Australia for women aged 25 years and over were studied in the period from 1907 to 1977. Initially, the mortality rate was 28.5/100 000 and increased to reach a peak of 41.5/100 000 in 1940-1944. Thereafter, rates fell to 37.1/100 000 in 1960-1964, but have begun to rise again since 1970. The 1940-1944 peak was largely confined to women over the age of 50 years, and further analysis of the age-specific mortality rates showed the peak to be cross-sectional in type (that is, affecting each age group in the same calendar period). The rise after 1970 occurred mainly in women aged between 30 and 44 years and 60 and 79 years.
ABSTRACT Hepatitis B virus (HBV)-specific T-cell responses are important in the natural history of HBV infection. The number of known HBV-specific T-cell epitopes is limited, and it is not clear whether viral evolution occurs in chronic HBV infection. We aimed to identify novel HBV T-cell epitopes by examining the relationship between HBV sequence variation and the human leukocyte antigen (HLA) type in a large prospective clinic-based cohort of Asian patients with chronic HBV infection recruited in Australia and China ( n = 119). High-resolution 4-digit HLA class I and II typing and full-length HBV sequencing were undertaken for treatment-naïve individuals (52% with genotype B, 48% with genotype C, 63% HBV e antigen [HBeAg] positive). Statistically significant associations between HLA types and HBV sequence variation were identified ( n = 49) at 41 sites in the HBV genome. Using prediction programs, we determined scores for binding between peptides containing these polymorphisms and associated HLA types. Among the regions that could be tested, HLA binding was predicted for 14/18 (78%). We identified several HLA-associated polymorphisms involving likely known anchor residues that resulted in altered predicted binding scores. Some HLA-associated polymorphisms fell within known T-cell epitopes with matching HLA restriction. Enhanced viral adaptation (defined as the presence of the relevant HLA and the escaped amino acid) was independently associated with HBeAg-negative disease ( P = 0.003). Thus, HBV appears to be under immune pressure in chronic HBV infection, particularly in HBeAg-negative disease.
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