Nicholas P. Kennedy

Bio: Nicholas P. Kennedy is an academic researcher from Trinity College, Dublin. The author has contributed to research in topics: Population & Coeliac disease. The author has an hindex of 25, co-authored 49 publications receiving 2293 citations. Previous affiliations of Nicholas P. Kennedy include Oklahoma State University Center for Health Sciences.

Newly identified genetic risk variants for celiac disease related to the immune response

Abstract: Our genome-wide association study of celiac disease previously identified risk variants in the IL2-IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P < 5 x 10(-7)). Six regions harbor genes controlling immune responses, including CCR3, IL12A, IL18RAP, RGS1, SH2B3 (nsSNP rs3184504) and TAGAP. Whole-blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ, IL2-IL21, CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways.

Protein–energy undernutrition in hospital in-patients

Abstract: Impaired nutritional status has been frequently reported in surveys estimating its prevalence amongst patients in hospital. While there is no doubt that protein-energy undernutrition has serious implications for health, recovery from illness or surgery and hospital costs, lack of nationally or internationally accepted cut-off points and guidelines for most nutrition-related variables make nutritional assessment difficult and proper comparisons between studies impossible. In reviewing published work in which the prevalence of undernutrition has been assessed, it can be seen that each study defined undernutrition, or nutritional risk, using different methodology. This present review aims to highlight the problems which arise when deciphering these studies, and the resulting difficulty in determining the true prevalence of undernutrition and nutritional risk, amongst both general and specific groups of hospital in-patients. It is widely agreed that routine hospital practices can further adversely affect the nutritional status of sick patients in hospital. How this occurs, and the potential effects of impaired nutritional status on clinical outcome are examined. The methods currently available to assess nutritional status are evaluated in the knowledge that such assessments are difficult in clinical practice. The review concludes by proposing that if we want the medical and nursing professions to consider the nutritional status of hospital patients seriously, definitions of undernutrition and nutritional risk, and cut-off values for the nutritional variables measured must be agreed to allow evidence-based practice. Outcome measures which allow clear comparisons between groups and treatments must be used in studies assessing the effects of nutritional interventions.

Contribution of the MHC region to the familial risk of coeliac disease

Abstract: Susceptibility to coeliac disease is genetically determined by possession of specific HLA-DQ alleles, acting in concert with one or more non-HLA linked genes. The pattern of risk seen in sibs and twins in coeliac disease is most parsimonious with a multiplicative model for the interaction between the two classes of genes. Based on a sib recurrence risk for coeliac disease of 10% and a population prevalence of 0.0033, the sib relative risk is 30. To evaluate the contribution of the MHC region to the familial risk of coeliac disease, we have examined haplotype sharing probabilities across this region in 55 coeliac disease families. Based on these probabilities the sib relative risk of coeliac disease associated with the MHC region is 3.7. Combining these results with published data on allele sharing at HLA, the estimated sib relative risk associated with the MHC region is 3.3. Therefore, the MHC genes contribute no more than 40% of the sib familial risk of coeliac disease and the non-HLA linked gene (or genes) are likely to be the stronger determinant of coeliac disease susceptibility.

Anthropometric measurements from a cross-sectional survey of Irish free-living elderly subjects with smoothed centile curves.

Abstract: Anthropometric screening has been recommended for the detection of undernutrition as it is simple, inexpensive and non-invasive. However, a recent study estimating the prevalence of undernutrition on admission to hospital in Dublin, Republic of Ireland, highlighted that the anthropometric reference data currently available in the UK and Republic of Ireland are inadequate to accurately determine nutritional status. In order to provide current anthropometric data, we carried out a cross-sectional study of 874 free-living, apparently healthy Irish-born elderly individuals aged over 65 years. Height, weight, triceps skinfold thickness, mid-arm and calf circumference were measured, values for BMI, mid-arm muscle circumference and arm muscle area were calculated and smoothed centile data derived for each variable. One-third of these elderly individuals had a BMI between 20-25 kg/m2, approximately two-thirds (68.5 % of males and 61 % of females) were classified as overweight or obese, almost one-fifth having a BMI over 30 kg/m2 (17 % of men and 20 % of women). Very few were underweight, only 3 % having a BMI below 20 kg/m2. Height, weight, BMI and muscle reserves decreased with increasing age. The reduction in muscle size was associated with lower handgrip strength. Fat reserves declined with age in females only. Just over half of elderly Irish women reported participating in active leisure of 20 min duration four or more times/week, although 13 % reported having no involvement in active leisure. These data for the Irish elderly extend the data generated from a recent countrywide survey of Irish adults aged 18-64 years, thus providing suitable reference standards for nutritional assessment of elderly Irish individuals.

Apparent low frequency of undernutrition in Dublin hospital in-patients: should we review the anthropometric thresholds for clinical practice?

Abstract: Protein-energy undernutrition, or the possibility of its development, has been documented to occur frequently in patients on admission to hospital. Deterioration in nutritional status is known to occur in hospital. In a prospective study of 594 sequential hospital admissions, we aimed to assess the prevalence of undernutrition among patients on admission to two acute teaching hospitals in Dublin, Republic of Ireland using the widely-accepted anthropometric criteria applied in a large study from Dundee, Scotland, UK (McWhirter & Pennington, 1994) and to determine changes in nutritional status in hospital. The mean prevalence of undernutrition (11 %) was considerably lower than was reported from Dundee (40 %). Unintentional weight loss before admission and functional impairment on admission occurred to a similar extent in both centres. Weight loss in hospital occurred in the same proportion of patients, but less frequently among those undernourished on admission to hospital, in Dublin compared with Dundee. The patients found to be undernourished on admission in this study had a mortality rate in hospital (6.5 %) over three times that of the adequately nourished group (2 %). The magnitude of the difference in prevalence of undernutrition between the two centres cannot be explained by ethnicity, case-mix or age distribution. With the secular increase in BMI in the population, the thresholds for classifying patients as undernourished or at risk of nutritional deterioration may need to be reviewed. For clinical use, recent weight loss and functional status may be more appropriate variables to use in the evaluation of nutritional status on admission to hospital.

ToppGene Suite for gene list enrichment analysis and candidate gene prioritization

Abstract: ToppGene Suite (http://toppgene.cchmc.org; this web site is free and open to all users and does not require a login to access) is a one-stop portal for (i) gene list functional enrichment, (ii) candidate gene prioritization using either functional annotations or network analysis and (iii) identification and prioritization of novel disease candidate genes in the interactome. Functional annotation-based disease candidate gene prioritization uses a fuzzy-based similarity measure to compute the similarity between any two genes based on semantic annotations. The similarity scores from individual features are combined into an overall score using statistical meta-analysis. A P-value of each annotation of a test gene is derived by random sampling of the whole genome. The protein-protein interaction network (PPIN)-based disease candidate gene prioritization uses social and Web networks analysis algorithms (extended versions of the PageRank and HITS algorithms, and the K-Step Markov method). We demonstrate the utility of ToppGene Suite using 20 recently reported GWAS-based gene-disease associations (including novel disease genes) representing five diseases. ToppGene ranked 19 of 20 (95%) candidate genes within the top 20%, while ToppNet ranked 12 of 16 (75%) candidate genes among the top 20%.

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Abstract: Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Bayesian test for colocalisation between pairs of genetic association studies using summary statistics.

Abstract: Genetic association studies, in particular the genome-wide association study (GWAS) design, have provided a wealth of novel insights into the aetiology of a wide range of human diseases and traits, in particular cardiovascular diseases and lipid biomarkers. The next challenge consists of understanding the molecular basis of these associations. The integration of multiple association datasets, including gene expression datasets, can contribute to this goal. We have developed a novel statistical methodology to assess whether two association signals are consistent with a shared causal variant. An application is the integration of disease scans with expression quantitative trait locus (eQTL) studies, but any pair of GWAS datasets can be integrated in this framework. We demonstrate the value of the approach by re-analysing a gene expression dataset in 966 liver samples with a published meta-analysis of lipid traits including >100,000 individuals of European ancestry. Combining all lipid biomarkers, our re-analysis supported 26 out of 38 reported colocalisation results with eQTLs and identified 14 new colocalisation results, hence highlighting the value of a formal statistical test. In three cases of reported eQTL-lipid pairs (SYPL2, IFT172, TBKBP1) for which our analysis suggests that the eQTL pattern is not consistent with the lipid association, we identify alternative colocalisation results with SORT1, GCKR, and KPNB1, indicating that these genes are more likely to be causal in these genomic intervals. A key feature of the method is the ability to derive the output statistics from single SNP summary statistics, hence making it possible to perform systematic meta-analysis type comparisons across multiple GWAS datasets (implemented online at http://coloc.cs.ucl.ac.uk/coloc/). Our methodology provides information about candidate causal genes in associated intervals and has direct implications for the understanding of complex diseases as well as the design of drugs to target disease pathways.

Genome-wide association study of blood pressure and hypertension

Abstract: Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 × 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 × 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.

Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci

Abstract: To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 x 10(-8)) in an analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5 and PXK. We also refined associations at two established rheumatoid arthritis risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed rheumatoid arthritis risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P < 0.05, many of which are validated autoimmune risk alleles, suggesting that most represent genuine rheumatoid arthritis risk alleles.