Ancestral diversity in lipoprotein(a) studies helps address evidence gaps.

Introduction: The independent and causal cardiovascular disease risk factor lipoprotein(a) (Lp(a)) is elevated in >1.5 billion individuals worldwide, but studies have prioritised European populations.

Methods: Here, we examined how ancestrally diverse studies could clarify Lp(a)'s genetic architecture, inform efforts examining application of Lp(a) polygenic risk scores (PRS), enable causal inference and identify unexpected Lp(a) phenotypic effects using data from African (n=25 208), East Asian (n=2895), European (n=362 558), South Asian (n=8192) and Hispanic/Latino (n=8946) populations.

Lipoprotein(a) Testing Patterns in a Large Health System.

Lipoprotein (a) [Lp(a)] is associated with increased risk of atherosclerotic cardiovascular disease (ASCVD). As directed therapy for Lp(a) emerges, it is important to understand patterns of Lp(a) testing in routine clinical practice. We set out to characterize Lp(a) testing across a large academic health system.

Subepidermal moisture (SEM) and bioimpedance: a literature review of a novel method for early detection of pressure-induced tissue damage (pressure ulcers).

Current detection of pressure ulcers relies on visual and tactile changes at the skin surface, but physiological changes below the skin precede surface changes and have a significant impact on tissue health. Inflammatory and apoptotic/necrotic changes in the epidermal and dermal layers of the skin, such as changes in interstitial fluid (also known as subepidermal moisture (SEM)), may precede surface changes by 3-10 days. Those same epidermal and subepidermal changes result in changes in the electrical properties (bioimpedance) of the tissue, thereby presenting an objective, non-invasive method for assessing tissue damage.

Organophosphate Pesticide Exposures, Nitric Oxide Synthase Gene Variants, and Gene-Pesticide Interactions in a Case-Control Study of Parkinson's Disease, California (USA).

Background: Nitric oxide synthase (NOS) genes are candidates for Parkinson's disease (PD) because NOS enzymes produce nitric oxide (NO), a pro-oxidant that can damage neurons. Widely used organophosphate (OP) pesticides can induce oxidative stress and are reported to increase PD risk. Additionally, two single nucleotide polymorphisms (SNPs) from the PON1 (paraoxonase 1) gene influence the ability to metabolize OPs.

Inter-operator and inter-device agreement and reliability of the SEM Scanner.

Objective: The SEM Scanner is a medical device designed for use by healthcare providers as part of pressure ulcer prevention programs. The objective of this study was to evaluate the inter-rater and inter-device agreement and reliability of the SEM Scanner.

Methods: Thirty-one (31) volunteers free of pressure ulcers or broken skin at the sternum, sacrum, and heels were assessed with the SEM Scanner.

APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease.

Importance: Cognitive impairment is a common and disabling problem in Parkinson disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important nonmotor feature.

Objective: To determine whether common variation in the APOE, MAPT, and SNCA genes is associated with cognitive performance in patients with PD.

People with Parkinson's disease and normal MMSE score have a broad range of cognitive performance.

Cognitive impairment, including dementia, is common in Parkinson's disease (PD). The Mini-Mental State Examination (MMSE) has been recommended as a screening tool for Parkinson's disease dementia (PDD), with values below 26 indicative of possible dementia. Using a detailed neuropsychological battery, we examined the range of cognitive impairment in PD patients with an MMSE score of 26 or higher.

Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease.

Objective: The objective of this study was to determine whether environmental and genetic alterations of neuronal aldehyde dehydrogenase (ALDH) enzymes were associated with increased Parkinson disease (PD) risk in an epidemiologic study.

Methods: A novel ex vivo assay was developed to identify pesticides that can inhibit neuronal ALDH activity. These were investigated for PD associations in a population-based case-control study, the Parkinson's Environment & Genes (PEG) Study.

Serum metabolomics of slow vs. rapid motor progression Parkinson's disease: a pilot study.

Progression of Parkinson's disease (PD) is highly variable, indicating that differences between slow and rapid progression forms could provide valuable information for improved early detection and management. Unfortunately, this represents a complex problem due to the heterogeneous nature of humans in regards to demographic characteristics, genetics, diet, environmental exposures and health behaviors. In this pilot study, we employed high resolution mass spectrometry-based metabolic profiling to investigate the metabolic signatures of slow versus rapidly progressing PD present in human serum.

Pooled analysis of iron-related genes in Parkinson's disease: association with transferrin.

Pathologic features of Parkinson's disease (PD) include death of dopaminergic neurons in the substantia nigra, presence of α-synuclein containing Lewy bodies, and iron accumulation in PD-related brain regions. The observed iron accumulation may be contributing to PD etiology but it also may be a byproduct of cell death or cellular dysfunction. To elucidate the possible role of iron accumulation in PD, we investigated genetic variation in 16 genes related to iron homeostasis in three case-control studies from the United States, Australia, and France.

Pesticides that inhibit the ubiquitin-proteasome system: effect measure modification by genetic variation in SKP1 in Parkinson׳s disease.

Cytoplasmic inclusions known as Lewy bodies, a hallmark of Parkinson's disease (PD) pathology, may protect against cytotoxic proteins. Since the ubiquitin-proteasome system (UPS) degrades cytotoxic proteins, dysfunction in the UPS may contribute to PD etiology. Our goal in this study was to screen pesticides for proteasome inhibition and investigate (i) whether ambient exposures to pesticides that inhibit the UPS increase PD risk and (ii) whether genetic variation in candidate genes of the UPS pathway modify those increased risks.

Functional paraoxonase 1 variants modify the risk of Parkinson's disease due to organophosphate exposure.

Background: We previously demonstrated that carriers of the "slower metabolizer" MM genotype of paraoxonase (PON1) who were also exposed to ambient organophosphate (OP) pesticides at their residences were at increased risk of developing Parkinson's disease (PD). Here, with a larger sample size, we extend our previous investigation to consider additional sources of ambient exposure and examined two additional functional PON1 variants.

Methods: From 2001 to 2011, we enrolled incident cases of idiopathic PD and population controls living in central California.

Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease.

Parkinson disease (PD) is a neurodegenerative disorder particularly characterized by the loss of dopaminergic neurons in the substantia nigra. Pesticide exposure has been associated with PD occurrence, and we previously reported that the fungicide benomyl interferes with several cellular processes potentially relevant to PD pathogenesis. Here we propose that benomyl, via its bioactivated thiocarbamate sulfoxide metabolite, inhibits aldehyde dehydrogenase (ALDH), leading to accumulation of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), preferential degeneration of dopaminergic neurons, and development of PD.

Common variation in the LRRK2 gene is a risk factor for Parkinson's disease.

Background: Common variants in the LRRK2 gene influence the risk of Parkinson's disease (PD) in Asians, but whether the same is true in European-derived populations is less clear.

Methods: We genotyped 66 LRRK2 tagging single-nucleotide polymorphisms (SNPs) in 575 PD patients and 689 controls from the northwestern United States (tier 1). PD-associated SNPs (P < .

α-Synuclein genetic variants predict faster motor symptom progression in idiopathic Parkinson disease.

Currently, there are no reported genetic predictors of motor symptom progression in Parkinson's disease (PD). In familial PD, disease severity is associated with higher α-synuclein (SNCA) expression levels, and in postmortem studies expression varies with SNCA genetic variants. Furthermore, SNCA is a well-known risk factor for PD occurrence.

Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee.

Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group.

Replication of GWAS associations for GAK and MAPT in Parkinson's disease.

In the investigation of disease aetiology, the genome-wide association study (GWAS) provides a hypothesis-free investigation of the broader human genome and, as with all scientific investigations, replication is essential to validate any findings. To date, six GWAS have been performed to investigate the influence of common genetic variation in Parkinson's disease (PD) and only two associations have been replicated: alpha synuclein (SNCA) and microtubule-associated protein tau (MAPT), both PD candidate genes before GWAS. In our population-based study, we genotyped four of the top single-nucleotide polymorphisms (SNPs) from a previous study.

α-Synuclein gene may interact with environmental factors in increasing risk of Parkinson's disease.

Background: Although of great interest and suggested in prior reports, possible α-synuclein (SNCA) gene-environment interactions have not been well investigated in humans.

Methods: We used a population-based approach to examine whether the risk of Parkinson's disease (PD) depended on the combined presence of SNCA variations and two important environmental factors, pesticide exposures and smoking.

Results/conclusions: Similar to recent meta- and pooled analyses, our data suggest a lower PD risk in subjects who were either homozygous or heterozygous for the SNCA REP1 259 genotype, and a higher risk in subjects who were either homozygous or heterozygous for the REP1 263 genotype, especially among subjects with an age of onset ≤68 years.

L-type calcium channel blockers and Parkinson disease in Denmark.

Objective: This study was undertaken to investigate L-type calcium channel blockers of the dihydropyridine class for association with Parkinson disease (PD), because some of these drugs traverse the blood-brain barrier, are potentially neuroprotective, and have previously been evaluated for impact on PD risk.

Methods: We identified 1,931 patients with a first-time diagnosis for PD between 2001 and 2006 as reported in the Danish national hospital/outpatient database and density matched them by birth year and sex to 9,651 controls from the population register. The index date for cases and their corresponding controls was advanced to the date of first recorded prescription for anti-Parkinson drugs, if prior to first PD diagnosis in the hospital records.

Application of Bayesian classification with singular value decomposition method in genome-wide association studies.

To analyze multiple single-nucleotide polymorphisms simultaneously when the number of markers is much larger than the number of studied individuals, as is the situation we have in genome-wide association studies (GWAS), we developed the iterative Bayesian variable selection method and successfully applied it to the simulated rheumatoid arthritis data provided by the Genetic Analysis Workshop 15 (GAW15). One drawback for applying our iterative Bayesian variable selection method is the relatively long running time required for evaluation of GWAS data. To improve computing speed, we recently developed a Bayesian classification with singular value decomposition (BCSVD) method.

Polymorphism in the human major histocompatibility complex and early viral decline during treatment of chronic hepatitis C.

The dynamics of the viral decline immediately after the start of therapy for chronic hepatitis C virus (HCV) infection may have prognostic potential for ultimate sustained virologic response. Considerable interindividual variability in the decline has been reported, including differences by race. The human major histocompatability complex (MHC) genes encode the human leukocyte antigens, which are important in the immune response to viral infections.

Genetics of iron regulation and the possible role of iron in Parkinson's disease.

Parkinson's disease (PD) is acknowledged as the second most common neurodegenerative disorder after Alzheimer's Disease. Older age may be the only unequivocal risk factor for PD although the male to female ratio is consistently greater than 1 in populations of European ancestry. Characteristic features of PD include dopaminergic neuron death in the substantia nigra (SN) pars compacta, accumulation of alpha-synuclein inclusions known as Lewy bodies in the SN, and brain iron accumulation beyond that observed in non-PD brains of a similar age.

Association of single nucleotide polymorphisms in interferon signaling pathway genes and interferon-stimulated genes with the response to interferon therapy for chronic hepatitis C.

Background/aims: Interferon signaling pathway genes (IPGs) and interferon-stimulated genes (ISGs) are associated with the host response to hepatitis C virus (HCV) infection. We studied single nucleotide polymorphisms (SNPs) in IPGs and ISGs for their associations with response to pegylated interferon alpha-2a (Peg-IFN-alpha) plus ribavirin therapy in HCV genotype-1 infected patients.

Methods: A two-stage study design was used.

Evidence for improving palliative care at the end of life: a systematic review.

Background: Many persons and their families are burdened by serious chronic illness in late life. How to best support quality of life is an important consideration for care.

Purpose: To assess evidence about interventions to improve palliative and end-of-life care.