Malgache, qui es-tn?' This question seeking the ancestry o f the Malagasy remains unanswered five centuries after the debate on the proposed hypotheses of Malagasy origins began. Historical, archaeological, linguistic and some genetic data suggest two major sources o f ancestry: Africa and Indonesia, with minor contributions from Arabia, India and China, but the evidence for the suggestions is sparse and inconclusive. All Malagasy, irrespective of their ethnic backgrounds speak a common language, Malagasy, but differences in physical appearance and culture suggests that they may have different ancestral histories. The goals of this study are to utilize genetic variation present in the Malagasy in conjunction with available data to reconstruct their prehistory and to provide evidence confirming and/or refining existing theories concerning their prehistory. The genetic profiles of eleven of the eighteen Malagasy ethnic groups, a South African Indian and six African populations were compared at thirteen loci; eight autosomal and five Y chromosomal. The markers include four STR loci each on the autosornes (HUMCSF1PO, HUMTH01, HUMCD4 and an (AC)n repeat m the DRD2 gene) and on the Y chromosome (DYS3.93, DYS19, DYS390 and DYS391), two Alu polymorphisms (CD4-/Uw and YAP) and three RtLP loci within the DRD2 gene, Some o f these loci were used to derive autosomal an-j Y chromosome haplotypcs, Population trees as well as principal component analyses- bast-d ba the different data sets consistently revealed very close affinities between the eleven Malagasy groups examined, The intermediate clustering of the Malagasy between African and South Asians also reaffirms that these two groups have contributed significantly to the Malagasy gene pool. Admixture estimates made using autosomal data suggest that approximately 50% o f the Malagasy gene pool is derived from an African source while Y chromosome data indicates an African contribution o f at least 60%. Networks constructed using Y chromosome haplotypes identified a ‘Malagasy-specific’ haplotype cluster. A divergence time of 2864 years (95% confidence intervals, 1227 - 7472 years) is estimated for this cluster which is consistent with archaeological data suggesting that the colonization of Madagascar occurred within the past 3000 years. Both autosomal and Y chromosomal ihta from the present study supports a recent common ancestry for the Malagasy from founders whose gene pool contained contributions from Indonesians and Africans.

A Thesis Submitted to the School of Public Health, Faculty of Health Sciences University of the Witwatersrand, Johannesburg, South Africa, in fulfilment of the requirements for the Degree of Doctor of Philosophy 15 June 2017 / Background HIV infection has remained a major global health burden since its discovery in 1983 and Sub-Saharan Africa remains the region hardest hit by the HIV/AIDS pandemic. The HIV pandemic continues to ravage most parts of Southern African countries, current prevalence between 10-20%. Individuals worldwide differ in their degree of susceptibility to HIV infection and genetic polymorphisms play a major role. Mannose Binding Lectin (MBL) is one such immunological factor found in serum/plasma, it is a normal liver-derived protein and is a key component of the innate immune defence system. MBL deficiency, due to mutations in the MBL2 gene and promoter region, leading to decreased plasma/serum MBL concentration, characterised by defective opsonisation activities of the innate immune system and increased susceptibility to infections including HIV-1 and schistosomiasis. Rationale While there is a lot of advancement in HIV prevention and treatment in Southern African countries, there is still need to investigate host genetic molecules in adults and mother-baby pairs that could be playing a role in HIV-1 transmission/acquisition, disease progression and survival. It was imperative to carry out this study because of the need to quantify the burden of MBL deficiency in this Zimbabwean adult and PMTCT study populations. Alsoto contribute to the knowledge gap on the role of MBL deficiency in HIV-1 transmission, disease progression and survival in African populations in adults and children. The available literature shows that the majority of studies on the association of MBL deficiency and HIV-1 infection in adults and children have been done on populations outside the African continent. There is dearth of information on the role of MBL in this era when access to ART has greatly improved even in developing countries like Zimbabwe. This will be the second study that will assess MBL2 genes and promoter typing in mother-infant pairs in HIV vertical transmission/acquisition. This study aimed to identify and explore potential biomarkers for susceptibility to HIV infection and disease progression. We assessed role of MBL deficiency in HIV-1 and schistosoma infections in Zimbabwean adults enrolled in the Mupfure Schistosomiasis and HIV Cohort (MUSH Cohort) (Paper 1).We also assessed the role of MBL deficiency on HIV progression and survival in this African adult population. We hypothesized that MBL deficiency has a role to play in HIV infection by increasing HIV disease progression and decreasing survival (Paper 2). We also determined prevalence of MBL deficiency, as estimated by MBL2 haplotypes among Zimbabwean mothers and their children aged 9-18 months old as well as its association with risk of HIV-1 infection and vertical transmission from their HIV positive mothers (Paper 3). Main Aim The broad objective of this study was to determine the relationship between MBL deficiency and HIV infection in an adult population of males and females and among mother-infant pairs in Zimbabwe. Study Specific Objectives 1. To determine the prevalence of MBL deficiency among the Zimbabwean adult population. 2. To determine the relationship of MBL deficiency with HIV infection among the Zimbabwean adult population. 3. To determine the effect of MBL deficiency on disease progression and survival among the Zimbabwean adult population. 4. To determine prevalence of MBL deficiency among mothers and their infants in a Zimbabwean population. 5. To determine the relationship between MBL deficiency and HIV transmission from mother to child in a Zimbabwean population. Methods DNA and plasma samples for MBL and HIV analysis were collected from the 379 adult males and females from the MUSH cohort and stored dried blood samples from 622 mother infant pairs from a national PMTCT survey. HIV-1, S. haematobium and S. mansoni infections were determined at baseline using HIV commercial kits and parasitologically respectively. Plasma MBL concentration was measured by ELISA and MBL2 genotypes determined by PCR. We calculated and compared the proportions of plasma MBL deficiency, MBL2 structural variant alleles B (codon 54A>G), C (codon 57A>G), and D (codon 52T>C) as well as MBL2 promoter variants -550(H/L), -221(X/Y) and +4(P/Q) between HIV-1 and schistosoma co-infection and control groups using Chi Square test (Paper 1). We also assessed the role of MBL deficiency on HIV disease progression and survival inthe adult (MUSH) cohort.We analysed blood samples for MBL levels, MBL2 genotypes, HIV-1 status, viral load and CD4+ T cell counts (Paper 1). Participants were followed up for 3 years wherein the endpoints were measured at baseline, 6 weeks, 3, 6, 12, 24 and 36 months. Disease progression was measured as the rate of decline in CD4+ T cell counts and the rate of increase in HIV viral load (Paper 2). Generalised Estimating Equations (GEE) models were used to compare rates of change of the CD4+ T cell count and viral load measurements over the three-year follow-up period. The role of plasma MBL deficiency and MBL2 genetic variants on survival over the 3-year period were estimated using the Cox proportional hazard models. Regression analysis was used to test for interaction and confounding between MBL deficiency, MBL2 genetic variance, age and sex. We used the Wald Chi-square statistic to choose between full and nested models. We also assessed MBL2 polymorphisms in Zimbabwean HIV positive mothers and their children enrolled in a national PMTCT survey carried out in 2012. MBL deficiency was defined as presence of A/O and O/O genotypes in the mothers and their children. We extracted DNA from two dried blood spots for 622 mothers and infant pairs using the Gene Extract and Amp kit reagents. MBL2 Exon 1 genotypes and promoter region alleles -221(X/Y) and -550(H/L) SNP were detected by pyrosequencing. Differences in distribution frequency between HIV infected and uninfected children, of the MBL2 genotypes, promoter region variants and MBL2 haplotypes, were determined by the Chi square test or Fisher’s exact tests (Paper 3). Key findings For specific objective number 1, we assessed 379 adults, 80% females, median age (IQR) 30 (17-41) years. HIV-1, S. haematobium and S. mansoni prevalence were 26%, 43% and 18% respectively in the MUSH baseline survey. Median (IQR) plasma MBL concentration was 800μg/L (192-1936μg/L). Prevalence of plasma MBL deficiency was 18% with high frequency of the C (codon 57G>A) mutant allele (20%). For specific objective number 2, we found no significant difference in median plasma MBL levels between HIV negative (912μg/L) and HIV positive (688μg/L), p=0.066. However plasma MBL levels at the assay detection limit of 20μg/L were more frequent among the HIV-1 infected (p=0.007). S. haematobium andS. mansoni infected participants had significantly higher MBL levels than uninfected. All MBL2 variants were not associated with HIV-1 infection but promoter variants LY and LL were significantly associated with S. haematobium infection (Paper 1). For specific objective number 3, we assessed 197 HIV positive adults where 83% (164) were women with a median age of 31 years old. Prevalence of plasma MBL deficiency (less than 100μg/L) and MBL2 deficient genetic variants (A/O and O/O genotypes) was 21% (42 out of 197) and 39% (74 out of 190), respectively. We did not observe a significant role to explain individual variation in mortality, change of CD4+ T cell count and viral load by MBL plasma deficiency or MBL2 genetic variants from baseline to 3 years follow up period in this adult population (Paper 2). For specific objective number 4, from the PMTCT study, the median age (IQR) of the mothers was 30(26 - 34) years and the children mean age (IQR) was 12 (11-15) months old at the time of enrolment. All 622 mothers were HIV-1 infected, 574 babies were HIV negative and 48 were HIV-1 positive babies. MBL2 normal structural allele A and variants B (codon 5A>G), C (codon 57 A>G) and promoter region SNPs -550(H/L) and -221(X/Y) were detected. Prevalence of MBL deficiency was 34% among the mothers and 32% among the children. For specific objective number 5, we found no association between maternal MBL2 deficiency and HIV-1 transmission to their children. We found no difference in the distribution of HIV-1 infected and uninfected children between the MBL2 genotypes of the mothers and those of the children (Paper 3). Conclusions The results from our study indicate high prevalence of MBL deficiency but we found no evidence of association between MBL deficiency and HIV-1 infection. However, lower plasma MBL levels were associated with reduced prevalence of both S. haematobium and S. mansoni infections and MBL2 promoter and variants LY and LL were associated with increased susceptibility to S. haematobium infection (Paper 1). Our findings attest to the large between-population variability in a host of factors that can predispose individuals susceptible to HIV progression and mortality. We therefore cannot recommend at this time the use of plasma MBL levels or MBL2 genetic variants as a prognostic marker in HIV infection, disease progression and survival in this adult population in Africa (Paper 2). MBL deficiency was not associated with HIV-1 infection among the children nor was it associated with HIV-1 vertical transmission in this study population (Paper 3). / MT2017

Orientador: Carmen Silvia Passos Lima / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-10T01:04:22Z (GMT). No. of bitstreams: 1 Silva_EricaFurquimSoledadeNeves_M.pdf: 1247474 bytes, checksum: fb164930ca8036640d7d8a9b9f56bca8 (MD5) Previous issue date: 2007 / Resumo: As glutationa S-transferases (GSTs) são enzimas detoxificantes que atuam no mecanismo de proteção contra a carcinogênese. Os genes GSTM1 e o GSTT1 são polimórficos em humanos e estão deletados de forma homozigótica em 40-50% e 15-25% dos indivíduos de diferentes populações étnicas, respectivamente. Os polimorfismos T6235C e A4889G do gene CYP1A1 estão também associados ao metabolismo de carcinógenos e as formas variantes CC e GG são identificadas em 5-20% e 5% dos indivíduos de diferentes populações étnicas. O objetivo deste estudo é avaliar se os polimorfismos destes genes influenciam o risco de ocorrência do carcinoma epidermóide (CEC) de cabeça e pescoço ou se estão associados com os aspectos clínicos dos pacientes com a doença. Para tanto, foram avaliados 142 pacientes com CEC de cabeça e pescoço e 142 controles. A genotipagem foi realizada por meio da reação em cadeia da polimerase (multiplex-PCR) e PCR e digestão enzimática, respectivamente. O significado estatístico das diferenças entre grupos foi calculado por meio do teste da probabilidade exata de Fisher. As determinações dos riscos de ocorrência do CEC, foram obtidas por meio das razões das chances (ORs) considerando um intervalo de confiança de 95% (IC 95%). Não foram observadas diferenças entre as freqüências da deleção homozigótica dos genes GSTM1 (40,8% versus 46,5%; P= 0,16) e GSTT1 (25,3% versus 20,4%; P= 0,94) em pacientes e controles. Entretanto a freqüência da deleção homozigótica do gene GSTM1 em pacientes com tumor dos estádios I a III foi menor do que a observada em pacientes com tumores do estádio IV (20,4% versus 51,8%; P= 0,002). A freqüência da deleção homozigótica do gene GSTM1 em pacientes com os estádios I a III do tumor foi também menor do que a observada em controles (20,4% versus 46,5%; P= 0,0008). As freqüências combinadas dos genótipos TC + CC do polimorfismo T6235C do gene CYP1A1 foram similares em pacientes e controles (36,6% versus 33,8%; P= 0,85). Em contraste, a freqüência combinada dos genótipos TC + CC em pacientes com tumor de laringe foi menor do que a observada em pacientes com tumores de outras localizações (21,6% versus 41,9%; P= 0,03). Já as freqüências combinadas dos genótipos AG + GG do polimorfismo A4889G do gene CYP1A1 foram similares em pacientes e controles (33,8% versus 28,2%; P= 0,71) e em pacientes estratificados por aspectos clínicos, anátomo-patológicos e biológicos do tumor. Os resultados deste estudo, em seu conjunto, sugerem que a presença dos genes GSTM1 parecem proteger indivíduos da ocorrência do CEC mais localizado de cabeça e pescoço, enquanto que a deleção homozigótica do gene GSTM1 parece atuar na agressividade do tumor em nossos casos. Os genótipos variantes TC + CC do polimorfismo T6235C do gene CYP1A1 parecem proteger indivíduos de nossa região do câncer de laringe. Já os genótipos do polimorfismo A4889G do gene CYP1A1 parecem não influenciar o risco de corrência da doença ou de suas manifstações clínicas, bem como as carcterísticas anátomo-patológicas e biológicas do tumor em nossos casos / Abstract: The glutathione S-transferases (GSTs) are metabolic enzymes involved in carcinogenic detoxification. GSTM1 and GSTT1 polymorphic genes are deleted in humans and null genotypes frequencies are different in several ethnic groups; 40-50% and 15-25% of different population, respectively. Genetic CYP1A1 polymorphisms T6235C and A4889G are also associated to carcinogenic metabolism and variant genotypes CC and GG are identified in 5-20% and 5% of individuals at several ethnic groups. It¿s unclear if these genetic polymorphisms influence head and neck epidermoide carcinoma (CEC) risk, or its association with patients stratified by clinical features. Therefore, 142 patients diagnosed with head and neck cancer and 142 control subjects were evaluated. Genotyping was performed by using polymerase chain reaction (multiplex-PCR) and PCR and subsequent restriction enzyme digestion, respectively. The different statistical significances between groups, was calculated by using the Fisher exact test or Chi ² test. Crude odds ratios (ORs) were calculated and are given with the 95% confidence intervals (IC). There were no difference frequencies statistically significant of GSTM1 null genotype (40,8% versus 46,5%; P= 0,16) neither GSTT1 null genotype (25,3% versus 20,4%; P= 0,94) between patients and controls. However, the homozygous deletion of the GSTM1 gene in patients with tumors of stages I to III was lower than that seem in patients with advanced (stage IV) tumors (20,4% versus 51,8%; P= 0,002). The homozygous deletion of the GSTM1 gene was also less common in stage I to III patients than in controls (20,4% versus 46,5%; P= 0,0008). The frequencies of the combined variant genotypes TC + CC of the CYP1A1 T6235C polymorphism were similar in patients and controls (36,6% versus 33,8%; P= 0,85). In contrast, the combined genotype TC + CC in patients with tumor of larynx was lower than that observed in patients with other tumors (21,6% versus 41,9%; P= 0,03). The frequencies of the combined variant genotypes AG + GG of the CYP1A1 A4889G polymorphism were similar in patients and controls (33,8% versus 28,2%; P= 0,71) and in patients stratified by clinical features, and anatomo-pathological and biological aspects of the tumor. In sumary, the results of this study sugest that the presence of the GSTM1 genes seems to protect individuals against localized tumors, while the homozygous deletion of the GSTM1 gene seems to be associated to the agressiveness of the tumor; the variant genotypes TC + CC of the CYP1A1 T6235C polymorphism seem to protect individuals against larynx cancer; and the genotypes of the CYP1A1 A4889G polymorphism seem do not influence the risk for head and neck tumor, as well as the clinical features of the disease, and anatomo-pathological and biological aspects of the tumor in our cases / Mestrado / Patologia / Mestre em Estomatopatologia

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 6 uppsatser.

Thesis (Ph. D.)--University of Chicago, Pritzker School of Medicine, Committee on Genetics, August 2001. / Includes bibliographical references. Also available on the Internet.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 8 uppsatser.