This project was carried out under a broad theme of Maori health and investigates the genetics of rheumatoid arthritis (RA) and gout within two Maori case-control cohorts. In addition, it reports on the developmental stages of a whanau project focussing on the compilation of our whakapapa and collation of information relating to type 2 diabetes within the Parata whanau, which I whakapapa to. My conducting this research in light of me being Maori is also considered: much of the prevailing literature on Maori and science describes science as the handmaid of colonisation, and singles out genetic research as being "neo-colonial". I reject those that would label me a "sell-out" and show how my research is shaped by, and consistent with, the history of my immediate tipuna, and my iwi more generally, since European contact.
RA is an autoimmune disease of the joints and affects approximately 1% of the general population. There is currently very little data available on its prevalence in New Zealand although it is thought that it is similar to those of the rest of the world. Gout is the most common form of inflammatory arthritis in Caucasian males and recent data suggests a worldwide increase in prevalence in many populations. Gout is characterised by the deposition of monosodium urate or uric acid crystals in the joints, which produces an inflammatory response. In New Zealand, the prevalence of gout is estimated to be 3% in Caucasians and twice this in Maori. Both RA and gout are complex arthritic diseases and are influenced by a combination of genetic and environmental factors. It is likely that numerous genetic susceptibility loci are responsible for the genetic components of these diseases.
This project tests various genetic regions for susceptibility to or protection against both RA and gout in two separate Maori case cohorts and a common control cohort. To do this, the confounding factor of population stratification, resulting from population admixture, was overcome via developing a method specific for these Maori cohorts. This tool utilised genotype data from a set of unlinked genome-wide markers and the structure and STRAT software packages, allowing valid case-control studies to be carried out in the presence of population stratification. These data showed that four sub-populations exist in the Maori RA case-control cohort and three in the Maori gout case-control cohort.
A number of studies have confirmed the HLA region as the major genetic determinant of autoimmunity and recently, PTPN22 and CTLA-4 variants have been shown to be common to the onset of a number of autoimmune phenotypes. The IDDM6 region on chromosome 18 has also been implicated in type 1 diabetes, RA and autoimmune thyroiditis and contains a number of candidate genes for a role in RA, many of which were investigated in this thesis. Polymorphisms within the PTPN22, CTLA-4, BCL2, SMAD4, DCC, TNFRSF11A, PADI4, CCR5 and CCL3L1 genes were tested for association with RA in the Maori cohort (98 cases and 109 controls) with some significant association results obtained. The HLA-DRB1*02 and HLA-DRB1*08 loci were associated with the protection against and susceptibility for RA, respectively (P = 0.004 and 0.017). The deviation of CCL3L1 copy-number from the cohort mean (two copies) was also associated with the RA development. Copy-number <2 indicated association with protection against RA (P = 0.012) and copy-number >2 indicated association with susceptibility to RA (P = 0.002). However, it must be stressed that these results were obtained without accounting for the presence of population stratification.
The organic anion transporter (OAT) and the urate transporter 1 (URAT1) genes, involved in the regulation of blood urate levels, are members of the solute carrier transporter (SLC) family and provide good candidates for a role in gout. A number of polymorphisms within the OAT, URAT1 and the SLC5A8 genes were tested for association with gout in the Maori cohort (72 cases and 109 controls) with some success. The SLC5A8 rs1709189 SNP was significantly associated with gout in this cohort (P = 0.004). Polymorphisms within two alcohol dehydrogenase (ADH) genes were also tested for association due to their role in alcohol metabolism and the association between alcohol consumption and gout. The ADH2 rs1229984 SNP was also significantly associated with gout in this cohort (P = 0.012). These significant results were obtained after population stratification was taken into account.
The data presented in this thesis confirm the presence of population stratification in the two Maori case-control cohorts and demonstrate some association of the HLA-DRB1 region and CCL3L1 with RA and the SLC5A8 and ADH2 genes with gout. An extensive whakapapa of our whanau has also been compiled and associated type 2 diabetes information collected. However, this is by no means a completed task and work will continue on this project under the guidance of the Parata whanau.
| Identifer | oai:union.ndltd.org:ADTP/217830 |
| Date | January 2008 |
| Creators | Wyeth, Emma Hana, n/a |
| Publisher | University of Otago. Department of Biochemistry |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://policy01.otago.ac.nz/policies/FMPro?-db=policies.fm&-format=viewpolicy.html&-lay=viewpolicy&-sortfield=Title&Type=Academic&-recid=33025&-find), Copyright Emma Hana Wyeth |
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