Complex genetic approaches to neurodegenerative diseases.

Neurodegenerative diseases are fatal disorders in which disease pathogenesis results in the progressive degeneration of the central and/or the peripheral nervous systems. These diseases currently affect -2% of the population but are expected to increase in prevalence as average life expectancy increases. The majority of these diseases have a complex genetic basis. The work presented in this thesis aimed to investigate the genetic basis of two neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and the human prion diseases kuru and sporadic Creutzfeldt-Jakob disease (sCJD), using novel complex genetic approaches. ALS is a fatal neurodegenerative disease in which motor neurons are seen to degenerate. It is a complex disease with 10% of individuals having a family history and the remaining 90% of non-familial cases having some genetic component. The gene DYNC1H1 is involved in retrograde axonal transport and is a good candidate for ALS. In this thesis the genetic architecture of DYNC1H1 was elucidated and a mutation screen of exons 8, 13 and 14 was undertaken in familial forms of ALS and other motor neuron diseases. No mutations were found. A linkage disequilibrium (LD) based association study was conducted using two tagging single nucleotide polymorphisms (tSNPs) which were identified as sufficient to represent genetic variation across DYNC1HI. These tSNPs were tested for an association with sporadic ALS (SALS) in 261 cases and 225 matched controls but no association was identified. Kuru is a devastating epidemic prion disease which affected a highly geographically restricted area of the Papua New Guinea highlands, predominantly affected adult women and children. Its incidence has steadily declined since the cessation of its route of transmission, endocannibalism, in the late 1950's. Kuru imposed strong balancing selection on codon 129 of the prion gene (PRNP). Analysis of kuru-exposed and unexposed populations showed significant deviations from Hardy-Weinberg equilibrium (HWE) consistent with the known protective effect of codon 129 heterozygosity. Signatures of selection were investigated in the surviving populations, such as deviations from HWE and an increasing cline in codon 129 valine allele frequency, which covaried with disease exposure. A novel PRNP G127V polymorphism was detected which, while common in the area of highest kuru incidence, was absent from kuru patients and unexposed population groups. Genealogical analysis revealed that the heterozygous PRNP G127V genotype confers strong prion disease resistance, which has been selected by the kuru epidemic. Finally, PRNP copy number was investigated as a possible genetic mechanism for susceptibility to kuru and sCJD. No conclusive copy number changes were identified

Integration of genetics into a systems model of electrocardiographic traits using humanCVD BeadChip

<p>Background—Electrocardiographic traits are important, substantially heritable determinants of risk of arrhythmias and sudden cardiac death.</p> <p>Methods and Results—In this study, 3 population-based cohorts (n=10 526) genotyped with the Illumina HumanCVD Beadchip and 4 quantitative electrocardiographic traits (PR interval, QRS axis, QRS duration, and QTc interval) were evaluated for single-nucleotide polymorphism associations. Six gene regions contained single nucleotide polymorphisms associated with these traits at P<10−6, including SCN5A (PR interval and QRS duration), CAV1-CAV2 locus (PR interval), CDKN1A (QRS duration), NOS1AP, KCNH2, and KCNQ1 (QTc interval). Expression quantitative trait loci analyses of top associated single-nucleotide polymorphisms were undertaken in human heart and aortic tissues. NOS1AP, SCN5A, IGFBP3, CYP2C9, and CAV1 showed evidence of differential allelic expression. We modeled the effects of ion channel activity on electrocardiographic parameters, estimating the change in gene expression that would account for our observed associations, thus relating epidemiological observations and expression quantitative trait loci data to a systems model of the ECG.</p> <p>Conclusions—These association results replicate and refine the mapping of previous genome-wide association study findings for electrocardiographic traits, while the expression analysis and modeling approaches offer supporting evidence for a functional role of some of these loci in cardiac excitation/conduction.</p&gt

The role of cytokine gene polymorphisms in the pathogenesis of abdominal aortic aneurysms: A case-control study

AbstractBackground: Cytokines are the primary mediators of inflammation and also influence matrix metalloproteinase expression, both of which are important in development of abdominal aortic aneurysm (AAA). A significant, but as yet unknown, familial factor contributes to the pathogenesis of AAA. Many cytokine genes contain polymorphic sites, some of which affect cytokine production in vitro. Cytokine gene polymorphisms may therefore influence the pathogenesis of AAA. The purpose of this study was to determine whether there is any association between cytokine gene polymorphisms and AAA. Methods and Results: This case-control study comprised 100 patients with AAA and 100 age-matched and sex-matched control subjects. For each case and control subject in the study, genotypes at the following cytokine gene polymorphic loci were determined: interleukin (IL)-1β +3953, IL-6 −174, IL-10 −1082, IL-10 −592, and tumor necrosis factors-α −308. Allele and genotype frequencies were compared between AAA and control groups, and odds ratios (OR) were calculated for the presence of AAA with each allele at each locus examined as risk factors. The IL-10 −1082 A allele was significantly more common in the AAA group than the control group (P =.03). The OR for the IL-10 −1082 A allele as a risk factor for AAA was 1.8 (95% confidence interval, 0.9-3.6). Discussion: These associations suggest a significant role for IL-10 in the pathogenesis of AAA. This association of AAA with the IL-10 −1082 A allele is also biologically plausible; the IL-10 −1082 A allele is associated with low IL-10 secretion, and it may be that AAA develops in patients who are unable to mount the same anti-inflammatory response as those who do not have AAA. (J Vasc Surg 2003;37:999-1005.

New di-ferrocenyl-ethynylpyridinyl triphenylphosphine copper halide complexes and related di-ferricenyl electro-crystallized materials

Three di-ferrocenyl-ethynylpyridinyl copper complexes have been synthesised and CV measurements made.</p

Prognostic Value of Routine Cardiac Magnetic Resonance Assessment of Left Ventricular Ejection Fraction and Myocardial Damage An International, Multicenter Study

International audienc

A genetic locus on chromosome 2q24 predicting peripheral neuropathy risk in type 2 diabetes: Results from the ACCORD and BARI 2D studies

Genetic factors have been postulated to be involved in the etiology of diabetic peripheral neuropathy (DPN), but their identity remains mostly unknown. The aim of this study was to conduct a systematic search for genetic variants influencing DPN risk using two wellcharacterized cohorts. A genome-wide association study (GWAS) testing 6.8 million single nucleotide polymorphisms was conducted among participants of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial. Included were 4,384 white case patients with type 2 diabetes (T2D) and prevalent or incident DPN (defined as a Michigan Neuropathy Screening Instrument clinical examination score &gt;2.0) and 784 white control subjects with T2D and no evidence of DPN at baseline or during follow-up. Replication of significant loci was sought among white subjects with T2D (791 DPN-positive case subjects and 158 DPNnegative control subjects) from the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) trial. Association between significant variants and gene expression in peripheral nerves was evaluated in the Genotype-Tissue Expression (GTEx) database. A cluster of 28 SNPs on chromosome 2q24 reached GWAS significance (P &lt; 5×10-8) in ACCORD. The minor allele of the lead SNP (rs13417783,minor allele frequency = 0.14) decreased DPN odds by 36%(odds ratio [OR] 0.64, 95% CI 0.55-0.74, P = 1.9×10-9). This effect was not influenced by ACCORD treatment assignments (P for interaction = 0.6) or mediated by an association with known DPN risk factors. This locus was successfully validated in BARI 2D (OR 0.57, 95%CI 0.42-0.80,P=9×10-4; summary P=7.9×10-12). In GTEx, the minor, protective allele at this locus was associated with higher tibial nerve expression of an adjacent gene (SCN2A) coding for human voltage-gated sodium channel NaV1.2 (P = 9×10-4). To conclude, we have identified and successfully validated a previously unknown locus with a powerful protective effect on the development of DPN in T2D. These results may provide novel insights into DPN pathogenesis and point to a potential target for novel interventions

Single Spin Asymmetry ANA_N in Polarized Proton-Proton Elastic Scattering at s=200\sqrt{s}=200 GeV

We report a high precision measurement of the transverse single spin asymmetry $A_N$ at the center of mass energy $\sqrt{s}=200$ GeV in elastic proton-proton scattering by the STAR experiment at RHIC. The $A_N$ was measured in the four-momentum transfer squared $t$ range $0.003 \leqslant |t| \leqslant 0.035$ \GeVcSq, the region of a significant interference between the electromagnetic and hadronic scattering amplitudes. The measured values of $A_N$ and its $t$-dependence are consistent with a vanishing hadronic spin-flip amplitude, thus providing strong constraints on the ratio of the single spin-flip to the non-flip amplitudes. Since the hadronic amplitude is dominated by the Pomeron amplitude at this $\sqrt{s}$, we conclude that this measurement addresses the question about the presence of a hadronic spin flip due to the Pomeron exchange in polarized proton-proton elastic scattering.Comment: 12 pages, 6 figure