Anne L. Leaver

Bio: Anne L. Leaver is an academic researcher from University of Western Australia. The author has contributed to research in topics: Haplotype & Population. The author has an hindex of 1, co-authored 1 publications receiving 242 citations.

The HLA genomic loci map: expression, interaction, diversity and disease

Abstract: The human leukocyte antigen (HLA) super-locus is a genomic region in the chromosomal position 6p21 that encodes the six classical transplantation HLA genes and at least 132 protein coding genes that have important roles in the regulation of the immune system as well as some other fundamental molecular and cellular processes. This small segment of the human genome has been associated with more than 100 different diseases, including common diseases, such as diabetes, rheumatoid arthritis, psoriasis, asthma and various other autoimmune disorders. The first complete and continuous HLA 3.6 Mb genomic sequence was reported in 1999 with the annotation of 224 gene loci, including coding and non-coding genes that were reviewed extensively in 2004. In this review, we present (1) an updated list of all the HLA gene symbols, gene names, expression status, Online Mendelian Inheritance in Man (OMIM) numbers, including new genes, and latest changes to gene names and symbols, (2) a regional analysis of the extended class I, class I, class III, class II and extended class II subregions, (3) a summary of the interspersed repeats (retrotransposons and transposons), (4) examples of the sequence diversity between different HLA haplotypes, (5) intra- and extra-HLA gene interactions and (6) some of the HLA gene expression profiles and HLA genes associated with autoimmune and infectious diseases. Overall, the degrees and types of HLA super-locus coordinated gene expression profiles and gene variations have yet to be fully elucidated, integrated and defined for the processes involved with normal cellular and tissue physiology, inflammatory and immune responses, and autoimmune and infectious diseases.

Defining the Role of the MHC in Autoimmunity: A Review and Pooled Analysis

Abstract: The major histocompatibility complex (MHC) is one of the most extensively studied regions in the human genome because of the association of variants at this locus with autoimmune, infectious, and inflammatory diseases. However, identification of causal variants within the MHC for the majority of these diseases has remained difficult due to the great variability and extensive linkage disequilibrium (LD) that exists among alleles throughout this locus, coupled with inadequate study design whereby only a limited subset of about 20 from a total of approximately 250 genes have been studied in small cohorts of predominantly European origin. We have performed a review and pooled analysis of the past 30 years of research on the role of the MHC in six genetically complex disease traits - multiple sclerosis (MS), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), ulcerative colitis (UC), Crohn's disease (CD), and rheumatoid arthritis (RA) - in order to consolidate and evaluate the current literature regarding MHC genetics in these common autoimmune and inflammatory diseases. We corroborate established MHC disease associations and identify predisposing variants that previously have not been appreciated. Furthermore, we find a number of interesting commonalities and differences across diseases that implicate both general and disease-specific patho- genetic mechanisms in autoimmunity.

The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases

Abstract: An individual's major histocompatibility complex (MHC) ancestral haplotype (AH) is the clearest single determinant of susceptibility to MHC associated immunopathological disease, as it defines the alleles carried at all loci in the MHC. However, the direct effects of any of the 150-200 genes that constitute the MHC are difficult to determine since recombination only occurs at defined hotspots. This review concerns the 8.1 AH (HLA-A1, C7, B8, C4AQ0, C4B1, DR3, DQ2), which is carried by most Caucasians with HLA-B8. It is associated with accelerated human immunodeficiency virus (HIV) disease, and susceptibility to insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus, dermatitis herpetiformis, common variable immunodeficiency and IgA deficiency, myasthenia gravis and several other conditions. We have mapped susceptibility genes for HIV, IDDM and myasthenia gravis to the central MHC between HLA-B and the tumour necrosis factor or complement genes. Here we consider which of the remaining 8.1-associated diseases are more closely associated with HLA-DR3 and/or DQ2. Several candidate genes in the central MHC have the potential to modulate immune or inflammatory responses in an antigen-independent manner, as is seen in studies of cultured cells from healthy carriers of the 8.1 AH. Hence these genes may act as a common co-factor in the diverse immunopathological conditions associated with the 8.1 AH.

A polymorphic variation in a putative regulation box of the TNFA promoter region

Abstract: The genes encoding tumor necrosis factor alpha (TNFA) and beta (TNFB) are located close to each other within the class III region of the HLA complex (Spies et al. 1986; Nedwin et al. 1985; Browning et al. 1993). TNF alpha is a cytokine showing a potent immunomodulator activity (Beutler and Cerami 1989); its expression is induced by bacterial lipopolysaccharide, mitogens, and viruses, and it is regulated both transcriptionally and postranscriptionally (Golfeld et al. 1990, 1991; Economou et al. 1990; Sung et al. 1991; Han et al. 1990, 1991). The level of TNFA expression has been correlated with the HLA genotype, in particular HLA-DR alleles (Bendtzen et al. 1988; Jacob et al. 1990) and with polymorphic sequences closely linked to the TNFB locus: namely, the Nco I restriction fragment length polymorphism (RFLP) in the first intron and microsatellites within the first intron or the upstream region of the TNFB gene (Pociot et al. 1993). These findings suggest that TNFA expression depends on polymorphic variations in linkage disequilibrium with the above HLA markers. The best candidate would be a polymorphic variation in the promoter region of the TNFA gene itself. A study by Messer and co-workers (1991) analyzing the TNFA promoter region from position -687 to -370 did not reveal any polymorphic sequence variation. More recently, a biallelic polymorphism has been described by Wilson and co-workers (1993), consisting of a G vs A transition at position -308. The aim of the present study was to find polymorphisms in the TNFA promoter region that could be interesting not only as genetic markers but also for their involvement in the regulation of TNFA expression. Among the possible polymorphisms, those inducing

Genomics of the major histocompatibility complex: haplotypes, duplication, retroviruses and disease

Abstract: Summary: The genomic region encompassing the Major Histocompatibility Complex (MHC) contains polymorphic frozen blocks which have developed by local imperfect sequential duplication associated with insertion and deletion (indels), In the alpha block surrounding HLA-A, there are ten duplication units or beads on the 62,1 ancestral haplotype. Each bead contains or contained sequences representing Class 1, PERB11 (MHC Class I chain related (MIC)) and human endogenous retrovirus (HERV) 16, Here we consider explanations for co-occurrence of genomic polymorphism, duplication and HERVs and we ask how these features encode susceptibility to numerous and very diverse diseases. Ancestral haplotypes differ in their copy number and indels in addition to their coding regions. Disease susceptibility could be a function of all of these differences. We propose a model of the evolution of the human MHC. Population-specific integration of retroviral sequences could explain rapid diversification through duplication and differential disease susceptibility. If HERV sequences can be protective, there are exciting prospects for manipulation. In the mean-while, it will be necessary to understand the function of MHC genes such as PEKB11 (MIC) and many others discovered by genomic sequencing.