Abstract Sensorineural hearing impairment (SNHI) is a well-recognized manifestation of mitochondrial diseases and occurs either in a non-syndromic form or as a part of a syndrome. Mitochondrial deafness is bilateral, usually progressive and is inherited maternally. Approximately 70% of patients with the most common syndromes, Kearns-Sayre, MELAS or MERRF, have SNHI. Several mutations in mitochondrial DNA (mtDNA) have been found to cause non-syndromic SNHI, including 1555A>G, 7445T>C, 7472insC and 7511T>C. In order to estimate prevalences of pathogenic mtDNA mutations in population-based cohorts of patients with SNHI, we obtained samples from 133 patients with SNHI, reportedly representing 117 separate maternal lineages. We found five patients with the 3243A>G mutation and three with the 1555A>G mutation, whereas the other point mutations associated with SNHI were absent. The frequencies of the mutations in the cohort were thus 4.3 % for 3243A>G and 2.6 % for 1555A>G, suggesting a total frequency of 6.9 % for mtDNA mutations known to be associated with hearing impairment. We found a mutation 10044A>G, which has been reported as pathogenic, in our patients with SNHI, but we also found it among the controls. Our results show it to be a homoplasmic polymorphism associated with a fairly rare haplotype within mtDNA haplogroup H which has recently been confirmed as subcluster H4. These results highlight the difficulty in determining the pathogenicity of a mtDNA mutation when it is identified only in one family. Therefore, in addition to the previously published criteria, we suggest that a sufficient number of haplotype-specific controls should be screened before the pathogenic nature of a mtDNA mutation can be verified. We determined the complete mtDNA sequences for 121 Finns, and after complementing our recent data, for a total of 192 Finns, and were able to construct a phylogenetic network based on complete mtDNA sequences, the largest set of complete sequences available at that time. These mtDNAs provide a rich source of information for studies in population genetics and a potential tool for analysing new substitutions and genotypes that entail a risk of mitochondrial disease. We used the phylogenetic network to find new pathogenic mutations or risk genotypes for SNHI. The entire coding region sequences of mtDNA were determined in 32 patients with SNHI and compared with the network. The patients were found to harbour more rare polymorphisms and haplotypes than the controls and to show increased variation in their mtDNA sequences, suggesting mildly deleterious effects for these substitutions. Two of the new mutations were suggested as putatively pathogenic.

Background: Lipoprotein(a) [Lp(a)] is composed of a low density-lipoprotein (LDL) particle and a glycoprotein molecule known as apolipoprotein(a) [apo(a)]. Apo(a) exists in several differently-sized isoforms and is responsible for the unique properties of Lp(a). Although Lp(a) has been known for the past 40 years its relationship with coronary heart disease (CHD) has not been characterized in sufficient detail. Whether Lp(a) causes CHD is not clear. Furthermore, the role of apo(a) isoform variation and other sources of Lp(a) heterogeneity (e.g., level of oxidized phospholipids) in Lp(a)-disease association has not been determined. Objectives: To characterize in detail the association of circulating Lp(a) levels with the risk CHD To assess the nature of Lp(a)-CHD association using an integrative genetic study To explore the role of Lp(a) heterogeneity in its association with CHD Data sources: 1. The Emerging Risk Factors Collaboration (ERFC) database (36 studies, 127,000 participants) 2. The European Prospective Investigation of Cancer – Norfolk (EPIC-Norfolk) study (2200CHD cases, 2200 controls) 3. The Pakistani Risk of Myocardial Infarction Study (PROMIS) (1800 MI cases and 1800 controls) 4. Systematic quantitative reviews of published epidemiological studies Results: ERFC data - Analyses of cross-sectional data on up to 127,000 participants (predominantly of European descent) demonstrated that Lp(a) is generally not strongly correlated with known CHD risk factors. Weakly positive correlations were observed with LDL-cholesterol, apolipoprotein B100 and fibrinogen. Levels were over 2-fold higher in Blacks compared to Whites. Analyses of available data on repeat measurements in 6600 participants demonstrated that Lp(a) values have very high long-term within-person consistency (regression dilution ratio ~ 0.9). Outcome data involved 9300 incident CHD events, 1900 ischaemic strokes and 8100 nonvascular deaths. The risk ratio for CHD per 1SD higher Lp(a) concentration, adjusted for age, sex, lipids and other conventional vascular risk factors, was 1.13 (95% CI, 1.09-1.18). The corresponding risk ratios for ischaemic stroke and nonvascular death were 1.10 (1.02 – 1.18) and 1.01 (0.98-1.05), respectively. Data were too limited to assess association in nonwhites. PROMIS data – the adjusted odds ratio for MI in South Asians was comparable to that of Europeans. EPIC-Norfolk genetic data - The odds ratio for CHD per 1-SD higher Lp(a) concentration, after adjustment for cardiovascular risk factors, was 1.37 (1.20-1.56). Tagging SNPs rs10455872 and rs11751605 (minor allele frequency: 8% and 18%, respectively) were associated with 207% (95% CI, 188 - 227%) and 38% (31 - 46%) higher Lp(a) concentrations per copy of minor allele, respectively. These SNPs accounted for 35% and 5% of the variation in circulating Lp(a) levels, respectively, and were associated with an odds ratio for CHD of 1.34 (1.14-1.58) and 1.17 (1.04-1.33), respectively. The observed SNP-CHD associations were consistent with expected odds ratios corresponding to the Lp(a) effect of the SNPs. Systematic reviews – meta-analysis of published data from 40 studies (11,300 cases, 47,000 controls) demonstrated that people with smaller apo(a) isoforms have about a 2-fold higher risk of CHD or ischemic stroke than those with larger isoforms. Meta-analysis of published data from 10 studies (1500 cases, 10,200 controls) showed that people in the top third of baseline distribution of oxidized LDL levels have a 1.8-fold higher risk of CHD than those in bottom third. EPIC-Norfolk biomarker data – Levels of oxidized phospholipids were strongly correlated with Lp(a) concentration (r = 0.7, p-value < 0.0001). One SD higher concentration of oxidized phospholipids was associated with an adjusted odds ratio for CHD of 1.31 (1.15-1.49). The risk ratio was no longer significant after adjustment for Lp(a) concentration (1.08; 95% CI, 0.91-1.29). Conclusion: Lp(a) concentration is specifically, continuously and independently associated with the risk of ischaemic vascular outcomes. Available evidence supports the causal role of the particle in CHD. Lp(a) appears to induce vascular damage through causal mechanisms that involve apo(a) isoforms and oxidized phospholipids. A comprehensive study of markers of Lp(a) heterogeneity should help to understand the full impact of Lp(a) on cardiovascular diseases. In addition, further study is needed in nonwhites to assess the relevance of the factor to vascular disease risk in these populations.

Gene-environment (GE) interactions involving the IGF pathway may affect childhood obesity. Detecting such interactions using longitudinal family studies requires accounting for individual and familial correlations. Simulations were performed to study three methods to test for GE interactions in longitudinal family data using repeated outcomes (linear mixed model) or individual outcome averages as summary statistics (twin model, partition based score I test). Interactions between the IGF pathway genes (IGF-1, IGFALS) and environmental factors (physical activity, daycare attendance and sleep duration) were tested using the Quebec Newborn Twin Study data. The twin model yielded the best performance. Results from the QNTS analysis showed suggestive association for an IGF-1 variant at position 102791894 of chromosome 12 interacting with physical activity. However, this association was not statistically significant after multiple testing correction. More robust methods and studies are needed to better understand the IGF pathway’s role in childhood obesity.

No description available.

No description available.

No description available.

A doença cardiovascular é a principal causa de morte no mundo e no Brasil. A manifestação da doença cardiovascular aterosclerótica, a mais comum das doenças cardiovasculares, é evidenciada principalmente na vida adulta, entretanto o processo aterosclerótico inicia-se na infância e, em ambas as fases, este processo se atrela à presença de fatores de risco cardiovascular. Por outro lado, a prática regular de atividade física e a manutenção de uma aptidão física elevada auxiliam no controle do risco cardiovascular. Entretanto, as relações entre esses aspectos (risco cardiovascular, atividade física e aptidão física) são influenciadas por fatores genéticos e ambientais. Visando o entendimento mais profundo dessas associações em um contexto socioeconômico pouco explorado, uma cidade de pequeno porte, esta tese teve por objetivo investigar em famílias nucleares de Muzambinho - MG: i) a associação entre indicadores de risco cardiovascular e de atividade e aptidão físicas em crianças/adolescentes e adultos e; ii) a agregação familiar e a heritabilidade desses fenótipos. Para tanto, foram utilizados dados coletados entre 2008 e 2009, em 139 famílias de Muzambinho, compostas por 237 pais e 246 filhos, nos quais foram avaliados: composição corporal (índice de massa corporal e circunferência da cintura), fatores metabólicos (glicemia e colesterolemia de jejum), fatores cardiovasculares (pressão arterial sistólica e diastólica), indicadores de atividade física (volume semanal de atividade física total) e a aptidão física (aptidão aeróbica e força manual). A análise estatística incluiu análise exploratória, regressões simples e múltiplas e técnicas de análise de Epidemiologia Genética. Observou-se que nas crianças/adolescentes, os indicadores de obesidade diminuíram com o aumento da aptidão aeróbica, enquanto que a glicemia e o risco cardiovascular global diminuíram com o aumento do volume semanal de atividade física total. Nos adultos, o índice de massa corporal diminuiu com o aumento da força manual, enquanto que a pressão arterial diastólica diminuiu com o aumento do volume semanal de atividade física total. Nas famílias de Muzambinho, os indicadores de risco cardiovascular apresentaram agregação familiar e heritabilidade baixas a moderadas, o que também foi observado para a força muscular manual. Esses resultados sugerem que, numa população com características semelhantes às da população de Muzambinho, as associações entre risco cardiovascular e atividade/aptidão física variam de um indicador para outro e que há influência genética e do ambiente compartilhado pela família nos indicadores de risco cardiovascular e na força manual / Cardiovascular disease is the leading cause of death in the world and in Brazil. Atherosclerotic cardiovascular disease, the most common cardiovascular disease, usually triggers cardiovascular events during adulthood; however, the atherosclerotic process begins during childhood. In addition, at both phases of life, this process is associated with the presence of cardiovascular risk factors. On the other hand, regular physical activity and maintaining high fitness help in controlling cardiovascular risk. However, the relationships among all these aspects (cardiovascular risk, physical activity and physical fitness) are influenced by genetic and environmental factors. To develop a deeper understanding about these associations under an underexplored socioeconomic context, a small size city, this thesis had as an objective to investigate, in nuclear families from Muzambinho - MG: i) the association between cardiovascular risk and physical activity and fitness in children/adolescents and adults; and ii) the familial aggregation and heritability of these phenotypes. For that, the study used the data collected between 2008 and 2009 in 139 families of Muzambinho, consisting of 237 parents and 246 children. At that time, body composition (body mass index and waist circumference), metabolic factors (glycemia and fasting blood cholesterol), cardiovascular factors (systolic and diastolic blood pressures), physical activity marker (total weekly volume of physical activity) and physical fitness (aerobic fitness and manual strength) were assessed. Statistical analysis includes exploratory analysis, simple and multiple regressions and Genetic Epidemiology analysis techniques. Results in children/adolescents showed that obesity markers decreased with increasing aerobic fitness, while glycemia and global cardiovascular risk decreased with increasing total weekly volume of physical activity. In adults, body mass index deceased with increasing manual strength, and diastolic blood pressure decreased with increasing total weekly volume of physical activity. In Muzambinho\'s families, cardiovascular risk markers presented low to moderate familiar aggregations and heritabilities, which was also observed for manual strength. These results suggest that, in a population similar to Muzambinho\'s population, the associations between cardiovascular risk and physical activity and fitness vary from one marker to another, and that genetic and familiar common environment factors influence cardiovascular risk markers and manual strength

Les maladies cardiovasculaires (MCV) sont d’une étiologie complexe et elles sont soumises à de nombreux facteurs environnementaux ainsi que génétiques. Malgré les succès obtenus, pendant la dernière décennie, et pour réduire la mortalité CV il est nécessaire l’identification de nouveaux biomarqueurs en utilisant des approches différentes. Cette thèse propose une approche intégrative pour découvrir de nouvelles associations génétiques associés avec les MCV. Nous avons d’abord réuni les résultats existants grâce à des GWAS précédents, puis nous avons recherché la pléiotropie de ces gènes et nous avons dirigé nos efforts vers une possible traduction des résultats obtenus dans l’application clinique. Nous avons détecté les effets pléiotropiques de différent gènes (IL-6R et ABO) avec différents phénotypes lipidiques et inflammatoires. Par ailleurs, nous avons trouvé quelques associations gène-genre intéressantes pour certains gènes étudiés (ABO et GNB3). Concernant l’implémentation clinique des connaissances obtenues par cette thèse, une SNP dans le gène TREM-1, pourrait être utilisé comme un marqueur de risque pour différentes maladies, et nous avons déposé un brevet Européen et nous envisageons de mener des essais cliniques de chez les patients. D’autre part, nous avons détecté une haplotype du gène IL6R qui pourrait être utilisés dans la médecine personnalisée. Nos résultats aident à mieux comprendre comment les gènes étudiés exercent leurs effets au niveau moléculaire, en influant finalement sur l’état des patients souffrant de MCV. Nous espérons que nos résultats vont être pris en compte pour faire progresser la médecine personnalisée / Cardiovascular diseases (CVD) are complex diseases where many environmental and genetic factors are involved. Although the genetic aetiology of the CVD has been extensively investigated the last two decades, alternative approaches are needed in order to keep advancing in the pathophysiology of CVD. In this thesis, we propose an integrative approach to discover new genetic associations potentially involved in CVD. We chose previous GWAS hits and we centred our efforts in studying the pleiotropic and gene-gender interaction effects. Finally, we focused on the implementation of personalized genome-based therapy of the results obtained. New pleiotropic effects were discovered in the IL-6R and ABO genes relating them with different inflammatory and lipid phenotypes. In addition, we studied the gene-gender interaction effects, finding some sex-specific associations in two of the genes studied (ABO and GNB3). Further, we centered our efforts in implementing the results obtained during the thesis at the clinical level. One SNP within the TREM-1 gene was associated with increased levels of its protein and could be used as a predictor or risk biomarker for different diseases. Due to the high potential of this SNP, we applied a European patent and we are planning to start clinical trials in patients. Also, one haplotype in the IL-6R gene could be used in the treatment of personalized medicine. During this thesis, we discovered new gene-phenotype associations involved in CVD and other diseases. Our results help to better understand how the studied genes are exerting their effects at the molecular level. Our results will hopefully be taken into account in future personalized treatments

A doença cardiovascular é a principal causa de morte no mundo e no Brasil. A manifestação da doença cardiovascular aterosclerótica, a mais comum das doenças cardiovasculares, é evidenciada principalmente na vida adulta, entretanto o processo aterosclerótico inicia-se na infância e, em ambas as fases, este processo se atrela à presença de fatores de risco cardiovascular. Por outro lado, a prática regular de atividade física e a manutenção de uma aptidão física elevada auxiliam no controle do risco cardiovascular. Entretanto, as relações entre esses aspectos (risco cardiovascular, atividade física e aptidão física) são influenciadas por fatores genéticos e ambientais. Visando o entendimento mais profundo dessas associações em um contexto socioeconômico pouco explorado, uma cidade de pequeno porte, esta tese teve por objetivo investigar em famílias nucleares de Muzambinho - MG: i) a associação entre indicadores de risco cardiovascular e de atividade e aptidão físicas em crianças/adolescentes e adultos e; ii) a agregação familiar e a heritabilidade desses fenótipos. Para tanto, foram utilizados dados coletados entre 2008 e 2009, em 139 famílias de Muzambinho, compostas por 237 pais e 246 filhos, nos quais foram avaliados: composição corporal (índice de massa corporal e circunferência da cintura), fatores metabólicos (glicemia e colesterolemia de jejum), fatores cardiovasculares (pressão arterial sistólica e diastólica), indicadores de atividade física (volume semanal de atividade física total) e a aptidão física (aptidão aeróbica e força manual). A análise estatística incluiu análise exploratória, regressões simples e múltiplas e técnicas de análise de Epidemiologia Genética. Observou-se que nas crianças/adolescentes, os indicadores de obesidade diminuíram com o aumento da aptidão aeróbica, enquanto que a glicemia e o risco cardiovascular global diminuíram com o aumento do volume semanal de atividade física total. Nos adultos, o índice de massa corporal diminuiu com o aumento da força manual, enquanto que a pressão arterial diastólica diminuiu com o aumento do volume semanal de atividade física total. Nas famílias de Muzambinho, os indicadores de risco cardiovascular apresentaram agregação familiar e heritabilidade baixas a moderadas, o que também foi observado para a força muscular manual. Esses resultados sugerem que, numa população com características semelhantes às da população de Muzambinho, as associações entre risco cardiovascular e atividade/aptidão física variam de um indicador para outro e que há influência genética e do ambiente compartilhado pela família nos indicadores de risco cardiovascular e na força manual / Cardiovascular disease is the leading cause of death in the world and in Brazil. Atherosclerotic cardiovascular disease, the most common cardiovascular disease, usually triggers cardiovascular events during adulthood; however, the atherosclerotic process begins during childhood. In addition, at both phases of life, this process is associated with the presence of cardiovascular risk factors. On the other hand, regular physical activity and maintaining high fitness help in controlling cardiovascular risk. However, the relationships among all these aspects (cardiovascular risk, physical activity and physical fitness) are influenced by genetic and environmental factors. To develop a deeper understanding about these associations under an underexplored socioeconomic context, a small size city, this thesis had as an objective to investigate, in nuclear families from Muzambinho - MG: i) the association between cardiovascular risk and physical activity and fitness in children/adolescents and adults; and ii) the familial aggregation and heritability of these phenotypes. For that, the study used the data collected between 2008 and 2009 in 139 families of Muzambinho, consisting of 237 parents and 246 children. At that time, body composition (body mass index and waist circumference), metabolic factors (glycemia and fasting blood cholesterol), cardiovascular factors (systolic and diastolic blood pressures), physical activity marker (total weekly volume of physical activity) and physical fitness (aerobic fitness and manual strength) were assessed. Statistical analysis includes exploratory analysis, simple and multiple regressions and Genetic Epidemiology analysis techniques. Results in children/adolescents showed that obesity markers decreased with increasing aerobic fitness, while glycemia and global cardiovascular risk decreased with increasing total weekly volume of physical activity. In adults, body mass index deceased with increasing manual strength, and diastolic blood pressure decreased with increasing total weekly volume of physical activity. In Muzambinho\'s families, cardiovascular risk markers presented low to moderate familiar aggregations and heritabilities, which was also observed for manual strength. These results suggest that, in a population similar to Muzambinho\'s population, the associations between cardiovascular risk and physical activity and fitness vary from one marker to another, and that genetic and familiar common environment factors influence cardiovascular risk markers and manual strength

Introduction – Animal studies suggested that NFKB1, SOCS3 and IKBKB genes could be involved in the association between overnutrition and obesity. This study aims to investigate interactions involving these genes and nutrition affecting obesity-related phenotypes. Methods – We used multifactor dimensionality reduction (MDR) and penalized logistic regression (PLR) to better detect gene/environment interactions in data from the Toronto Nutrigenomics and Health Study (n=1639) using dichotomized body mass index (BMI) and waist circumference (WC) as obesity-related phenotypes. Exposure variables included genotypes on 54 single nucleotide polymorphisms, dietary factors and ethnicity. Results – MDR identified interactions between SOCS3 rs6501199 and rs4969172, and IKBKB rs3747811 affecting BMI in whites; SOCS3 rs6501199 and NFKB1 rs1609798 affecting WC in whites; and SOCS3 rs4436839 and IKBKB rs3747811 affecting WC in South Asians. PLR found a main effect of SOCS3 rs12944581 on BMI among South Asians. Conclusion – MDR and PLR gave different results, but support some results from previous studies.