Nicotinic acid (NA) has been clinically used for over 50 years to regulate lipid plasma levels. It is the only drug in current clinical use that significantly raises HDL cholesterol and reduces inflammatory markers. However, mechanistic understanding into its wide range of actions remains unclear. The recent identification of the Gi-coupled protein receptor HCAR2, for which NA is a potent agonist, provides intriguing insight due to its anti-lipolytic action and restricted, yet specific, expression in adipose tissue and immune cells. The HCAR2 gene is 96% homologous to HCAR3, but the HCAR3 receptor shares neither the specificity for NA, nor the range of functional effects. Moreover, the close homology makes it difficult to separate the genetic variability and regulation of the two genes. To this end, I resequenced HCAR2 and HCAR3 in a selected population to characterize the variability of the two genes and to inform the subsequent design of specific genotyping assays. The Oxford Biobank, which is a random population-based collection of 30-50 year old men and women in Oxfordshire with a wide range of collected phenotypes, was used to explore genetic associations. A preliminary trend with HDL and rs7314976 in HCAR2 motivated the further search associations. However after increasing the sample size, the HDL association did not reach significance. When looking at inflammatory phenotypes, a 20% lower level of systemic hsCRP was found in males with a promoter region variant in HCAR3 (N=1808, p=0.007 for rs55718746). Replication of this finding in two relevant cohorts (NPHS-II, N=2185 and Whitehall, N=4228) resulted in conflicting findings. After optimising the specific detection of both HCAR2 and HCAR3 transcripts, I characterized gene expression in human AT biopsies. This revealed an 18% increase in HCAR2 expression in the female abdominal depot (N=106, p<0.0001) and a reduction in abdominal HCAR2 in both males (β=-0.37, p<0.001, N=107) and females (β=-0.251, p=0.005, N=106) with increasing adiposity. The rs55718746 variant in HCAR3 was also seen to influence expression of both HCAR2 (N=182, p=0.018 in the abdominal depot) and HCAR3 (N=198, p=0.005) but surprisingly in opposite directions, establishing it as the first cis-eQTL for this genomic region. Finally, I used human adipocyte in vitro culture systems to setup a pilot to study the anti-inflammatory effects of NA. The gene expression of HCAR2 and HCAR3 increased significantly with adipocyte differentiation in vitro. NA led to a drop in IL-6 transcript abundance in two out of three of the in vitro differentiated human adipocytes. In conclusion, genetic variability in HCAR2 and HCAR3 shows weak associations with cardiovascular disease risk phenotypes relating to their respective pathways. The relevance of HCAR2 and HCAR3 gene expression and the role of the receptor in the control of inflammation will require further studies.

Thesis (MScMedSc)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: The purpose of this study was to investigate the association of the selected MYH9 single nucleotide polymorphisms (SNPs) with chronic kidney disease (CKD) and its related co-morbidities in the South African mixed ancestry population residing in Bellville South, Cape Town. In 2008, two landmark studies identified SNPs in the MYH9 gene which explained most of the increased risk for non-diabetic CKD in African Americans. These polymorphisms were later found to be weakly associated with diabetic nephropathy. Three SNPs that exhibited independent evidence for association with CKD were selected (rs5756152, rs4821480 and rs12107). These were genotyped using a Taqman genotyping assay on a BioRad MiniOpticon and confirmed by sequencing in 724 subjects from Bellville South, Cape Town, South Africa. Prevalent CKD was defined based on the estimated glomerular filtration rate calculated using the modification of diet in renal disease (MDRD) formula. Chronic kidney disease was present in 214 subjects (29.6%), 96.3% were stage 3 and only 8 subjects were stage 4. In additive allelic models, adjusted for age and gender, rs5756152 demonstrated an association with kidney function whereby each G allele of rs5756152 increased eGFR by 3.67 ml/min/1.73, reduced serum creatinine by 4.5% and increased fasting plasma glucose by 0.51 mmol/L. When an interaction model was used, the effect of rs5756152 on serum creatinine, eGFR and blood glucose levels was retained, and enhanced, but only in diabetic subjects. In addition, rs4821480 T allele increased eGFR while rs12107 A allele decreased glucose levels in diabetic subjects. In contrast to reports that MYH9 SNPs are strongly associated with non-diabetic end stage renal disease, our study demonstrated that rs5756152 and rs4821480 are associated with early kidney function derangements in type 2 diabetes whilst rs12107 is associated with glucose metabolism. Our findings, along with previous reports, suggest that the MYH9 gene may have a broader genetic risk effect on different types of kidney diseases than previously thought. / AFRIKAANSE OPSOMMING: Hierdie studie het ondersoek ingestel na die verband tussen drie gekose MYH9-enkelnukleotied-polimorfismes (SNP’s) en chroniese niersiekte (hierna ‘niersiekte’), wat verwante ko-morbiditeite insluit, onder ’n Suid-Afrikaanse populasie van gemengde afkoms in Bellville-Suid, Kaapstad. Twee rigpuntstudies het in 2008 op SNP’s in die MYH9-geen afgekom wat verklaar het waarom Afro-Amerikaners ’n hoër risiko vir niediabetiese niersiekte toon. Later is bevind dat hierdie polimorfismes ook ’n swak verband met diabetiese nefropatie het. Drie SNP’s wat elk onafhanklik bewys gelewer het van ’n verband met niersiekte is vervolgens gekies (rs5756152, rs4821480 en rs12107). Die SNP’s is daarná met behulp van die Taqman-toets op ’n BioRad MiniOpticon aan genotipering onderwerp, en is toe deur middel van reeksbepaling by 724 proefpersone van Bellville-Suid, Kaapstad, Suid-Afrika, bevestig. Die voorkoms van niersiekte is bepaal op grond van die geraamde glomerulêre filtrasietempo (eGFR), wat aan die hand van die ‘niersiekte-dieetveranderings’- (MDRD-)formule bereken is. Daar is bevind dat 214 proefpersone (29,6%) aan chroniese niersiekte ly – 96,3% was in fase 3 en slegs agt proefpersone in fase 4. In toegevoegde alleliese modelle wat vir ouderdom en geslag aangepas is, het rs5756152 ’n verband met nierfunksie getoon: Elke G-allel van rs5756152 het eGFR met 3,67 ml/min/1,73 verhoog, serumkreatinien met 4,5% verlaag en vastende plasmaglukose met 0,51 mmol/L verhoog. Toe ’n interaksiemodel gebruik is, is die effek van rs5756152 op serumkreatinien, eGFR en bloedglukosevlakke behou en versterk, hoewel slegs by diabetiese proefpersone. Daarbenewens het die T-allel van rs4821480 eGFR verhoog, terwyl die A-allel van rs12107 ook glukosevlakke by diabetiese proefpersone verlaag het. In teenstelling met bewerings dat MYH9-SNP’s ’n sterk verband met niediabetiese eindstadiumniersiekte toon, het hierdie studie bewys dat rs5756152 en rs4821480 met vroeë nierfunksieversteurings by tipe 2-diabetes verband hou, terwyl rs12107 weer met glukosemetabolisme verbind word. Tesame met vorige studies, doen hierdie navorsingsbevindinge dus aan die hand dat die MYH9-geen dalk ’n groter genetiese risiko-effek op verskillende tipes niersiekte het as wat voorheen vermoed is. / Cape Peninsula University of Technology Research Fund / University of Stellenbosch Merit Bursary

Female reproductive performance is a critical component of sustainable pig production systems. There is abundant evidence of genetic variation in these traits among pig breeds. The aims of this study were to identify quantitative trait loci (QTL) affecting reproductive traits and to identify and characterise positional candidate gene(s) underlying the QTL. A Large White - Meishan F2 population was scanned for QTL with effects on reproductive traits. This analysis revealed 13 putative QTLs on seven different chromosomes with effects on five different traits: ovulation rate (OR), teat number (TN), prenatal survival (PS), total born alive (TBA) and litter size (LS). QTL for PS and LS on chromosome 8 were fine mapped and Secreted Phosphoprotein 1 (SPP1) confirmed as a candidate gene. A genome-wide association study was performed on a diverse population of different breeds and crosses lines, for reproductive traits including LS, TBA, number of stillborn piglets, and number of mummified piglets. Fourteen SNPs were found significantly associated with reproductive traits. The functional study of SPP1 examined the hypothesis that differences in foetal growth may be associated with the effectiveness of conceptus attachment, as measured by SPP1 expression. Patterns of SPP1 mRNA and protein expression in placental and uterine tissues supplying the smallest and a normal-sized foetus from the same uterus were examined in Large White-Landrace (LW-LR), Large White (LW) and Meishan (MS) females 40 and 45 of pregnancy. The smallest LW-LR foetuses tended to have a higher level of SPP1 mRNA in endometrium tissue compared to the normal-sized foetuses. However, placenta expression was higher in the normal-sized foetuses compared to the smallest ones. SPP1 protein levels in normal sized foetuses were significantly higher than in the smallest litter mates for all the tissues. Significantly higher levels of SPP1 mRNA and protein were found in MS compared to LW. In both breeds, significant differences between sizes were found in some tissues, with similar expression patterns in respect to size, for both mRNA and protein in endometrial tissues when compared to contemporary LW. In placenta, the direction of the expression differed between breeds, with a higher expression of mRNA and protein in the normal-sized MS foetuses and in the smallest sized LW foetuses. The comparison of SPP1 expression between different foetal sizes and different breeds revealed associations between breed, foetal size, and SPP1 protein, factors implicated in PS and LS. These results together with the genetic evidence indicate that the potential role of SPP1 in placental and foetal development merits further investigation.

Nous avons investigué la relation entre les polymorphismes de nucléotides simples (SNPs) chez trois gènes/loci candidats : DARC, CXCL2 et le loci ORMDL3-GSDMA-CSF3 situés sur le chromosome 17q21 et les complications neutropéniques et infectieuses qui en résultent durant la chimiothérapie chez les patients atteints de la leucémie lymphoblastique aigue. Ces loci codent pour certaines composantes du système immunitaire altérant la concentration de chémokines et leur distribution (DARC), stimulant le relâchement et la migration des neutophiles de la moelle épinière (CXCL2) et régulant la prolifération et la survie des granulocytes (G-CSF). Il est possible que des polymorphismes dans ces loci lorsqu’associés à de la chimiothérapie puissent mettre des individus suceptibles à un risque plus élevé de complication reliées à la chimiothérapie. Une sélection des marqueurs SNPs dans ces gènes ont été génotypés chez des enfants traités au CHU Ste-Justine pour une ALL entre 1989 et 2005. Après correction pour tests multiples, un polymorphisme DARC rs3027012 situé dans le 5’UTR a été associé à un compte phagocytaire peu élevé (APC<500 et <1000 cellules/µL, p=0.001 and p=0.0005, respectivement) ainsi qu’une hospitalisation due à une neutropénie (p=0.007) ou due à une infection et/ou neutropénie (p=0.007). Un effet protecteur a été identifié pour la mutation non sense Gly42Asp variant rs12075 (p=0.006). Des polymorphismes sur le chromosome 17q2 étaient associés à une hospitalisation due à une infection (rs3859192, p= 0.004) et à une neutropénie (rs17609240, p=0.006) L’infection était aussi modulée par CXCL2 (rs16850408, p=0.008) Cette étude identifie pour la première fois que les loci modulant le décompte des leucocytes et des neutrophiles pourraient jouer un rôle dans de déclenchement de complications dues à la chimiothérapie et pourraient ainsi servir de marqueurs pour un ajustement et un suivi du traitement. / We investigated the relationship between single nucleotide polymorphisms (SNPs) in 3 candidate genes/chromosomal loci: DARC, CXCL2 and ORMDL3-GSDMA-CSF3 locus on chromosome 17q21, and neutropenic and infectious complications during chemotherapy in pediatric acute lymphoblastic leukemia (ALL) patients. These loci encode the components of immune system altering chemokine concentration and distribution (DARC), stimulating neutrophil release from bone marrow and migration (CXCL2) and regulating granulocyte proliferation and survival (G-CSF). It is possible that polymorphisms of these loci when associated with chemotherapy may put susceptible individuals at higher risk of chemotherapy complications. Selected tag SNPs in these genes are genotyped in children treated at the CHU Sainte-Justine for (ALL) between 1989 and 2005. After correction for multiple testing, DARC polymorphism rs3027012 in 5’UTR was associated with low absolute phagocyte count (APC<500 and <1000 cells/µL, p=0.001 and p=0.0005, respectively) and hospitalisation due to febrile neutropenia (p=0.007) or due to infection and/or febrile neutropenia (p=0.007). A protective effect was instead noted for missense Gly42Asp variant rs12075 (p=0.006). The polymorphisms on chromosome 17q2 were associated with hospitalisation due to infection (rs3859192, p= 0.004) and neutropenia (rs17609240, p=0.006). Infection was also modulated by CXCL2 (rs16850408, p=0.008) This study identifies for the first time that the loci modulating white blood cell and neutrophil count may play a role in the onset of chemotherapy complications and may thus serve as markers for adjustment or follow-up of the treatment.

La glycosylation est un processus enzymatique permettant l'ajout de sucres à des composés (sucres, lipides ou protides), modifiant ainsi leurs propriétés. La glycosylation est impliquée dans la détoxification des xénobiotiques et des variations d'activité des enzymes responsables ont été identifiées comme facteur de risque de cancer en particulier dans les organes exposés aux xénobiotiques. Dans la première partie de notre travail nous étudions l'impact des polymorphismes génétiques de certaines enzymes responsables de la détoxification (UGT1A7, GST et XRCC1) sur le risque de carcinome hépatocellulaire. Nous montrons que la combinaison de certains polymorphismes génétiques peut entraîner une augmentation du risque de CHC. Des modifications d'expression des glycoprotéines de surface ont été observées dans les cellules cancéreuses jouant un rôle dans leurs interactions avec le microenvironnement. Dans la seconde partie, nous étudions l'effet de l'inhibition des interactions des cellules de CHC/cellules endothéliales par le blocage du couple sialyl Lewis x/E-sélectine sur la croissance tumorale. Ce blocage est obtenu, d'une part par transfert du gène de la Fucosyl-transferase I, inhibant l'expression de sLex à la surface des cellules de CHC, et d'autre part, par utilisation de cimétidine ou d'amiloride permettant une inhibition de l'expression de la E-sélectine par les cellules endothéliales. Nous obtenons une inhibition de la croissance tumorale in vivo par blocage de la néoangiogénèse. Ces travaux permettent donc d'identifier des facteurs de risque génétiques de CHC et d'envisager une autre voie de traitement du CHC. / Glycosylation is an enzymatic process that consists of the addition of glycosyl groups to compounds (sugars, lipids or proteins), thus modifying their properties. Glycosylation is involved in the detoxification of xenobiotics and variations in activity of enzymes responsible have been identified as a potential risk factor for cancer in particular in organs in contact with the external environment. In the first part of our work we study the impact of polymorphisms of detoxification enzyme (UGT1A7, GST and XRCC1) on the risk of hepatocellular carcinoma. We show that the combination of genetic polymorphisms of such enzymes may increase the risk of HCC. Modifications in the expression of surface glycoproteins have been observed in cancer cells and play a role in their interactions with the tumoral microenvironment. In the second part, we study the effect of inhibition of interactions of HCC cells / endothelial cells on tumor growth by blocking the interaction between sialyl Lewis x and E-selectin. First, we achieved the inhibition of the expression of sLex on the surface of HCC cells by introducing fucosyl transferase- I gene in HCC cells. In a second part of our work we used cimetidine and amiloride to inhibit the expression of E-selectin by endothelial cells. This approach resulted in inhibition of HCC cells / endothelial cells interaction and thereby tumor growth inhibition in vivo. This effect is mediated by an inhibition of tumor neoangiogenesis. This work therefore identifies genetic risk factors for HCC and allows considering another way of treatment of HCC.

No description available.

Ainda são escassos estudos que avaliem biomarcadores para diferenciação de transtorno depressivo maior (TDM) e transtorno bipolar (TB), principalmente relativo à etiologia desses transtornos e sua relação com os receptores glicocorticoides (GR) e, principalmente, com os receptores mineralocorticoides (MR). Objetivo: Encontrar biomarcadores genéticos e/ou hormonais e observar sua associação entre si e/ou a fatores externos (estresse precoce - EP) para compreender melhor sua fisiopatogenia e auxiliar no diagnóstico diferencial entre TDM e TB. Material e Métodos: Participaram deste estudo N=273 sujeitos, sendo n=113 controles, n=78 unipolares e n=82 bipolares. A triagem diagnóstica de todos os sujeitos foi realizada por meio do MINI PLUS, checagem de história de trauma na infância pela CTQ, avaliação de sintomas depressivos pela GRID-HAM-D21, e demais comorbidades pela BAI, BHS e BSI. Na busca de biomarcador genético, observou-se as frequências genotípicas e alélicas de 3 polimorfismos de receptor de glicocorticoide (GR) (N363S, R22/23K e BclI) e de 2 polimorfismos de MR (MI180V e -2G/C) após realizada a discriminação alélica por reação em cadeia da polimerase quantitativa (qPCR). Foram avaliados de forma intragrupo as variáveis genéticas e endócrinas (e combinadas) e o efeito do EP sobre tais variáveis. Também, as variáveis polimorfismos, níveis hormonais e exposição a EP foram comparadas entre grupos para avaliar se havia diferença de prevalência, de perfil endócrino, ou se havia suscetibilidade maior por parte dos unipolares ou bipolares para alteração dos níveis hormonais e/ou intensidade do quadro depressivo frente a EP ou a determinado genótipo. Resultados: Todos os sujeitos unipolares e bipolares mostraram piora de seus sintomas depressivos frente a EP e seus subtipos, sendo eles unipolares ou bipolares. Como biomarcador hormonal, comparando-se controles x unipolares x bipolares, ou apenas unipolares x\' bipolares, foi possível observar que os níveis de cortisol e os níveis de aldosterona apresentaram-se os altos em unipolares e os baixos mais em bipolares, quando estes pacientes estavam com depressão grave ou gravíssima. Também, bipolares expostos a EP global, abuso físico e emocional mostraram níveis mais baixos de aldosterona que bipolares que não foram expostos. Frente a exposição a esses EP global e abuso físico, os bipolares tenderam a se mostrar mais suscetíveis que os unipolares a alteração dos níveis de aldosterona. Para biomarcador genético, frequência de genótipos ou alelos não diferenciaram unipolares de bipolares. Entretanto, houve maior prevalência do genótipo heterozigoto AG de GR N363S em pacientes depressivos uni e bipolares quando comparados com controles. Combinando-se os biomarcadores genéticos e hormonais, unipolares apresentaram níveis mais baixos de cortisol e de aldosterona quando carregavam genótipo variante GG de MR -2G/C, enquanto bipolares mostraram tendência a redução de cortisol quando carregavam o alelo variante G de MR MI180V. Quando comparados os genótipos por si só, intragrupo, novamente o polimorfismo MR -2G/C mostra influência sobre o fenótipo unipolar. Em unipolares, presença do alelo variante G de MR -2G/C piora significativamente o quadro depressivo, mas o alelo variante G de MI180V mostrou-se protetor frente a EP. Tanto os unipolares frente aos outros 4 polimorfismos, quanto os bipolares frente a todos os polimorfismos estudados, apresentaram piora significativa de seu quadro depressivo se expostos a EP. Bipolares mostraram uma tendência a ser mais suscetíveis que unipolares a alterações endócrinas (aldosterona) quando expostos a EP global e abuso físico. Conclusão: Tendo em vista os vários achados significativos a cerca dos polimorfismos de MR, tanto para unipolar quanto para bipolar, sua influência sobre os níveis de aldosterona e cortisol basais, reforça-se a importância do papel dos receptores MR dentro da etiologia dos transtornos depressivos unipolares e bipolares, e a forma diferente de funcionamento do MR para a distinção entre TDM e TB / There are still few studies assessing biomarkers for differentiation of major depressive disorder (MDD) and bipolar disorder (TB), mainly related to the etiology of these disorders and its relationship with glucocorticoid receptors (GR) and, manily, with mineralocorticoid receptors (MR). Aim: Finding genetic and / or hormonal biomarkers and observing their association to each other and / or external factors (early-life stress - ELS) for better comprehend their pathophysiology and, then, assisting in differential diagnosis between MDD and TB. Material and Methods: A total of N = 273 subjects composed the study sample, being n = 113 control, n = 78 unipolar, and n = 82 bipolar subjects. The diagnostic screening of all subjects was performed applying MINI PLUS, for history of ELS, CTQ; assessment of depressive symptoms, GRID-HAM-D21; and assessment of other comorbidities, BAI, BHS, and BSI. Researching for genetic biomarker, genotypic and allelic frequencies of 3 GR polymorphisms (N363S, R22 / 23K and BclI) and 2 MR polymorphisms (MI180V and -2G/C) were evaluated after allelic discrimination by quantitative polymerase chain reaction (qPCR). Genetic and endocrine variables (and their combination), and the effect of ELS over these variables were assessed intragrups. Also, polymorphisms, hormonal levels and history to ELS were compared between groups to assess whether there was difference in prevalence, endocrine profile, or whether there was greater susceptibility on the part of unipolar or bipolar for alteration of hormonal levels and / or severity of depressive symptoms considering history of ELS and/or a specific genotype. Results: All unipolar and bipolar subjects showed worsening of their depressive symptoms in the presence of ELS and its subtypes. As hormonal biomarker, comparing unipolar x bipolar x control subjects, or comparing unipolar x bipolar, cortisol and aldosterone levels were higher in unipolar subjects, and lower in bipolar subjects, when these patients presented severe or very severe depressive symptoms. Also, bipolar subjects\' exposed to global ELS, physical and emotional abuse showed lower basal levels of aldosterone than did bipolar who were not exposed to ELS. Concerning global ELS and physical abuse, bipolar tended to be more susceptible than unipolar for aldosterone levels to change. For genetic biomarker, frequency of genotypes or alleles did not distinguished unipolar from bipolar sample. However, there was a higher prevalence of GR N363S heterozygous genotype (AG) in unipolar and bipolar depressive patients when compared to controls. Combining the genetic and hormonal biomarkers, unipolar had lower levels of cortisol and aldosterone when carrying GG variant genotype of MR-2G / C, while bipolar showed tendency to reduce cortisol when carrying the variant G allele of MR MI180V. When comparing the genotypes (intragroup), again, MR-2G/C polymorphism shows influence on the unipolar phenotype. In unipolar, the presence of the variant G allele of MR-2G / C significantly worsens the depressive condition, unlike variant G allele of MI180V has shown to be protective against ELS. Both the unipolar compared to the other 4 polymorphisms, and the bipolar ones against all polymorphisms studied, presented a significant worsening of their depressive condition if exposed to ELS. Bipolar tend to be more susceptible than unipolar to endocrine changes (aldosterone) when exposed to global ELS and physical abuse. Conclusion: Considering the several significant findings regarding MR polymorphisms, for both unipolar and bipolar subjects, and their influence on basal aldosterone and cortisol levels, we highlight importance of the role of MR receptors within the etiology of depressive unipolar and bipolar disorders, and different way of MR functioning in each disorder for assisting the distinction between MDD and TB

We developed a pipeline to identify the copy number polymorphisms (CNPs) in the Northern Swedish population using whole genome sequencing (WGS) data. Two different methodologies were applied to discover CNPs in more than 1,000 individuals. We also studied the association between the identified CNPs with the expression level of 438 plasma proteins collected in the same population. The identified CNPs were summarized and filtered as a population copy number matrix for 1,021 individuals in 243,987 non-overlapping CNP loci. For the 872 individuals with both WGS and plasma protein biomarkers data, we conducted linear regression analyses with age and sex as covariance. From the analyses, we detected 382 CNP loci, clustered in 30 collapsed copy number variable regions (CNVRs) that were significantly associated with the levels of 17 plasma protein biomarkers (p &lt; 4.68×10-10).

Estima-se que mais de 800.000 cirurgias cardíacas de revascularização do miocárdio por ano são realizadas no mundo. Nesta intervenção terapêutica uma das complicações mais comuns é a fibrilação atrial, que esta intimamente relacionada com aumento de risco de morbidade e mortalidade pós-operatória. Os fatores determinantes desta manifestação podem ser pré, intra e pós-operatórios que possivelmente se relaciona com as proteínas pró-inflamatórias, canais iônicos e sistema renina-angiotensina. Portanto, os polimorfismos nos genes que codificam essas proteínas podem ter importante papel no desenvolvimento da FAPo. O objetivo deste trabalho foi de avaliar a associação entre os polimorfismos dos genes IL6 (G-174C), KCNE5 (C97T) e AGT (A-217G) e a incidência da FAPo e seus efeitos na expressão de RNAm, em apêndice atrial direito e em sangue periférico. Para o estudo foram selecionados 76 indivíduos portadores de insuficiência coronariana obstrutiva com indicação de intervenção cirúrgica de revascularização do miocárdio. Desses, 16 com FAPo, 52 sem FAPo e 8 pacientes foram excluídos por motivo de óbito. Amostras de sangue periférico foram obtidas para análise de parâmetros bioquímicos e para extração de DNA genômico e RNA total, antes e 48 horas após a cirurgia cardíaca. Os polimorfismos de nucleotídeo único (SNP) dos genes da IL-6, KCNE5 e do AGT foram detectados pela PCR-RFLP e confirmados por sequenciamento de DNA. A expressão de RNAm em leucócitos totais de sangue periférico e de tecido foi analisada pela PCR em tempo real, utilizando o gene GAPDH como referência endógena. A freqüência do alelo -174G foi de 75 % no GFA e 69,2% no GC e não foi associada ao desenvolvimento de FAPo. A freqüência do alelo 97T foi de 0% no GFA e 10,8% no GC e não foi associada a menor incidência de FAPo. A freqüência do alelo -217A foi de 12,5% no GFA e 15,9% no GC e também não foi associado ao desenvolvimento de FAPo. A expressão de RNAm da IL-6 em LTSP foi reduzida do pré para o pós-operatório de cirurgia de RM em ambos os grupos e não houve correlação entre a expressão de RNAm da IL-6 em LTSP e apêndice auricular direito. A expressão de RNAm do KCNE5 em LTSP foi reduzida do pré para o pós-operatório de cirurgia de RM, exceto em indivíduos do gênero masculino do GC, sugerindo a influência do gênero na expressão desse gene. Não houve correlação entre a expressão de RNAm do KCNE5 em LTSP e apêndice auricular direito. Não se detectou expressão de RNAm do AGT em LTSP e sua expressão em apêndice auricular direito foi extremamente baixa, portanto não está associada ao desenvolvimento de FAPo. / It is estimated that more than 800,000 heart surgery coronary artery bypass grafting are performed annually in the world. This therapeutic intervention of the most common complication was atrial fibrillation, which is closely related to increased risk of morbidity and postoperative mortality. The determining factors of this event can be pre, intra and postoperative possibly relates to the pro-inflammatory proteins, ion channels and renin-angiotensin system. Therefore, polymorphisms in the genes encoding these proteins may play an important role in the development of PoAF. The objective of this study was to evaluate the association between polymorphisms of IL6 gene (G-174C), KCNE5 (C97T) and AGT (A-217G) and the incidence of PoAF and its effects on mRNA expression in right atrial appendage and peripheral blood. For the study we selected 76 individuals with obstructive coronary artery disease with indication for surgical myocardial revascularization. Of these, 16 with PoAF, 52 without PoAF and 8 patients were excluded because of death. Blood samples were obtained for biochemical analysis and extraction of genomic DNA and total RNA before and 48 hours after cardiac surgery. The single nucleotide polymorphisms (SNPs) of IL-6, KCNE5 and AGT were detected by PCR-RFLP and confirmed by DNA sequencing. mRNA expression in total leukocytes in peripheral blood and tissue were analyzed by real-time PCR, using GAPDH gene as endogenous reference. The frequency of-174G allele was 75% in the GFA and 69.2% in GC and was not associated with the development of FAPO. The 97T allele frequency was 0% in GFA and 10.8% in GC and was not associated with a lower incidence of PoAF. The frequency of allele-217A was 12.5% in the GFA and 15.9% in GC and was not associated with the development of PoAF. The mRNA expression of IL-6 on LTSP was reduced from preoperative to the postoperative period of CABG in both groups and no correlation between mRNA expression of IL-6 on LTSP and right atrial appendage. The mRNA expression of KCNE5 LTSP was reduced in the pre and postoperative CABG, except among males in the CG, suggesting the influence of gender on expression of this gene. There was no correlation between the expression of mRNA KCNE5 in LTSP and right auricular appendage. There was no mRNA expression of AGT in LTSP and its expression in right atrial appendage was extremely low, so it is associated with the development of PoFA.

A dependência de álcool acomete de 10 a 12% da população mundial, estando a associação entre uso abusivo do álcool e pancreatite crônica bem estabelecida. A suscetibilidade pancreática ao álcool é variável e apenas 5 a 10% dos etilistas crônicos desenvolvem pancreatite crônica, sendo o papel dos fatores genéticos neste processo praticamente desconhecido. O gene CFTR (cystic fibrosis transmenbrane conductance regulator) codifica proteína que funciona na membrana plasmática de células epiteliais e que tem papel chave na função pancreática exócrina normal, promovendo a regulação, da secreção de fluídos e bicarbonato, importantes para a diluição e a alcalinização do suco pancreático. Quando a função desta proteína é inadequada, observa-se obstrução de pequenos ductos por rolhas protéicas. Várias pesquisas buscam documentar a associação fibrose cística - pancreatite crônica, porém os resultados são conflitantes. Este trabalho pesquisou a freqüência de polimorfismos no trato de politiminas e poli TGs no intron 8 do gene CFTR em pacientes portadores de pancreatite crônica alcoólica. Foram estudados três grupos de pacientes: Grupo A - adultos alcoolistas com diagnóstico de pancreatite crônica; Grupo B - adultos alcoolistas sem pancreatopatia ou cirrose hepática e Grupo C - adultos sadios não alcoolistas. O DNA genômico para análise do gene CFTR foi extraído do sangue periférico, pesquisando-se a freqüência de polimorfismos no trato de politiminas e poli TGs no intron 8. O genótipo 5T/7T foi mais encontrado no grupo A do que no B (p = 0,0481), não havendo diferença quando comparados os grupos A e C (p = 0,1317). Pacientes com pancreatite crônica por álcool com o genótipo 5T/7T tiveram menor incidência de diabetes melito do que aqueles com outros genótipos (p = 0,0465). A combinação de haplótipos 10TG 7T / 11TG 7T foi mais freqüente nos grupos B e C do que no A e poderia, eventualmente, ser um fator protetor contra o desenvolvimento da pancreatite crônica. (p = 0,0080 e 0,0162). Em conclusão, há diferenças no intron 8 do gene CFTR em pacientes com pancreatite crônica alcoólica, quando comparados com alcoolistas não pancreatopatas e indivíduos com o genótipo 5T/7T teriam maior risco de desenvolver pancreatite crônica quando se tornam alcoolistas crônicos. / The alcohol dependence affects from 10 to 12% of the world-wide population, being the association between alcohol abuse and chronic pancreatitis well established. The pancreatic susceptibility to the alcohol is only 5 to 10%, being the paper of the genetic factors practically unknown. The CFTR gene (cystic fibrosis transmenbrane conductance regulator) codifies a protein that functions in the epithelial cells and has a role in pancreatic exocrine function, promoting regulation of the secretion of fluids and bicarbonate, important for the dilution and the alcalinization of the pancreatic juice. When the function of this protein is inadequate, blockage of small ducts occurs. Some research regist the association cystic fibrosis - chronic pancreatite, however the results are conflicting. This work searched the frequency of polymorphisms in the polyT and poly TGs tracts in intron 8 of CFTR gene in patients with alcoholic chronic pancreatitis. Three groups of patients have been studied: Group A - adult alcoholics with chronic pancreatitis; Group B - adult alcoholics without pancreatic disease or hepatic cirrhosis and Group C - non alcoholics healthy adults. DNA analysis of CFTR gene was made after extraction from peripheral blood samples. The 5T/7T genotype was more frequently found in group A that in B (p = 0.0481), with no difference when compared to group C (p = 0,1317). Patients with alcoholic chronic pancreatitis and 5T/7T genotype had less incidence of diabetes mellitus that those with other genotypes (p = 0,0465). The haplotype combination 10TG 7T / 11TG 7T was more frequent in groups B and C that in A and it could, eventually, be a protective factor against the development of alcoholic chronic pancreatitis. (p = 0,0080 and 0,0162). In conclusion, we found differences when these tree groups are compared and individuals with 5T/7T genotype would have greater risk to develop chronic pancreatitis if they become alcoholics.