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1. I have described a population of children and young adults with asthma in primary and secondary care, in terms of relevant history, medication use and exacerbations. 2. My thesis presents observations reported for the first time that asthmatic children and young adults homozygous for the Arg16 allele on the ß2 adrenergic receptor gene (ADRB2), on frequent doses of on demand short-acting ß2-agonists are at greater risk of asthma exacerbations.I have shown an increase in the risk of exacerbations per copy of Arg16 allele in children and young adults with asthma on the regular long-acting ß2-agonist salmeterol. 4. I have shown that there is an increase in risk of exacerbations per copy of Arg16 allele in children and young adults with asthma on frequent (once daily or more) as required doses of inhaled salbutamol. This effect is not observed on participants with asthma who are not exposed to ß2-agonist on a daily basis. 5. I have shown that the Arg16Arg variant status may be associated with worse airway obstruction, as measured by the FEV1/FVC ratio.6. I have shown that the individuals with FLG null alleles have a significantly increased risk of exacerbations requiring hospital admissions, courses of oral steroids, or experiencing school absences

Most of genes contained in a genome have been shown to exist in forms of families; however, little is known about their variation and evolution during the course of genome evolution. The present study shows that the numbers of the genes of the NBS-LRR-encoding gene family vary extremely significantly among different lines or cultivars of a species and among related species from the same genus. This suggests that plant genetics and evolution depend on not only gene sequence variation, but also the number of genes in multigene families. This study has further revealed that the variation of number of genes in the gene family in the Gossypium species is affected significantly not only by genome size variation, polyploidization and natural selection, but also by domestication/breeding. There is a positive correlation (P less than or equal to 0.05) between genome size and number of genes in the family, suggesting that species with larger genomes tend to have more NBS-LRR-encoding genes. It was observed that natural polyploids have significantly larger numbers of genes in the family and larger genomes than the artificial polyploids of their putative diploid ancestors. This indicates that polyploidization, perhaps post-polyploidization as well, either led to the loss of the genes in a gene family or slowed the process of gene number increase after polyploidization. It was shown that cultivated cottons have significantly more NBSLRR- encoding genes than wild species at both diploid and polyploidy levels. This result indicates that plant breeding likely allows accumulation of NBS-LRR-encoding genes that potentially provide resistance to pathogens. Therefore, plant breeders have selected not only for favorable alleles and favorable allele combinations, but also for the number of genes. Finally, difference (P less than or equal to 0.001) was found in number of genes in the NBS-LRR-encoding gene family among the species native to different geographical regions, suggesting that natural selection has played an important role in the variation in number of genes in the NBS-LRR-encoding gene family. The gene members that are favorable for fitness at the time are selected and accumulated in the genomes, but those that are not favorable for fitness at the time are lost in natural selection. As this is the first study in the field, further studies remain. These include, but not limited to, the universality of the findings in plants and animals, the universality of the findings in different gene families, genetics of the gene family size variation, relationship between the gene family size variation and phenotypic variation, gene family size variation and breeding, etc. Nevertheless, the findings obtained from this study are sufficient to shed light on many fundamental questions in biology, diversity and complexity of plants and animals.

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (p. 121-128).

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An exciting new era has dawned for the prevention and management of CAD utilizing genetic risk variants. The recent identification of over 60 susceptibility loci for coronary artery disease (CAD) confirm not only the importance of established risk factors, but also the existence of many novel causal pathways that are expected to improve our understanding of the genetic basis of CAD and facilitate the development of new therapeutic agents over time. Concurrently, Mendelian randomization studies have provided intriguing insights on the causal relationship between CAD-related traits, and highlight the potential benefits of long-term modifications of risk factors. Lastly, genetic risk scores of CAD may serve not only as prognostic, but also as predictive markers and carry the potential to considerably improve the delivery of established prevention strategies. This review will summarize the evolution and discovery of genetic risk variants for CAD and their current and future clinical applications.

The ATP-binding cassette transporter, sub-family A, member 1 (ABCA1) mediates the major pathway for cholesterol exit from non-hepatic cells and thereby controls the rate-limiting step in the biogenesis of high density lipoprotein (HDL) particles. In humans,ABCA1 deficiency results in Tangier disease, characterized by low levels of HDL cholesterol, cellular cholesterol accumulation and increased risk for atherosclerosis. More than 100 coding variants have been described in the ABCA1 gene. We attempted to understand how both naturally occurring and engineered mutations in ABCA1 impact its role in cholesterol transport in a variety of in vitro and in vivo systems. We attempted to correlate specific genetic variants in ABCA 1 with phenotypes in patients carrying the sevariants, and used an evolutionary approach to predict which specific variants in ABCA1would impact its function. We then turned to the study of tissue-specific genetic deletion of ABCA1 in mice to study its role in HDL biogenesis, atherosclerosis and glucose metabolism. We found that intestinal ABCA1 is an important site of HDL biogenesis and that activation of intestinal ABCA1 raises HDL levels in vivo. Hepatic ABCA1, which is a major site of HDL biogenesis, was shown to significantly contribute to susceptibility to atherosclerosis. Finally, we show that ABCA1 plays an unsuspected role in B-cell function and insulin secretion. These studies have contributed to our understanding of the impact of genetic variation in ABCA1 on diverse biological and pathological processes, and have identified novel aspects of ABCA 1 function in specific cell types.

Cathelicidins (CATHLs) are small, cationic antimicrobial peptides that establish an early innate immune defense against infections in mammals. Beyond their wide spectrum of antimicrobial activity, these peptides play important roles in wound repair, chemotactic activity, and apoptosis. Thus, comprehensive characterizing of bovine CATHLs could potentially identify underlying inherited differences in innate immunity and disease resistance in cattle. The purpose of the present study was to verify the placement of the CATHL cluster at the distal end of bovine chromosome 22 (BTA22), identify any single nucleotide polymorphisms (SNPs) and insertion-deletion (indel) polymorphisms within the gene family, explore copy number variation, and investigate the functional impact any of these variants may have in overall bovine innate immunity. A framework radiation hybrid map was constructed with 7 markers screened against the bovine 12,000 rad whole genome RH (12K WG-RH) panel, which when compared to the current genome assembly (Btau_4.0) confirmed current gene order. Comparative sequence analysis for 10 domestic cattle breeds representing both Bos taurus taurus and Bos taurus indicus revealed 60 SNPs, 7 of which were nonsynonymous, and 5 indel mutations. Data from array comparative genomic hybridization (aCGH) between four Angus and four Nelore animals showed a 2-fold increase in copy number of the CATHL4 locus, which was verified by quantitative PCR (qPCR) of genomic DNA. Nelore animals showed an approximate 2-fold increase in the CATHL4 gene. Subsequently, the expression of CATHL4 in Nelore neutrophils exhibited a range of 2- to 5-fold increases in CATHL4 gene expression. Finally, a colorimetric bactericidal assay was performed on the neutrophils of the same Angus and Nelore animals previously genotyped for copy number variations (CNVs). After in vitro challenges to Staphylococcus aureus, Salmonella typhimurium, Mannheimia haemolytica, and Pasteurella multocida, the killing capacity of Nelore neutrophils was approximately 20 percent greater than Angus neutrophils for M. haemolytica and 10 percent greater for P. multocida. Characterization of this antimicrobial gene family is central to developing a firm understanding regarding the effects CATHL variation has with respect to bovine innate immunity.