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This thesis embodies much of my work done over the past 25 years. The impetus for these studies was the need to provide the best tissue typing available for organ transplantation and to overcome the problems of defining HLA antigens in different ethnic groups. These goals were achieved by extensive international collaboration and participation in the International Histocompatibility Workshops. The discovery that the HLA antigens are associated with many diseases led to an epidemic of investigations in which over 500 diseases have been studied. In retrospect, it is not surprising that auto-immune diseases such as diabetes and rheumatoid arthritis showed such marked associations with HLA antigens. The studies in Part II of this thesis were aimed at finding out if the HLA associations reported in Caucasian populations were also present in the Black and Indian populations. These research interests led to my being invited by the National Science Council of the Republic of China in Taiwan to be a Visiting Professor at the National Taiwan University in Taipei for the 1989 academic year. I investigated the association between HLA and naso-pharyngeal carcinoma in Chinese during that year. I wish to express my appreciation to Dr Peter Brain who inspired the early investigations and continued to encourage and support my research. I am grateful to all my co-authors and the many colleagues, clinicians and laboratory staff who have contributed to the various research programmes. Studies of the relationship of the HLA system to cancer, diabetes, arthritis and other diseases have been supported in part by grants from the National Cancer Association and the Medical Research Council of South Africa. / Thesis (D.Sc.)-University of Natal, Durban, 1992.

Thesis (M. Phil.)--University of Hong Kong, 1997. / Includes bibliographical references (leaf 118-137).

Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2006. / On t.p. "+" is superscript. Includes bibliographical references (leaves 107-131). Also available in electronic version.

Genome-wide association (GWA) studies confirmed that the HLA genes were strongly associated with schizophrenia but the HLA variants identified by GWA studies had a lower frequency in patients with schizophrenia than control subjects. The HLA molecules have function of presenting peptide antigens to T lymphocytes in order to initiate an immune response. Environmental factors such as infection and dietary proteins have been found to be associated with schizophrenia. This PhD program has thus focused on the following objectives: (1) identification of genetic variants for schizophrenia in the HLA region and (2) investigation of circulating antibodies to linear peptide antigens derived from wheat gluten in schizophrenia. The major findings from this work are as follows: 1. The HLA-DQ2.5 variants were strongly associated with schizophrenia; this finding is consistent with that from GWA study. 2. The NOTCH4 association was replicated in our study samples, in which a CNV in exon 19 of the gene may be associated with risk of schizophrenia. 3. There was no HLA-II variant identified to be associated with a high risk of schizophrenia but a CNV present in the HLA-DQ/DR region might confer risk of the disease. 4. The levels of circulating antibodies to linear peptide antigens derived from wheat gluten were significantly lower in schizophrenia patients than controls. This finding is inconsistent with previous studies that showed elevated levels of circulating antibodies in schizophrenia across subpopulations. In conclusion, it is likely that not one but many HLA variants lead to risk of schizophrenia development. From this research it is likely that anti-gluten antibodies are not an environmental trigger for this disease. Further investigation is needed to clarify the role of the HLA region in bridging the gap between genetic make-up and environmental factors in developing schizophrenia.

published_or_final_version / Microbiology / Doctoral / Doctor of Philosophy

There has been an increase in rates of chromosomal abnormalities in newborns as a result of reproductive aging. For the past decades, a lot of effort has been placed on identifying pregnancies at risk of genetic defects. Conventional prenatal genetic diagnosis is achieved by invasive procedures that have been associated with an increased risk of pregnancy loss. This has led the researchers to explore the use of non-/minimally invasive techniques for prenatal diagnosis. Trophoblasts are known to be shed from regressing chorionic villi into the lower uterine pole of pregnant women during the first trimester. These cells are trapped within cervical mucus, which can be retrieved with a cytobrush. By using human leukocyte antigen G (HLA-G) and cytokeratin-7 (CK7) as trophoblast markers, this study aims to investigate the possibility of isolating individual fetal trophoblast from transcervical samples for genetic diagnosis. 195 healthy pregnant women requesting for legal termination of pregnancy (TOP) were recruited in this study. Transcervical cells were collected from them with the use of a cytobrush before TOP. HLA-G+ or CK7+ cells were then isolated by a combination of mucolytic action, fluorescent immunohistochemistry, and micromanipulation. The origin of these cells was subsequently investigated by either fluorescent in situ hybridization (FISH) or allelic profiling by quantitative fluorescent polymerase chain reaction (QF-PCR) based on chromosome 16, chromosome X, amelogenin gene and sex determining region Y (SRY) gene. This study first demonstrated the presence of fetal cells in transcervical samples based on the detection of chromosome Y signal by ordinary PCR. Cells expressing HLA-G and CK7 were also identified among transcervical cells. Immunopositive cells were isolated by micromanipulation under fluorescent microscopy. One isolated cell expressing CK7 was shown to inherit paternal allele at a locus on chromosome 16, suggesting the possible fetal origin of this cell. However, this study was still hampered by a number of technical factors. Further optimization of the protocol is required before transcervical trophoblasts can be retrieved in a reliable manner. / published_or_final_version / Obstetrics and Gynaecology / Master / Master of Philosophy

Deficiency of the cytochrome P-450 steroid 21-hydroxylase (21-OHase) which causes Congenital Adrenal Hyperplasia (CAH) is a monogenic autosomal recessive disorder which is linked to HLA. There are two 21-OHase genes in man, A and B, and they are mapped to the HLA class III region ~ 3 kb 3' to the complement genes C4A and C4B, respectively. Two genes encoding 21-OHase were isolated, characterized and sequenced. Both 21-OHase genes are ~ 3.3 kb in length and are split into 10 exons by nine introns. Comparison of the two genes showed that although they are highly conserved, there are three deleterious mutations in the 21-OHase A gene which cause frameshifts and introduce in phase premature termination codons. Thus the 21-OHase A gene is a pseudogene. Comparison of the 21-OHase B gene to the other cytochrome P-450 sequences revealed that although the cysteine-429 was conserved in 21-OHase, there is very little homology with other cytochrome P-450, indicating it belongs to a separate family of genes within the superfamily. Clear evidence of polymorphism in 21-OHase is apparent on comparison with other 21-OHase B sequences. There is a size polymorphism of 494 and 495 amino acids. The differing severities of 21-OHase deficiency in CAH may be due to allelic variants of the 21-OHase B gene, since in most cases the defect is not due to gene deletion (Rumsby et al., 1986). A 21-OHase B gene from a patient with CAH was characterized and sequenced. There were 13 nucleotide alterations in his single 21-OHase B gene, one of which at codon 269 caused a serine to change to a threonine residue. The G → C transversion in the 21-OHase B gene from the patient at codon 269 introduced a new NcoI restriction site into the gene. This restriction fragment length polymorphism (RFLP) was used to study other patients with CAH and normal individuals. The NcoI RFLP was found not to be confined to the 21-OHase B gene but was also present in some 21-OHase A genes. It is likely therefore that the mutation occurred in the pseudogene first and then transferred to some 21-OHase B genes.

Bibliography : leaves 182-203. / 203 leaves : ill, map ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Describes the molecular analysis of the HLA class I and class II genes in the Australian Aboriginal population and also provides a comparison of serological and molecular tissue typing methods in view of genetic mutations at the HLA loci and the expression of serological HLA "blanks". / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1996?