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Thesis (M. Sc.)--Memorial University of Newfoundland, Faculty of Medicine, 1999. / Typescript. Includes bibliographical references (leaves 156-206).

Thesis (MMed)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: There is growing interest in how genetic and environmental risk factors interact to confer risk for dysregulated iron homeostasis, which is considered a possible pathogenic mechanism in multiple sclerosis (MS). While iron deficiency has been associated with greater disability and disease progression, cerebral accumulation and overload of insoluble iron has also been reported in MS patients. Variation in the matriptase-2 (TMPRSS6) gene has recently been described that may lead to reduced iron levels, which raised the question of whether it may be involved in dysfunctional iron regulation as a pathogenic mechanism in MS. The aims of the study were as follows: 1)) comparison of the allele frequencies and genotype distribution for TMPRSS6 A736V (rs855791, c.2207C>T) and HFE C282Y (rs1800562, c.845G>A) between patients diagnosed with MS and unaffected controls; 2) determination of the effects of clinical characteristics, relevant lifestyle factors and genotype on serum iron parameters in MS patients compared to population matched controls; and 3) determination of clinical outcome in relation to age of onset and degree of disability in MS patients. The study population included 121 Caucasian MS patients and 286 population-matched controls. Serum iron, transferrin, ferritin and transferrin saturation levels were available from previous studies and lifestyle factors were subsequently documented in a subgroup of 68 MS patients and 143 controls using the study questionnaire. Genotyping of TMPRSS6 A736V and HFE C282Y were performed using allele-specific TaqMan technology. The genotype distribution and allele frequencies of TMPRSS6 A736V and HFE C282Y did not differ between MS patients and controls. MS patients homozygous for the iron-lowering minor T-allele of TMPRSS6 A736V had significantly lower serum iron levels (p=0.03) and transferrin saturation levels (p=0.03) compared to CC homozygotes. In MS patients the iron-loading minor A-allele of HFE C282Y was also associated with a paradoxical decrease in serum ferritin (p<0.01) compared to GG homozygotes. When considering the combined effect of the minor alleles of TMPRSS6 A736V and HFE C282Y with opposite effects on iron levels, we found a significant reduction in serum ferritin levels (p<0.05), independent of age, sex, body mass index (BMI) or dietary red meat intake in MS patients. A similar effect was not observed in the population- and age-matched controls. Higher dietary red meat intake correlated significantly with increased ferritin only in controls (p=0.01 vs. 0.21 for MS patients). In the presence of the minor allele of HFE C282Y, the TMPRSS6 A736V CT and TT genotypes were associated with a significantly earlier age of onset of MS when the post hoc test was applied (p=0.04). All the study aims were successfully accomplished. Our results support the possibility of an epistatic effect between TMPRSS6 A736V and HFE C282Y associated with reduced ferritin levels in MS patients. Pathology-supported genetic testing (PSGT) applied in this study as a new concept for analysis of complex diseases with a genetic component, is well placed to optimise clinical management in patients with MS. / AFRIKAANSE OPSOMMING: Daar heers toenemende belangstelling in hoe die wisselwerking tussen genetiese en omgewingsfaktore die risiko tot wanregulering van yster-homeostase beïnvloed. Laasgenoemde is ‘n moontlike patogeniese meganisme vir meervoudige sklerose (MS). Alhoewel verhoogde gestremdheid en siekteprogressie met ystertekort geassosieer is, is ysterophoping in die serebrum asook ‘n oormaat onoplosbare yster al by MS-pasiënte gevind. Variasie in die matriptase-2 (TMPRSS6) geen wat tot verlaging in ystervlakke kan lei, is onlangs beskryf en laat die vraag ontstaan of dit betrokke is by wanregulering van yster-homeostase as patogeniese meganisme in MS. Die doelwitte van die studie was as volg: 1) vergelyking van alleelfrekwensies en genotipeverspreiding vir TMPRSS6 A736V (rs855791, c.2207C>T) en HFE C282Y (rs1800562, c.845G>A) tussen MS-pasiënte en ongeaffekteerde kontroles; 3) bepaling van die effekte van kliniese indikators, relevante leefstylfaktore en genotipe op serum yster parameters in MS-pasiënte in vergelyking met populasie-ooreenstemmende kontroles; en 4) bepaling van kliniese uitkoms ten opsigte van aanvangsouderdom en graad van MS-aantasting. Die studiepopulasie het uit 121 kaukasiese MS-pasiënte en 286 kontroles van dieselfde populasie, wat nie die siekte het nie, bestaan. Serum yster, transferrin, ferritien en transferrien-versadigingsvlakke was beskikbaar vanaf vorige studies. Leefstylfaktore is in ‘n subgroep van 68 MS-pasiënte en 143 kontroles gedokumenteer met behulp van die studie-vraelys. TMPRSS6 A736V en HFE C282Y genotipering is met alleel-spesifieke TaqMan-tegnologie uitgevoer. Beide pasiënte en kontroles het dieselfde genotipeverspreiding en alleelfrekwensies getoon. Die A-alleel van HFE C282Y is met ‘n paradoksale verlaging in serum ferritien geassosieer (p<0.01) in MS-pasiënte met TMPRSS6 A736V, moontlik weens geen-geen interaksie wat nie deur ouderdom, liggaamsmassa-indeks of inname van rooivleis in die dieet beïnvloed is nie (p<0.05) en nie by kontroles gevind is nie. MS-pasiënte wat homosigoties is vir die T-alleel van TMPRSS6 A736V, het statisties betekenisvolle laer serum ystervlakke (p=0.03) en transferrienversadiging (p=0.03) getoon in vergelyking met CC-homosigote. In MS-pasiënte was die yster-oorlading A-alleel van HFE C282Y ook geassosieer met ‘n paradoksale afname in serum ferritien (p<0.01) in vergelyking met GG-homosigote. Wanneer die gekombineerde effek van die risiko-geassosieerde allele van TMPRSS6 A736V en HFE C282Y met teenoorgestelde effekte op ystervlakke geanaliseer word, is daar ‘n statisties beteknisvolle afname in serum ferritienvlakke (p<0.05), onafhanklik van ouderdom, geslag, liggaamsmassa-indeks of rooivleisinname in MS-pasiënte. ‘n Soortgelyke effek is nie waargeneem in populasie- en geslag-gelyke kontroles nie. Die inname van rooivleis in die dieet was betekenisvol minder by MS-pasiënte teenoor kontroles (p=0.03) en dit het slegs betekenisvol met verhoogde ferritien by kontroles gekorreleer (p=0.01 teenoor 0.21 by MS-pasiënte). In die teenwoordigheid van die risiko-geassosieerde alleel van HFE C282Y, is die TMPRSS6 A736V CT en TT genotipes geassosieer met ‘n statisties-betekenisvolle vroeër aanvangsouderdom van MS soos bepaal met die post hoc-toets (p=0.04). Al die doelwitte van die studie is suksesvol uitgevoer. Die resultate ondersteun die moontlikheid van ‘n epistatiese effek tussen TMPRSS6 A736V en HFE C282Y wat geassosieer is met ‘n verlaging in ferritienvlakke in MS-pasiënte. Patologie-gesteunde genetiese toetsing soos toegepas in hierdie studie as ‘n nuwe konsep vir analise van komplekse siektes met ‘n genetiese komponent, is goed geplaas om kliniese hantering van MS-pasiënte te optimaliseer.