Genetics of complex disease

Throughout biomedical research, there is growing interest in the use of ancestry informative markers (AIMs) to deconstruct racial categories into useful variables. Studies on recently admixed populations have shown significant population substructure due to differences in individual ancestry; however, few studies have examined Caribbean populations. Here we used a panel of 28 AIMs to examine the genetic ancestry of 298 individuals of African descent from the Caribbean islands of Jamaica, St. Thomas and Barbados. Differences in global admixture were observed, with Barbados having the highest level of West African ancestry (89.6% ± 2.0) and the lowest levels of European (10.2% ± 2.2) and Native American ancestry (0.2% ± 2.0), while Jamaica possessed the highest levels of European (12.4% ± 3.5) and Native American ancestry (3.2% ± 3.1). St. Thomas, USVI had ancestry levels quite similar to African Americans in continental U.S. (86.8% ± 2.2 West African, 10.6% ± 2.3 European, and 2.6% ± 2.1 Native American). Significant substructure was observed in the islands of Jamaica and St. Thomas but not Barbados (K=1), indicating that differences in population substructure exist across these three Caribbean islands. These differences likely stem from diverse colonial and historical experiences, and subsequent evolutionary processes. Most importantly, these differences may have significant ramifications for case-control studies of complex disease in Caribbean populations.

As Alzheimer's disease (AD) is a complex disease, we decided to estimate how previously reported genetic polymorphisms interact to increase the risk for the disease. Five candidate genes were chosen: apolipoprotein E (APOE), a2-macroglobulin, cathepsin D, myeloperoxidase and nitric oxide synthase. Genotyping was performed in 100 cases of late-onset AD and 100 healthy controls. We found a highly significant difference in APOE 14 distribution between groups (P , 0:005). However, no evidence of association for other studied loci was found. Cumulative analysis of five genetic polymorphisms was performed, but it also failed to reveal any synergistic effect of candidate genes greater than that caused by APOE itself. Our results suggest that the APOE 14 allele is the only known genetic risk factor for late-onset, sporadic AD. q

Nephritis is the most frequent severe manifestation of anti-neutrophil cytoplasm antibody associated (ANCA) systemic vasculitis (AASV) and systemic lupus erythematosus (SLE) and carries substantial morbidity. Although immunosuppressive medications and glucocorticoids are effective at inducing remission, patients still suffer from high relapse rates and experience significant treatment-related toxicity. Rituximab (RTX), a chimeric antibody directed against CD20, found on B lymphocytes, shows potential as a treatment for both AASV and SLE. Although direct comparisons with standard therapies are currently unavailable, patients in several studies of refractory and relapsing disease have achieved a remission despite the failure of standard therapies. These reports are supported by several lines of experimental evidence that underlie the rationale for using targeted B-cell therapies and have improved our understanding of the pathogenesis of these complex diseases. Future randomized control trials and long-term follow-up studies are required to confirm the role of RTX and other B-cell targeting therapies in AASV and SLE.

This contribution aims to highlight how the fluidity of symptoms and their interpretation make Huntington’s disease a constant, changing and insidious presence around which the daily actions of the patient and his or her family revolve. Through the analysis of the illness narratives, the onset of symptoms is identified through connections and reinterpretations of the events of the patient and his family’s past, while activating surveillance processes towards people at risk.

Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness among older adults in the USA and throughout the developed world. Etiological research suggests that AMD is a complex disease, caused by the actions and interactions of multiple genes and environmental factors. Familial aggregation studies, twin studies, and segregation analyses have provided strong evidence for the heritability

Hashimoto's thyroiditis (HT) is an organ-specific T-cell mediated disease. It is a complex disease, with a strong genetic component. To date, significant progress has been made towards the identification and functional characterization of HT susceptibility genes. In this review, we will summarize the recent advances in our understanding of the genetic input to the pathogenesis of HT.

Consanguinity is the union of closely related individuals – which can have genetic implications on the health of offspring(s). Consanguineous families with disorders have been extensively analysed by geneticists and this has led to the identification of many autosomal recessive disorder causal variants and genes. Two copies of the ‘inactivating’ or loss of function (LoF) allele are required to cause an autosomal recessive disorder, one inherited from the mother and the other from the father. In outbreeding populations these LoF alleles very rarely meet their counterpart (as it requires both parents to possess the allele), thus are passed down the generations silently – sometimes for millennia. However, consanguineous and/or endogamous offspring have elevated levels of homozygosity, which dramatically increases the probability of any allele to be in a homozygous (or more correctly autozygous) state. This increase in probability applies to LoF mutations also; and this elevation of levels of homozygosity is the main reason why extremely rare autosomal recessive disorders are usually only seen in populations where consanguinity (and/or endogamy) levels are high.

With the ever decreasing prices of DNA sequencing, whole-genome sequencing is becoming a reality for many laboratories. However, for now, whole-exome sequencing (WES) is the most feasible sequencing technique mostly due to cost factors. Combining the concepts of consanguinity and WES, the aim of this thesis was to identify ‘causal’ variants by analysing whole-exome data obtained from consanguineous families/individuals affected from autosomal recessive disorders such as Primary Ciliary Dyskinesia (PCD) and Autosomal Recessive Intellectual Disability (ARID). Using autozygosity mapping, a novel region located on chromosome 19 (p13.3) was identified to be associated with ARID (later sequenced by another research group and ADAT3 was identified as the causal gene). Using WES, rare homozygous nonsense mutations p.E309* in CCDC151 and p.R136* in DNAAF3 were found to be causal of PCD. Other variants such as p.M263T in MNS1, p.R263* in DNALI1, p.G734fs in HEATR2 and p.E328* in LRRC48 have also been identified which may be causal of PCD but studies in this thesis remained inconclusive due to various reasons. Additionally, a rare missense mutation p.G300D in CTSC was found to be Papillon-Lèfevre syndrome (PLS) causal. This latter finding illustrated the additional information that can be gained from WES data – which is discussed in the thesis.

Finding novel causal variants and gene functions can improve genetic counselling and lead to the identification of targets for preventive and/or curative medicine. In this respect, analysing consanguineous populations as a whole rather than ‘cherry picking’ families with disorders will have additional benefits and facilitate our understanding of the human genome – and this subject is also discussed in this thesis.

Quality-assessed biomedical samples are essential for academia- and industry driven research on human diseases. The etiologies and the molecular genetic factors relevant in African diseases, including both infections and complex degenerative diseases as well as cancer, need to be studied using well annotated and well-preserved biosamples acquired from native African ethnic groups and compare the results with non-African populations and/or with Afro-Americans. However, a number of difficulties negatively impact on the possibility to obtain clinically annotated biological samples in most Sub-Saharan African countries. This is mainly due to major organizational problems, lack of clinical centres that can dedicate resources to research, as well as lack of facilities in which biomaterials can be properly processed and safely stored. Harmonization of biosample acquisition, storage phenotyping schemes and biocomputer infrastructures are the principal objectives of biological resource cente...

There is compelling evidence from transgenic mouse studies and analysis of mutations in human carcinomas indicating that the TGF-β signal transduction pathway is tumor suppressive. We have shown that overexpression of TGF-β1 in mammary epithelial cells suppresses the development of carcinomas and that expression of a dominant negative type II TGF-β receptor (DNIIR) in mammary epithelial cells under control of the MMTV promoter/enhancer increases the incidence of mammary carcinomas. Studies of human tumors have demonstrated inactivating mutations in human tumors of genes encoding proteins involved in TGF-β signal transduction, including DPC4/Smad4, Smad2, and the type II TGF-β receptor (TβRII). There is also evidence that TGF-β can enhance the progression of tumors. This hypothesis is being tested in genetically modified mice. To attain complete loss of TβRII, we have generated mice with loxP sites flanking exon 2 of Tgfbr2 and crossed them with mice expressing Cre recombinase under control of the MMTV promoter/enhancer to obtain Tgfbr2 mgKO mice. These mice show lobuloalveolar hyperplasia. Mice are being followed for mammary tumor development. Tgfbr2 mgKO mice that also express polyoma virus middle T antigen under control of the MMTV promoter (MMTV-PyVmT) develop mammary tumors with a significantly shorter latency than MMTV-PyVmT mice and show a marked increase in pulmonary metastases. Our data do not support the hypothesis that TGF-β signaling in mammary carcinoma cells is important for invasion and metastasis, at least in this model system. The importance of stromal-epithelial interactions in mammary gland development and tumorigenesis is well established. These interactions probably involve autocrine and paracrine action of multiple growth factors, including members of the TGF-β family, which are expressed in both stroma and epithelium. Again, to accomplish complete knockout of the type II TGF-β receptor gene in mammary stromal cells, FSP1-Cre and Tgfbr2 flox/flox mice were crossed to attain Tgfbr2 fspKO mice. The Despite over a decade of scrutiny and over 20 published reports from various countries, the degree to which ATM mutations lead to breast References 1. Gatti RA, Tward A, Concannon P: Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol Biol Metab 1999, 68:419-423. 2. Spring K, Ahangari F, Scott SP, Waring P, Purdie DM, Chen PC, Hourigan K, et al.: Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer. Nat Genet 2002, 32:185-190. 3. Scott SP, Bendix R, Chen P, Clark R, Dork T, Lavin MF: Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer. Proc Natl Acad Sci USA 2002, 99:925-930. 4. Concannon P: ATM heterozygosity and cancer risk. Nat Genet 2002, 32:89-90. 5. Chenevix-Trench G, Spurdle AB, Gatei M, Kelly H, Marsh A, Chen X, Donn K, et al.: Dominant negative ATM mutations in breast cancer families.

Genetic isolates with a history of a small founder population, long-lasting isolation and population bottlenecks represent exceptional resources in the identification of genes involved in the pathogenesis of multifactorial diseases. In these populations, the disease allele reveals linkage disequilibrium (LD) with markers over significant genetic intervals, therefore facilitating disease locus identification. This study has been designed to examine the background LD extension in some subpopulations of Corsica. Our interest in the island of Corsica is due to its geographical and genetic proximity to the other Mediterranean island of Sardinia. Sardinian isolates in which the extension of the background LD is particularly high have been recently identified and are now the object of studies aimed at the mapping of genes involved in complex diseases. Recent evidence has highlighted that the genetic proximity between the populations of Corsica and Sardinia is particularly true for the internal conservative populations. Given these considerations, Sardinia and Corsica may represent a unique system to carry out parallel association studies whose results could be validated by comparison. In the present study, we have analyzed the LD extension on the Xq13 genomic region in three subpopulations of Corsica: Corte, Niolo and Bozio, all located in the mountainous north-center of the island. Our results show a strong degree of LD over long distance for the population of Bozio and to a less extent for the population of Niolo. Their LD extent is comparable to or higher than that reported for other isolates.

property has been widely observed across many species, from the level of gene transcription to the level of systemic homeostasis. For example, fate decision of λ phage -the result of which is the activation of either LYSIS or LYSOGENY pathways -was once considered the result of fine tuning of the binding affinity of promoters to corresponding regulatory factors. However, it has been shown that it is the structure of the network, which involves both positive and negative feedback, that is responsible for making sustainable commitment, not the specific binding affinity -the fate-decision behaviour was shown to be robust against point mutations in the promoter region 3 . In addition, cooperative binding of repressors that forms implicit local positive feedback also contributes to the stability of the switch 4-6 . Many examples of robust properties can be observed in different biological systems.

Coronary artery disease (CAD) is a complex disease with various components, genetic as well as environmental. Previous reports correlating ALOX5AP gene variants and CAD showed conflicting results depending on the population studied. In this study, we examined the contribution of ALOX5AP genetic predisposition to CAD in a group of CAD patients and controls carefully selected from the Lebanese population. We genotyped SNPs for ALOX5AP variants in 289 catheterized patients aged ≤52 years with >50% stenosis in at least one main coronary artery and 227 catheterized control subjects aged 60 years and above with 0% stenosis. Chi-square (χ 2) tests and logistic regression showed no significant difference in the allele and genotype frequencies between the CAD or myocardial infarction (MI) cases and the healthy controls. Haplotype analysis using PHASE showed that the distribution of the risk haplotypes among cases and controls were not significantly different and had no attributable risk to CAD (P = 1.00 and P = 0.5, respectively) or MI (P = 0.2 and P = 0.5, respectively). Our data revealed that ALOX5AP gene variants are not predictors of CAD risk or MI risk among Lebanese patients.

Cryptorchidism has the potential to affect the health of the human male. Although it is often considered a mild malformation, it represents the best-characterized risk factor for reduced fertility and testicular cancer. The aetiology of cryptorchidism remains, for the most part, unknown and cryptorchidism itself might be considered a complex disease. This reflects the intricate mechanisms regulating testicular development and descent from intra-abdominal location into the bottom of the scrotum, involving different anatomical and hormonal factors. Major actors of testicular descent are the Leydig cell-derived hormones testosterone and insulin-like factor 3, even if other factors may play a role. Although considerable evidence exists in animals to support a genetic cause, the genetic contribution to human cryptorchidism is only recently being elucidated. Environmental factors might also contribute to the aetiology of cryptorchidism and its increased incidence in recent years. Mutations in the gene for insulin-like factor 3 and its receptor and in the androgen receptor gene explain a minority of cases of cryptorchidism, but research on genetic polymorphisms that may also influence susceptibility to endocrine disruptors is shedding light on this field.

The use of genetically engineered mice (GEM) have been critical in understanding disease states such as cancer, and none more so than acute myelogenous leukaemia (AML), a disease characterized by over 100 distinct chromosomal translocations. A substantial proportion of cases exhibiting recurrent reciprocal translocations at diagnosis, such as t(8;21) or t(15;17) have been exhaustively studied and are currently employed in clinical diagnosis. However, a definitive conclusion regarding the leukaemogenic potential of defined transgenes for this disease remains elusive. While it is increasingly apparent that a number of cooperating mutations are necessary to develop a leukaemic phenotype, the number of models reflecting these synergisms remains few. Furthermore, little emphasis has been paid to the effect of chromosomal translocations other than recurrent genetic abnormalities, with no models reflecting the multiple abnormalities observed in high-risk cases of AML accounting for 8-10% of adult AML. Here we review the differing technologies employed in generation of GEM of AML. We discuss the relevance of GEM AML from embryonic stem cell-mediated (for example retinoic acid receptor-a fusions and AML1/ETO) models; through to the valuable retroviralmediated gene transfer models. The latter have been used to great effect in defining the transforming properties of chromosomal translocation products such as MLL (found in 5-6% of all AML cases) and NUP98 (denoting poor prognosis in therapy-related disease) and particularly when co-transduced with bad prognostic factors such as Flt3 mutations. Finally, we comment on the emergence of newer transduction technologies, which can regulate the level of expression to defined cell lineages in both primary murine and human xenografts, and discuss how combining multiple genetic modalities, more relevant models of this complex disease are being generated.

To understand the genetic epidemiology of obesity and cancer means to consider the genetics of not only these two complex diseases but also the many risk factors associated with them and the molecular mechanisms likely to contribute to their underlying etiology. It is therefore the purpose of this chapter to highlight the following: genetic mapping studies that have been done to isolate genes related to obesity, genetic studies aimed to identify genes for obesity risk factors, and, finally, a discussion of the genes shared across or among the studies of obesity and/or its risk factors and the various cancers. This is by no means an exhaustive discussion as these are each complex traits with complex molecular mechanisms. It is, however, intended to be an overview of the genes likely to be involved in the cascade of pathways linking obesity and cancer. It is well known that obesity continues to be a leading public health concern not only in the United States but now worldwide. From 1980 to 2002, the prevalence of obesity doubled in adults aged over 20 and overweight prevalence tripled in children and adolescents aged 6–9 years. The estimates of overweight and obesity in 2003–2004 showed that 17.1% of US children and adolescents were overweight and 32.2% of adults were obese [143]. The increasing rates of obesity among children are especially alarming and suggest continuing increases in the rates of obesity-related cancers. Since being overweight in childhood predicts obesity in adulthood [208], obesity occurring in childhood may operate as a ‘cumulative’ exposure that influences cancer risk in later life. Obese children may be subject to potentially long periods of hormonal exposures that operate during adolescence to influence propensity to neoplastic diseases. In females, childhood obesity may also affect the levels of sex hormone at adolescence. A prospective study of 55-year follow-up on 508 adolescents at 13–18 years from Harvard Growth Study showed that overweight adolescent boys had a nine-fold increased risk of colorectal cancer mortality [161]. Associations between adolescent weight and cancer persisted even after adjusting for adult BMI. A 50-year follow-up of >2,000 British children showed an overall 9% increase in cancer incidence per standard deviation increase in BMI, with effects three times larger for smoking-related cancers. There is also evidence from an Israeli case–control study which indicated that being in the upper quartile of BMI at age 18 years was associated with a 42% increase for ovarian cancer [24]. However, the mechanisms underlying the association between childhood obesity and cancer are not well understood, particularly in conjunction with genetic data. In one case–control study of 40 obese and 40 non-obese prepubertal children, the obese group showed higher levels of IGF-1, insulin, and lower sex-binding hormone than that of the non-obese group [182]. This suggests that high levels of growth factors and altered sex hormone profiles are present in obese children and the exposures to an adverse metabolic milieu may begin early in life.

A hundred years from its description, Chagas cardiomyopathy remains a challenging disease. Although successful vector-control strategies have decreased the incidence of Chagas disease in several Latin American countries, both migration to urban areas and immigration have spread the disease worldwide; and now, blood transfusion, organ transplantation, and vertical transmission are a concern. The pathogenesis of Chagas cardiomyopathy involves complex host-parasite interactions, where low-grade but incessant systemic infection and triggered autoimmune reaction are the main mechanisms for its development, with the contribution of autonomic damage and microvascular disturbances. Chagas cardiomyopathy is the most important clinical presentation of Chagas disease and comprises a wide range of manifestations, including heart failure, arrhythmias, heart blocks, sudden death, thromboembolism, and stroke. Recently, simple clinical prognostic scores have been developed to identify high-risk patients and help with management. The treatment of Chagas cardiomyopathy focuses mostly on managing heart failure, arrhythmias, and thromboembolism. The role of specific antiparasitic therapy in the chronic form is not yet defined, and a randomized trial is now under way to address this crucial point. In this article, we review the main clinical aspects of Chagas cardiomyopathy and underscore some upcoming challenges for the appropriate control, diagnosis, and management of this complex disease. (Prog Cardiovasc Dis 2010;52:300-316)

Fetal programming: link between early nutrition, DNA methylation, and complex diseasesn ure_265 87..98 Agata Chmurzynska Complex traits, including those involved in diet-related diseases, are determined by multiple genes and environmental influences. Factors influencing the development of complex traits should be expanded to include epigenetic factors, such as DNA methylation, which occurs in utero. Epigenetic factors regulate gene expression and thereby cell differentiation and organogenesis. The process of epigenotype establishment is sensitive to environmental conditions, with nutrition being one of the most important related factors. For example, DNA methylation depends on the availability of several nutrients including methionine and vitamins B 6 , B 12 , and folate. Epidemiological studies show that undernutrition during fetal life is associated with increased susceptibility to complex diseases. Numerous studies have been conducted on prenatal caloric and protein undernutrition. A reduction in the number of cells and changes in the structure and functioning of organs, as well as permanent changes in DNA methylation and gene expression, have been considered the molecular mechanisms responsible for metabolism programming.

Epigenomic regulation, via DNA methylation, histone modification and non-coding RNA, is increasingly recognised as having a key role in normal development and function of an organism, acting to control cellular and tissue growth and differentiation. It is also thought to be involved in many complex diseases now common in the Western world, including cardiovascular disease, type 2 diabetes, obesity and inflammatory bowel disease (IBD). There is a range of evidence to suggest that nutrition plays a vital role in the protection from such diseases. However, there is little information about the role of nutrition on the epigenetic regulation of IBD. This review aims to elucidate the interactions of nutrients and the epigenome in IBD. More specifically, the plasticity of epigenetic modifications that occur due to low selenium and folate levels in the diet during gestation and lactation will be discussed. A better understanding of this plasticity, and of nutrient-epigenome interactions, will have important implications for enhancing human health through foods.

OA is a complex disease of which the ethiopathology is not completely known and therapies to repair cartilage are still under investigation. The increase of collagen type II expression in osteoarthritic cartilage suggests an activated repair mechanism that is however ineffective in repairing or maintaining the ECM homeostasis. We therefore investigated the ability to modulate the formation of a functional collagen type II network that can ultimately contribute to innovation of cartilage repair in OA. To do so we used different approaches: addition of growth factors, inhibition of collagen cross-links, inhibition of proteoglycan formation, overexpression of cartilage oligomeric matrix protein (COMP) and knock-down of COMP and collagen IX, Of the growth factors used in this thesis, IGF1 had positive effects on the parameters in our chondrocyte alginate cultures. It stimulated chondrocytes to deposit more collagen and proteoglycans without affecting collagen cross-linking, it increased...

Idiopathic calcium nephrolithiasis is a multifactorial disease with a pathogenesis that involves a complex interaction of environmental and individual factors. This review discusses what is known about monogenic renal calcium stone-related disorders, provides an update on genetic research in calcium nephrolithiasis and such intermediate phenotypes as idiopathic hypercalciuria, discusses the problems that these conditions pose to clinicians and geneticists interested in their pathogenesis, and proposes some method tools potentially useful in this research frame of reference. Am J Kidney Dis 44:963-986.

O I Congresso Iberoamericano de Doenças Raras – I CIADR – aconteceu no Brasil, no dia 25 de setembro de 2013, em Brasília. O Congresso foi realizado no âmbito das actividades da AMAVI – Associação MariaVitoria, Brasil, com o apoio do Centro de Estudos Sociais da Universidade de Coimbra, Portugal. Sob o tema Um Olhar Social para o Paciente, contou com a participação de representantes de grandes associações da Europa, como a EURORDIS e EUCERD, cientistas, dirigentes do poder executivo, legislativo, representantes das associações civis e da indústria farmacêutica, familiares e pacientes com doenças raras. O público presente ultrapassou as 700 pessoas. Assim, o I CIADR constituiu um marco no campo das Doenças Raras, pelo número de pessoas presentes, pela sua diversidade, mas, também, pela originalidade no modelo organizativo. Registos e fontes diversas mostram que, no Brasil, os eventos promovidos neste domínio tinham tido, até ao momento, tendência para sofrer uma forte interferência de associações estrangeiras, da indústria farmacêutica ou do poder legislativo. O I CIADR foi o primeiro evento intercontinental no Brasil, organizado por uma Associação brasileira e apartidária.

It is widely anticipated that the study of variation in the human genome will provide a means of predicting risk of a variety of complex diseases. This paper presents a number of algorithmic and combinatorial problems that arise when studying a very common form of genomic variation, single nucleotide polymorphisms (SNPs). We review recent results and present challenging open problems.

The aim of this review is to present a general overview of the relationships among homocysteine metabolism, polymorphism of the genes encoding homocysteine metabolism-related enzymes, and the nutrients influencing the plasma homocysteine level. Combining these factors creates a profile of an individual's susceptibility to complex diseases associated with hyperhomocysteinemia. Homocysteine is an amino acid derived from the demethylation of methionine. Hyperhomocysteinemia is associated with an increased risk of several complex diseases, including cardiovascular diseases. The level of plasma homocysteine depends on the combined effects of genetic and environmental factors. Polymorphisms of genes encoding homocysteine metabolism-related enzymes, such as methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase, and cystathionine β-synthase, influence plasma homocysteine concentration and thereby cardiovascular health. On the other hand, homocysteine metabolism may be modulated by dietary intake of the nutrients involved in homocysteine metabolism (ie, folates, vitamin B 6 , and vitamin B 12 ). Thus, the appropriate health-promoting doses of these nutrients may vary among certain groups of individuals, depending on their genotypes and other risk factors for complex diseases. Better understanding of the relationship between genotype and nutrition influencing the plasma total homocysteine level and cardiovascular health may improve the cardiovascular diagnostic tests (ie, measurement of biologic markers). It could be possible to define the level of progression, severity, and susceptibility to disease much earlier than it is done now. In conclusion, the introduction of combined dietary and pharmacologic treatment would be possible at the initial stages of disease.

OBJECTIVE To review retrospectively, the resultsof Whipple's procedure from 1986 to December 2009 at the Aga Khan University Hospital. METHODS Patient's case notes were reviewed to extract information related to demographics, clinical and laboratory data, operative procedure and post operative period. Surgical mortality was defined as death within 30 days of procedure. RESULTS Hundred and twenty one patients underwent a successful pancreaticoduodenectomy during this period. There were 78 males and 43 females. Most presented with clinical features of obstructive jaundice. Perioperative evaluation in the majority included an abdominal ultrasound and contrast enhanced CT scan. A preoperative ERCP was performed in 64 (53%) patients and a stent was placed in 32 (26%). Stent related sepsis was noted in 8 patients (25%). Eighty four (69%) patients underwent a standard resection, 31% had a pylorus preserving procedure. The commonest pathology was adeno-carcinoma located in the pancr...

Recent genome-wide association studies (GWAS) of many complex diseases have successfully identified novel susceptibility loci, with many of them being associated with more than one condition. Taking into consideration that different autoimmune diseases may share some common pathogenetic pathways, we hypothesized that STAT4, a susceptibility gene found to be associated with increased risk for systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, Sj×gren's syndrome, Wegener's granulomatosis, Crohn's disease, and ulcerative colitis may also have a role in psoriasis. Psoriasis is an autoimmune, chronic inflammatory skin disease. Here we performed a case-control study in the population of island of Crete and demonstrated for the first time the association of a STAT4 single nucleotide polymorphism (SNP) with susceptibility to psoriasis, thus suggesting a putative key role of STAT4 in multiple autoimmune diseases. We found that mutated allele T of the STAT4 rs7574865 SNP, which previously was implicated in the predisposition to many autoimmune diseases, were more common in individuals with psoriasis than in controls (p ϭ 0.045, odds ratio ϭ 1.42, 95% confidence interval 1.01-2.00), thus concluding that the polymorphism examined is associated with the development of psoriasis in our population.

Objective: To identify groups of subjects with similar food consumption patterns so that complex disease ± diet relationships can be investigated at the level of the whole diet, rather than just in terms of nutrient intake. Subjects: 33,971 women in the UK Women's Cohort Study. 60,000 women on the World Cancer Research Fund mailing list were initially invited to take part. Subjects were selected to include a high proportion of vegetarians. Design: The cohort completed a 217 item food frequency questionnaire. Cluster analysis was used to identify groups of women with similar food consumption patterns. Clusters were compared on socio-demographic characteristics, indicators of health and diet, and nutrient intakes. Results: Seven clusters were identi®ed including two vegetarian clusters. Groups appeared to be differentiated by differences in food types and in diversity of diet. Socio-demographic, health and diet characteristics and nutrient intakes all differed signi®cantly between groups. Conclusion: Classifying diets in more pragmatic terms than just nutrient intake should provide valuable insight into understanding complex diet-disease relationships. Dietary advice, whilst based on nutrient content of meals, needs to take account of the combinations of different food types that people naturally choose to use together.

Therapy of tumor progression and the metastatic dis-agement of metastatic disease, The multiple -specifease is the biggest challenge of clinical oncology, ic and non-specific pathways and cellular targets of Discovery of the diverse molecular pathways behind tumor progression are outlined in this review, Such this complex disease outlined an approach to better an approach, individually designed for various cantreatment strategies, The development of combined cer types, may have a better chance to treat or even cytotoxic treatment protocols has produced promis-cure cancer patients with progressive disease, (pathoing results but no breakthrough in the clinical man-

Background: Risk for complex disease is thought to be controlled by multiple genetic risk factors, each with small individual effects. Meta-analyses of several independent studies may be helpful to increase the ability to detect association when effect sizes are modest. Although many software options are available for meta-analysis of genetic case-control data, no currently available software implements the method described by , which combines data from independent family-based and case-control studies.

The use of racial variables in genetic studies has become a matter of intense public debate, with implications for research design and translation into practice. Using research on smoking as a springboard, the authors examine the history of racial categories, current research practices, and arguments for and against using race variables in genetic analyses. The authors argue that the sociopolitical constructs appropriate for monitoring health disparities are not appropriate for use in genetic studies investigating the etiology of complex diseases. More powerful methods for addressing population structure exist, and race variables are unacceptable as gross proxies for numerous social/environmental factors that disproportionately affect minority populations. The authors conclude with recommendations for genetic researchers and policymakers, aimed at facilitating better science and producing new knowledge useful for reducing health disparities.

A qualitative study to investigate lymphatic filariasis related perceptions and practices that may be relevant for the design of appropriate health education and control programmes was conducted in four endemic villages in coastal Ghana. The villagers were aware of the common manifestations of filariasis, such as adenolymphangitis (ADL), lymphoedema, elephantiasis and hydrocele, which were specifically described with local terminology. ADL attacks were identified as the most dreaded health problem in the communities, and elephantiasis and hydrocele also ranked high in importance among reported diseases. Generally the respondents did not accept the mosquito theory of transmission, but they believed in other physical, and in spiritual and hereditary causes. Hydrocele was considered to have no link to the other disease manifestations. The manifestations were most often treated with herbal preparations which were used orally, smeared on affected parts or given as enema. In some cases the affected parts were scarified before herbal preparations were applied. The manifestations affected the work output of its victims and subjected them to hardships such as teasing, unsuitability for marriage, sexual dysfunction and divorce. Although the etiology was seen as different, the local perception of the developmental process of elephantiasis closely paralleled that of the biomedical understanding. It is suggested that this coincidence is used as an entry point for health education, to advance a broader biomedical knowledge on etiology, transmission and treatment options, and thereby to ensure co-operation of the target populations in the control of this complex disease. : S 0 0 0 1 -7 0 6 X ( 9 9 ) 0 0 0 3 7 -6

The use of conformal antenna array in the treatment of superficial diseases can significantly increase patient comfort while enhancing the local control of large treatment area with irregular shapes. Originally a regular square multi-fed slot antenna (Dual Concentric Conductor -DCC) was proposed as basic unit cell of the array. The square DCC works well when the outline of the treatment area is rectangular such as in the main chest or back area but is not suitable to outline diseases spreading along the armpit and neck area. In addition as the area of the patch increases, the overall power density decreases affecting the efficiency and thus the ability to deliver the necessary thermal dose with medium power amplifier (<50W). A large number of small efficient antennas is preferable as the disease is more accurately contoured and the lower power requirement for the amplifiers correlates with system reliability, durability, linearity and overall reduced cost. For such reason we developed a set of design rules for multi-fed slot antennas with irregular contours and we implemented a design that reduce the area while increasing the perimeter of the slot, thus increasing the antenna efficiency and the power density. The simulation performed with several commercial packages (Ansoft HFSS, Imst Empire, SemcadX and CST Microwave Studio) show that the size reducing method can be applied to several shapes and for different frequencies. The SAR measurements of several DCCs are performed using an in-house high resolution scanning system with tumor equivalent liquid phantom both at 915 MHz for superficial hyperthermia systems in US) and 433 MHz (Europe). The experimental results are compared with the expected theoretical predictions and both simulated and measured patterns of single antennas of various size and shapes are then summed in various combinations using Matlab to show possible treatment irregular contours of complex diseases. The local control is expected to significantly improve while maintaining the patient comfort.

Mexico is developing the basis for genomic medicine to improve healthcare of its population. The extensive study of genetic diversity and linkage disequilibrium structure of different populations has made it possible to develop tagging and imputation strategies to comprehensively analyze common genetic variation in association studies of complex diseases. We assessed the benefit of a Mexican haplotype map to improve identification of genes related to common diseases in the Mexican population. We evaluated genetic diversity, linkage disequilibrium patterns, and extent of haplotype sharing using genomewide data from Mexican Mestizos from regions with different histories of admixture and particular population dynamics. Ancestry was evaluated by including 1 Mexican Amerindian group and data from the HapMap. Our results provide evidence of genetic differences between Mexican subpopulations that should be considered in the design and analysis of association studies of complex diseases. In addition, these results support the notion that a haplotype map of the Mexican Mestizo population can reduce the number of tag SNPs required to characterize common genetic variation in this population. This is one of the first genomewide genotyping efforts of a recently admixed population in Latin America.

Breast cancer is a complex disease, whose heterogeneity is increasingly recognized. Despite considerable improvement in breast cancer treatment and survival, a significant proportion of patients seems to be over-or undertreated. To date, single clinicopathological parameters show limited success in predicting the likelihood of survival or response to endocrine therapy and chemotherapy. Consequently, new gene expression based prognostic and predictive tests are emerging that promise an improvement in predicting survival and therapy response. Initial evidence has emerged that this leads to allocation of fewer patients into high-risk groups allowing a reduction of chemotherapy treatment. Moreover, pattern-based approaches have also been developed to predict response to endocrine therapy or particular chemotherapy regimens. Irrespective of current pitfalls such as lack of validation and standardization, these pattern-based biomarkers will prove useful for clinical decision making in the near future, especially if more patients get access to this form of personalized medicine.

Interindividual variation in DNA-methylation level is widespread in the human genome, despite its critical role in regulating gene expression. The nature of this variation, including its tissue-specific nature, and the role it may play in human phenotypic variation and disease is still poorly characterized. The placenta plays a critical role in regulating fetal growth and development in ways that have lifelong effects on health. To identify genes with a high degree of interindividual DNA methylation variation in the human placenta, we surveyed the human genome using the Illumina GoldenGate Methylation Cancer panel targeting 1505 CpG sites of 807 genes. While many sites show a continuous pattern of methylation levels, WNT2, TUSC3 and EPHB4 were identified to have a polymorphic ''on-or-off'' pattern of DNA methylation variation at their promoter region which was confirmed by pyrosequencing. Methylation of these genes can be found in 7%-25% of over 100 placentas tested. The methylation state at the promoter of these genes is concordant with mRNA allelic expression. In three informative cases TUSC3 was observed to be methylated on the maternal allele, and it is thus possible this represents a polymorphically imprinted gene. Furthermore, TUSC3 promoter methylation showed evidence for association with preeclampsia.