Aims: To elucidate the aetiopathological mechanisms underlying the IIMs, through a combination of genotyping, serotyping and clinical phenotyping in a large cohort of Caucasian idiopathic inflammatory myopathy (IIM) patients. Methods: A cross-sectional study of prevalent IIM cases, ascertained through the Adult Onset Myositis Immunogenetic Collaboration, was performed. Cases were confirmed as possessing myositis according to Bohan and Peter (Bohan and Peter 1975a; Bohan and Peter 1975b). IIM clinical subtypes studied included polymyositis (PM), dermatomyositis (DM) and myositis associated with other connective tissue disease (myositis/CTD-overlap). Genotyping of major histocompatibility complex genes, including HLA-B, -DR, -DQ, tumour necrosis factor alpha (TNF-α), was performed using commercial kits. Serotyping of a comprehensive range of myositis specific/associated antibodies (MSA/MAAs) was undertaken. Results: Clinical subsets are described within the serological groupings, suggesting that the classification of the IIMs appears to be better served by the serotype than by the clinical subgrouping of disease. The IIMs possess HLA class I and II haplotype associations and genetic differences observed between PM and DM are accounted for by serological differences. The TNF-308A association is not independent of HLA class I, due to the strong LD within the MHC, but does form part of a haplotype with these factors. An absence of routinely tested for MSA/MAAs makes cancer associated myositis (CAM) more likely, especially in the DM subgroup. An antibody against a 155 and 140kDa doublet is associated with the development of CAM. Outcome measures in the IIMs show construct validity. HLA-DRB1*07 appears to predict a milder clinical phenotype with less disability. No convincing gene-environmental interaction was found capable of altering disease susceptibility or clinical phenotype. Conclusions: Myositis disease subtypes therefore appear to be defined by specific haplotypes acting as risk factors for the development of various MSAs and MAAs.

Unravelling the genetic architecture of common diseases is a continuing challenge in human genetics. While genome-wide association studies (GWAS) have proven to be successful in identifying many new disease susceptibility loci, the extension of these studies beyond single-SNP methods of analysis has been limited. The incorporation of multi-locus methods of analysis may, however, increase the power of GWAS to detect genes of smaller effect size, as well as genes that interact with each other and the environment. This investigation carried out large-scale simulations of four multi-locus model selection techniques; namely forward and backward selection, Bayesian model averaging (BMA) and least angle regression with a lasso modification (lasso), in order to compare the type I error rates and power of each method. At a type I error rate of ~5%, lasso showed the highest power across varied effect sizes, disease frequencies and genetic models. Lasso penalized regression was then used to perform three different types of analysis on GWAS data. Firstly, lasso was applied to the Wellcome Trust Case Control Consortium (WTCCC) data and identified many of the WTCCC SNPs that had a moderate-strong association (p<10-5) type 2 diabetes (T2D), as well as some of the moderate WTCCC associations (p<10-4) that have since been replicated in a large-scale meta-analysis. Secondly, lasso was used to fine-map the 17q21 childhood asthma risk locus and identified putative secondary signals in the 17q21 region, that may further contribute to childhood asthma risk. Finally, lasso identified three potential interaction effects potentially contributing towards coronary artery disease (CAD) risk. While the validity of these findings hinges on their replication in follow-up studies, the results suggest that lasso may provide scientists with exciting new methods of dissecting, and ultimately understanding, the complex genetic framework underlying common human diseases.

Doctor of Philosophy / Department of Agronomy / Guihua Bai / Allan K. Fritz / Wheat pre-harvest sprouting (PHS), germination of physiologically matured grains in a wheat spike before harvesting, can cause significant reduction in grain yield and end-use quality. Many quantitative trait loci (QTL) for PHS resistance have been reported in different sources. To determine the genetic architecture of PHS resistance and its relationship with grain color (GC) in US hard winter wheat, a genome-wide association study (GWAS) on both PHS resistance and GC was conducted using in a panel of 185 U.S. elite breeding lines and cultivars and 90K wheat SNP arrrays. PHS resistance was assessed by evaluating sprouting rates in wheat spikes harvested from both greenhouse and field experiments. Thirteen QTLs for PHS resistance were identified on 11 chromosomes in at least two experiments, and the effects of these QTLs varied among different environments. The common QTLs for PHS resistance and GC were identified on the long arms of the chromosome 3A and 3D, indicating pleiotropic effect of the two QTLs. Significant QTLs were also detected on chromosome arms 3AS and 4AL, which were not related to GC, suggesting that it is possible to improve PHS resistance in white wheat. To identify markers closely linked to the 4AL QTL, genotyping-by-sequencing (GBS) technology was used to analyze a population of recombinant inbred lines (RILs) developed from a cross between two parents, “Tutoumai A” and “Siyang 936”, contrasting in 4AL QTL. Several closely linked GBS SNP markers to the 4AL QTL were identified and some of them were coverted to KASP for marker-assisted breeding. To investigate effects of the two non-GC related QTLs on 3AS and 4AL, both QTLs were transferered from “Tutoumai A” and “AUS1408” into a susceptible US hard winter wheat breeding line, NW97S186, through marker-assisted backcrossing using the gene marker TaPHS1 for 3AS QTL and a tightly linked KASP marker we developed for 4AL QTL. The 3AS QTL (TaPHS1) significantly interacted with environments and genetic backgrounds, whereas 4AL QTL (TaMKK3-A) interacted with environments only. The two QTLs showed additive effects on PHS resistance, indicating pyramiding these two QTLs can increase PHS resistance. To improve breeding selection efficiency, genomic prediction using genome-wide markers and marker-based prediction (MBP) using selected trait-linked markers were conducted in the association panel. Among the four genomic prediction methods evaluated, the ridge regression best linear unbiased prediction (rrBLUP) provides the best prediction among the tested methods (rrBLUP, BayesB, BayesC and BayesC0). However, MBP using 11 significant SNPs identified in the association study provides a better prediction than genomic prediction. Therefore, for traits that are controlled by a few major QTLs, MBP may be more effective than genomic selection.

Fissura de lábio com ou sem fissura de palato não-sindrômica (FL/P NS) é uma malformação craniofacial frequente, com modelo de herança multifatorial, onde fatores de risco genéticos e ambientais atuam na manifestação da doença. Variações nos níveis de expressão gênica têm sido apontadas como um importante mecanismo de susceptibilidade a doenças complexas, e variantes no DNA que regulam esses níveis de expressão (eQTL) têm sido combinadas a estudos de associação para auxiliar no entendimento da etiologia de algumas doenças. No presente trabalho, integramos eQTLs e estudo de associação para 1) verificar se variantes já associadas com FL/P NS possuem um papel regulatório em células-tronco de músculo orbicular do lábio (OOMMSC, um tecido afetado em FL/P NS), e 2) verificar se eQTLs mapeados em OOMMSC teriam associação com a mesma. Para o primeiro objetivo, verificamos a correlação entre os genótipos das variantes rs642961 e rs590223 e os níveis de expressão de IRF6, e também entre rs987525 e os níveis de expressão de MYC. Não encontramos correlação para nenhuma das três variantes testadas. É possível que essas variantes possuam um papel funcional em algum momento específico da embriogênese, ou mesmo que não tenhamos detectado essa correlação devido ao número amostral analisado (N=46). Para o segundo objetivo, realizamos um estudo de associação do tipo caso-controle dos eQTLs rs5011163, rs1505443, rs4793213, rs4793229 e rs1242500. Não encontramos associação entre nenhuma das cinco variantes e FL/P NS. Uma possível explicação para a associação negativa seria a significância marginal dessas variantes como eQTLs em OOMMSC. Além disso, estudos com baixo poder, como o mapeamento de eQTLs em OOMMSC realizado em outro projeto pelo nosso grupo, geralmente detectam os eQTLs de maior efeito, sendo esses frequentemente compartilhados entre tecidos, e, assim, podem não ter relevância para a doença em si. Outros eQTLs de OOMMSC, selecionados por critérios diferentes do presente estudo, estão sendo testados para associação com FL/P NS, o que nos permitirá avaliar a relevância dessa abordagem para detectar variantes de susceptibilidade a FL/P NS / Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a frequent craniofacial malformation, with a multifactorial model of inheritance, in which genetic and environmental risk factors act in disease manifestation. Variation of gene expression has been pointed as an important susceptibility mechanism to complex diseases, and DNA variants that regulate expression levels (eQTLs) have been combined with association studies to help elucidate the etiology of some diseases. In the present work, we integrate eQTL and association studies to 1) verify if variants associated with NSCL/P have a regulatory role in orbicularis oris muscle mesenchymal stem cells (OOMMSC, a tissue affected by NSCL/P); and 2) verify if eQTLs mapped in OOMMSC are associated with the disease. For the first goal, we verified the correlation of the rs642961 and rs590223 genotype variants with IRF6 expression levels, and also between the rs987525 genotype and MYC expression levels. We did not find correlation for any of the three variants tested. Possibly, these variants have a functional role in specific moments of embryogenesis, or sample size (N=46) was insufficient to detect correlation. For the second goal, we did a case-control association study for eQTLs rs5011163, rs1505443, rs4793213, rs4793229 and rs1242500. We did not find association between these variants and NSCL/P. The negative association could be explained by the marginal significance of these variants as eQTLs in OOMMSC. Besides, low-power studies, as the OOMMSC eQTL mapping performed in another project by our group, usually detect eQTLs of larger effect, which are frequently shared among tissues; therefore, they may not be relevant for the disease itself. Other eQTLs, selected under different criteria, are currently being tested for association with NSCL/P, which will enable us to evaluate the relevance of this approach to detect susceptibility variants for NSCL/P

A obesidade comum é atualmente um dos problemas de saúde pública mais importante no mundo, frequentemente associada a outros distúrbios tais como hipertensão, diabetes, doenças cardiovasculares e câncer. Apesar da alta prevalência de obesidade em diversas populações, muitos dos estudos relacionados aos seus fatores de risco genéticos foram realizados com indivíduos de ascendência europeia ou asiática, mas foram poucos os realizados com populações de origem africana ou nativas americanas. Nosso trabalho tem por objetivo geral investigar potenciais fatores de risco genéticos associados ao sobrepeso e à obesidade em populações afrodescendentes remanescentes de quilombos do Vale do Ribeira - SP, comunidades rurais semi-isoladas, previamente bem caracterizadas do ponto de vista clínico, genealógico e genético-populacional. Nossa amostra constituiu-se de 759 indivíduos, pertencentes a doze populações de remanescentes de quilombos (Abobral, São Pedro, Galvão, Ivaporunduva, Pedro Cubas, André Lopes, Nhunguara, Sapatu, Pilões, Maria Rosa, Poça e Reginaldo), dos quais foram obtidos amostras de DNA, dados clínicos, informações genealógicas e medidas antropométricas. A investigação dos fatores de risco genéticos associados ao sobrepeso/obesidade foi realizada por duas abordagens: (1) estudo de associação baseado em famílias (N = 584, 59 famílias) e (2) estudo de associação populacional com indivíduos não aparentados (N=305). Foram selecionados para estudo nove polimorfismos em oito genes candidatos: LEP rs2167270, LEPR rs1137101, ADRB2 rs1042713, PPARG rs1801282, PLIN1 rs2289487, RETN rs1862513, INSIG2 rs7566605, FTO rs1121980 e FTO rs1421085. As análises de associação baseadas em família indicaram que, nessas populações, apenas o polimorfismo PLIN1 rs2289487 está associado significativamente com o grupo de risco em relação à razão cintura-quadril (RCQ >=0,85 para mulheres e >=0,90 para homens; P=0,013). Aparentemente não existem trabalhos anteriores que verificaram a associação deste polimorfismo com a obesidade por essa metodologia. As análises do estudo populacional com indivíduos não aparentados mostraram associação significativa entre: (i) o alelo G no polimorfismo LEPR rs1137101 e a variação do índice de massa corporal (IMC; P=0,027); (ii) o alelo G do polimorfismo LEPR rs1137101 e o fenótipo de sobrepeso/obesidade (IMC>=25 Kg/m²; P=0,027); (iii) o alelo G no polimorfismo ADRB2 rs1042713 e o fenótipo de risco (IMC>=25 Kg/m²; P=0,029); (iv) o polimorfismo PLIN1 rs2289487 (genótipo GG) e os menores valores do IMC (P=0,025); (v) o polimorfismo FTO rs1121980 (alelo G) e o fenótipo de risco (IMC>=25 Kg/m²), assim como a variação do IMC (P=0,037 e P=0,022 respectivamente); e (vi) o alelo A no polimorfismo FTO rs1421085 e maiores valores da circunferência da cintura (Cc; P=0,016) e da razão cintura-quadril (RCQ; P=0,030). Tomados em conjunto, nossos resultados sugerem a participação dos genes LEP, LEPR, ADRB2, PLIN1 e FTO no aumento da predisposição ao sobrepeso e à obesidade nas populações remanescentes de quilombos. Por fim, as elevadas estimativas de herdabilidade dos três fenótipos investigados (IMC=33%, Cc=33% e RCQ=70%) reforçam a relevância do papel dos fatores genéticos no acúmulo de gordura corporal. O trabalho apresentado é resultado de uma investigação cuidadosa sobre os componentes genéticos associados à regulação do peso corporal em uma população brasileira afrodescendente (com características históricas, ambientais e genéticas peculiares), corroborando a hipótese de que a obesidade comum nas populações quilombolas do Vale do Ribeira é condicionada por um mecanismo poligênico modulado por fatores ambientais importantes como o sedentarismo e a transição nutricional / One of the main international health problems is the common obesity and it is frequently associated with other disorders such as hypertension, diabetes, cardiovascular diseases and cancer. Despite the high prevalence of obesity in many populations, most association studies related to genetic risk factors have been carried out in subjects of European or Asian ancestry, but few studies were performed in African or in Native American populations. The aim of our study was to investigate potential genetic risk factors related to overweight and obesity in African-derived quilombo remnants from Vale do Ribeira region - São Paulo, Brazil. These rural semi-isolated communities were previously well characterized in terms of clinical, genealogical and population data. Our sample was composed by 759 individuals belonging to twelve different quilombo remnants (Abobral, São Pedro, Galvão, Ivaporunduva, Pedro Cubas, André Lopes, Nhunguara, Sapatu, Pilões, Maria Rosa, Poça e Reginaldo), whose DNA samples, clinical data, pedigree information and anthropometrical measures were already collected. The analyses of genetic factors related to overweight and obesity were performed by means of two different approaches: (1) family-based association (N=584, 59 families), and (2) population-based association with non-related individuals (N=305). Nine polymorphisms in eight obesity candidate genes were selected: LEP rs2167270, LEPR rs1137101, ADRB2 rs1042713, PPARG rs1801282, PLIN1 rs2289487, RETN rs1862513, INSIG2 rs7566605, FTO rs1121980 and FTO rs1421085. The family-based association analyses showed that the risk allele G from PLIN1 rs2289487 is significantly associated with the risk group in relation to waist to rip ratio phenotype (WHR >=0.85 for women and >=0.90 for men; P=0.013). Apparently, there have been no previous studies that investigated the association of this polymorphism with obesity by means of this approach. The population-based study showed a significant association between: (i) the allele G of the polymorphism LEPR rs1137101 and body mass index variation (BMI; P=0.027); (ii) the allele G of the polymorphism LEPR rs1137101 and overweight/obesity phenotype (BMI>=25 Kg/m²; P=0.027); (iii) the allele G of the polymorphism ADRB2 rs1042713 and the group of risk in relation to BMI (BMI>=25 Kg/m²; P=0.029); (iv) the polymorphism PLIN1 rs2289487 (genotype GG) and the lower BMI values (P=0.025); (v) the polymorphism FTO rs1121980 (allele G) and the group of risk in relation to BMI (BMI>=25 Kg/m²), as well BMI variation (P=0.037 and P=0.022; respectively); and (vi) the allele A of the polymorphism FTO rs1421085 and the higher values of both waist circumference (WC; P=0.016) and waist to hip ratio (WHR; P=0.030). Altogether, our results suggest that LEP, LEPR, ADRB2, PLIN1, and FTO polymorphisms genes are related to predisposition to overweight and obesity in quilombo remnants population. Finally, the high heritability estimates of the three investigated phenotypes (BMI=33%, WC=33% and WHR=70%) highlight the important role of genetic factors in body fat accumulation. We presented in this work a careful investigation about the genetic component of body weight regulation, using African-derived Brazilian populations (with peculiar historical, environmental and genetical characteristics) as a model. This study strengthens the hypothesis that obesity predisposition in the quilombos from Vale do Ribeira is conditioned by polygenic mechanism, which is modulated by important environmental factors such as sedentary lifestyle and nutritional transition

The publication of a draft equine genome sequence and the release by Illumina of a 50,000 marker single-nucleotide polymorphism (SNP) genotyping chip has provided equine researchers with the opportunity to use new approaches to study the relationships between genotype and phenotype. In particular, it is hoped that the use of high-density markers applied to population samples will enable progress to be made with regard to more complex diseases. The first objective of this thesis is to explore the potential for the equine SNP chip to enable such studies to be performed in the horse. The second objective is to investigate the genetic background of osteochondrosis (OC) in the horse. These objectives have been tackled using 348 Thoroughbreds from the US, divided into cases and controls, and a further 836 UK Thoroughbreds, the majority with no phenotype data. All horses had been genotyped with the Illumina Equine SNP50 BeadChip. Linkage disequilibrium (LD) is the non-random association of alleles at neighbouring loci. The reliance of many genomic methodologies on LD between neutral markers and causal variants makes it an important characteristic of genome structure. In this thesis, the genomic data has been used to study the extent of LD in the Thoroughbred and the results considered in terms of genome coverage. Results suggest that the SNP chip offers good coverage of the genome. Published theoretical relationships between LD and historical effective population size (Ne) were exploited to enable accuracy predictions for genome-wide evaluation (GWE) to be made. A subsequent in-depth exploration of this theory cast some doubt on the reliability of this approach in the estimation of Ne, but the general conclusion that the Thoroughbred population has a small Ne which should enable GWE to be carried out efficiently in this population, remains valid. In the course of these studies, possible errors embedded within the current sequence assembly were identified using empirical approaches. Osteochondrosis is a developmental orthopaedic disease which affects the joints of young horses. Osteochondrosis is considered multifactorial in origin with a variety of environmental factors and heredity having been implicated. In this thesis, a genome-wide association study was carried out to identify quantitative trait loci (QTL) associated with OC. A single SNP was found to be significantly associated with OC. The low heritability of OC combined with the apparent lack of major QTL suggests GWE as an alternative approach to tackle this disease. A GWE analysis was carried out on the same dataset but the resulting genomic breeding values had no predictive ability for OC status. This, combined with the small number of significant QTL, indicates a lack of power which could be addressed in the future by increasing sample size. An alternative to genotyping more horses for the 50K SNP chip would be to use a low-density SNP panel and impute remaining genotypes. The final chapter of this thesis examines the feasibility of this approach in the Thoroughbred. Results suggest that genotyping only a subset of samples at high density and the remainder at lower density could be an effective strategy to enable greater progress to be made in the arena of equine genomics. Finally, this thesis provides an outlook on the future for genomics in the horse.

<p>Linkage in the 2q37 region was evaluated using microsatellite markers in multi-case families from Sweden, Iceland and Norway. Both the two-point and the multipoint linkage analysis show highly significant LOD scores (Z=4.51 and 6.03, respectively). Linkage disequilibrium mapping indicates that some association exists in this region. The <i>PDCD1</i> gene was suggested as a candidate gene within the 2q37 locus due to its importance in immune regulation. Indeed, one haplotype, described by the presence of allele A of the PD1.3 SNP located within intron 4 of this gene, shows linkage to SLE in the Nordic families. The PD1.3A allele is also found to be strongly associated in familiar and sporadic cases of SLE in Europeans and Mexicans. Functional studies further support PD1.3A to be a susceptibility allele for SLE.</p><p>The 1q23 region, containing the genes for the low affinity Fcγ receptors, was fine mapped using single- and multi- case families of various origins. Genetic variants of those genes were analysed and association is found to both the risk alleles of <i>Fc</i>γ<i>RIIA</i> and <i>Fc</i>γ<i>RIIIA</i> in all families. In these families, a single haplotype carrying both risk alleles is predominantly transmitted to patients with SLE, suggesting a presence of linkage disequilibrium between those two genes. <i>Fc</i>γ<i>RIIA</i> and <i>Fc</i>γ<i>RIIIA</i> are also found to be associated to SLE and lupus nephritis in a case-control cohort from Sweden. In the same cohort, the PD1.3A allele shows strong association to lupus nephritis. We suggest that there may be an additive effect between <i>Fc</i>γ<i>RIIA</i> and <i>PDCD1</i>, since having the disease-associated genotypes at both loci gives an increased risk for developing lupus nephritis.</p><p>Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disorder with a complex multifactorial aetiology. Genetic studies suggest that several genes are involved in disease pathogenesis and that extended genetic heterogeneity is present.</p>

Linkage in the 2q37 region was evaluated using microsatellite markers in multi-case families from Sweden, Iceland and Norway. Both the two-point and the multipoint linkage analysis show highly significant LOD scores (Z=4.51 and 6.03, respectively). Linkage disequilibrium mapping indicates that some association exists in this region. The PDCD1 gene was suggested as a candidate gene within the 2q37 locus due to its importance in immune regulation. Indeed, one haplotype, described by the presence of allele A of the PD1.3 SNP located within intron 4 of this gene, shows linkage to SLE in the Nordic families. The PD1.3A allele is also found to be strongly associated in familiar and sporadic cases of SLE in Europeans and Mexicans. Functional studies further support PD1.3A to be a susceptibility allele for SLE. The 1q23 region, containing the genes for the low affinity Fcγ receptors, was fine mapped using single- and multi- case families of various origins. Genetic variants of those genes were analysed and association is found to both the risk alleles of FcγRIIA and FcγRIIIA in all families. In these families, a single haplotype carrying both risk alleles is predominantly transmitted to patients with SLE, suggesting a presence of linkage disequilibrium between those two genes. FcγRIIA and FcγRIIIA are also found to be associated to SLE and lupus nephritis in a case-control cohort from Sweden. In the same cohort, the PD1.3A allele shows strong association to lupus nephritis. We suggest that there may be an additive effect between FcγRIIA and PDCD1, since having the disease-associated genotypes at both loci gives an increased risk for developing lupus nephritis. Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disorder with a complex multifactorial aetiology. Genetic studies suggest that several genes are involved in disease pathogenesis and that extended genetic heterogeneity is present.

Prostate cancer constitutes the most common malignancy and the most common cause of cancer‐related death in Swedish men. A large body of evidence suggests that inherited genetic variants contribute to both development and progression of prostate cancer. The aim of this thesis is to identify genetic variants that alter prostate cancer risk and progression. All papers included in this thesis are based on a Swedish population‐based case‐control study (CAPS) comprising 2,965 incident prostate cancer cases and 1,823 controls. In paper I, we investigated if genetic variants in the E‐cadherin gene altered prostate cancer risk. Seven haplotype tagging SNPs(tagSNPs) were selected and genotyped in CAPS and families with hereditary prostate cancer. We confirmed association of a promoter SNP rs16260 previously reported to increase risk of hereditary prostate cancer (OR: 2.6; 95% CI: 1.6‐4.3) for homozygous ‘A’ carriers. In paper II, we assessed 46 polymorphisms earlier reported to be associated with prostate cancer risk. Six polymorphisms in five different genes were replicated. Interestingly, three of these genes were involved in the androgen biosynthesis. In paper III, we followed up on the results from paper II by genotyping 23 tagSNPs located in the hormone regulating genes AR, CYP17 and SRD5A2. Multiple SNPs and haplotypes were associated with prostate cancer risk, especially in the AR gene. Combining risk alleles from all genes revealed a substantial risk increase for each additional allele carried (OR: 1.12; 95% CI: 1.1‐1.2, P=0.00009). In paper IV, we collected information about cause of death for all case patients in CAPS. At time of follow‐up 300 study subjects were deceased from prostate cancer. We assessed AR, CYP17 and SRD5A2 variants for association with lethal prostate cancer and found overall no association. However, one AR promoter SNP was associated with an increased risk of dying from prostate cancer amongst men who received palliative hormonal therapy as primary treatment. In paper V, we assessed common genetic variation at the ERG locus for association between prostate cancer risk and survival. ERG is recognized as a protooncogene frequently overexpressed in prostate cancer. A total of 21 tagSNPs in the 5’ region of ERG were genotyped. There was no correlation between ERG SNPs and prostate cancer risk but common genetic variation located approximately 100,000 basepairs upstream of ERG was significantly associated with prostate cancer specific survival. In summary, our results suggest that common genetic variation in Ecadherin alters prostate cancer risk in Swedish men with a positive family history of prostate cancer. Moreover, common genetic variation in the androgen‐related genes AR, CYP17 and SRD5A2 affects the risk of developing prostate cancer but is unlikely to alter prostate cancer progression. However, genetic variants in AR may affect hormonal therapy response. Finally, ERG polymorphisms are associated with prostate cancer‐specific death but are not likely to play a role in prostate cancer development.

Prostate cancer remains a significant health concern for men throughout the world. Accumulating epidemiologic and molecular evidence suggests that inflammation is an important component in the aetiology of prostate cancer. Supporting this hypothesis, population studies have found an increased risk of prostate cancer in men with a prior history of certain sexually transmitted infections or prostatitis. More general evidence of a relationship between inflammation and prostate cancer has been provided by reports indicating that daily use of non steroidal anti-inflammatory drugs (NSAIDs) may be associated with a lower incidence of prostate cancer. The exact mechanism whereby inflammation might act in tumour development and progression remains to be elucidated, but is likely to be complex. The genetic contribution to inflammatory responses involved in the development of prostate cancer has not yet been extensively or systematically studied. However, this thesis evaluates the role of various inflammation-related genes in the pathogenesis of prostate cancer. The macrophage scavenger receptor 1 (MSR1) is a transmembrane protein that is mainly expressed by macrophages. This receptor mediates the binding, internalization and processing of a wide range of macromolecules, and is suggested to play a major role in the recognition and clearance of pathogenic and damaged cells. Recent reports have suggested MSR1 to be a candidate gene for hereditary prostate cancer. Therefore, we screened the MSR1 gene among men with hereditary prostate cancer and identified 18 sequence variants. One previously reported truncation mutation was found more frequently in men with prostate cancer than in unaffected men, in accordance with previously published results. However, the difference in frequencies we found between these groups was not statistically significant. In addition, we genotyped five common polymorphisms in MSR1 in 215 men with unselected prostate cancer and 425 controls. No association between any of the five common variants and prostate cancer were found. We then performed a comprehensive genetic study using extensive populationbased case-control material to evaluate possible associations between sequence variants in inflammation-related genes and prostate cancer. The first gene to be examined was interleukin-1 receptor antagonist (IL-1-RN), encoding a cytokine that plays an important role in regulation of the inflammatory response by binding to the IL-1 receptor and thus inhibiting the binding of the pro-inflammatory cytokines IL-1α and IL-1β. Collectively, these three cytokines exert a central role in the protection against diverse lesions, ranging from microbial colonisation to infection and malignant transformation. The genetic analysis of IL-1RN revealed that the most common haplotype was significantly associated with prostate cancer risk for patients with prostate cancer, and further this association appears to be stronger in cases with advanced disease. The macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth-factor-β superfamily has been shown to exert diverse biological functions, including regulation of macrophage activity in the inflammatory response and both growth inhibition and induction of apoptosis in epithelial and other tumour cell lines. The genetic analysis of MIC-1 revealed that a seuqence variant (H6D) appears to be associated with a decreased prostate cancer risk. We also performed measurements of MIC-1 serum levels among patients with prostate cancer and healthy controls. These data indicate that serum MIC-1 levels are associated with an increased risk for prostate cancer. Further, the clear relation between clinical stage and MIC-1 level also suggest that MIC-1 may be useful as a prognostic factor, where high serum concentration is associated with a poor prognosis. In summary, our results provide further support for the assumption that polymorphisms in inflammatory genes play critical roles in prostate cancer susceptibility. Additional studies are needed to elucidate the mechanisms whereby the demonstrated variations contribute to prostate cancer development.