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The ATXN2-SH2B3 locus is associated with peripheral arterial disease: an electronic medical record-based genome-wide association study.

ABSTRACT: OBJECTIVES:In contrast to coronary heart disease (CHD), genetic variants that influence susceptibility to peripheral arterial disease (PAD) remain largely unknown. BACKGROUND:We performed a two-stage genomic association study leveraging an electronic medical record (EMR) linked-biorepository to identify genetic variants that mediate susceptibility to PAD. METHODS:PAD was defined as a resting/post-exercise ankle-brachial index (ABI) ?0.9 or ?1.4 and/or history of lower extremity revascularization. Controls were patients without history of PAD. In Stage I we performed a genome-wide association analysis adjusting for age and sex, of 537, 872 SNPs in 1641 PAD cases (66 ± 11 years, 64% men) and 1604 control subjects (61 ± 7 year, 60% men) of European ancestry. In Stage II we genotyped the top 48 SNPs that were associated with PAD in Stage I, in a replication cohort of 740 PAD cases (70 ± 11 year, 63% men) and 1051 controls (70 ± 12 year, 61% men). RESULTS:The SNP rs653178 in the ATXN2-SH2B3 locus was significantly associated with PAD in the discovery cohort (OR = 1.23; P = 5.59 × 10(-5)), in the replication cohort (OR = 1.22; 8.9 × 10(-4)) and in the combined cohort (OR = 1.22; P = 6.46 × 10(-7)). In the combined cohort this SNP remained associated with PAD after additional adjustment for cardiovascular risk factors including smoking (OR = 1.22; P = 2.15 × 10(-6)) and after excluding patients with ABI > 1.4 (OR = 1.24; P = 3.98 × 10(-7)). The SNP is in near-complete linkage disequilibrium (LD) (r (2) = 0.99) with a missense SNP (rs3184504) in SH2B3, a gene encoding an adapter protein that plays a key role in immune and inflammatory response pathways and vascular homeostasis. The SNP has pleiotropic effects and has been previously associated with multiple phenotypes including myocardial infarction. CONCLUSIONS:Our findings suggest that the ATXN2-SH2B3 locus influences susceptibility to PAD.

SUBMITTER: Kullo IJ

PROVIDER: S-EPMC4070196 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Project description:Genetic linkage analyses, genome-wide association studies of single nucleotide polymorphisms, copy number variation surveys, and mutation screenings found the human chromosomal 12q24 locus, with the genes SH2B3 and ATXN2 in its core, to be associated with an exceptionally wide spectrum of disease susceptibilities. Hematopoietic traits of red and white blood cells (like erythrocytosis and myeloproliferative disease), autoimmune disorders (like type 1 diabetes, coeliac disease, juvenile idiopathic arthritis, rheumatoid arthritis, thrombotic antiphospholipid syndrome, lupus erythematosus, multiple sclerosis, hypothyroidism and vitiligo), also vascular pathology (like kidney glomerular filtration rate deficits, serum urate levels, plasma beta-2-microglobulin levels, retinal microcirculation problems, diastolic and systolic blood pressure and hypertension, cardiovascular infarction), furthermore obesity, neurodegenerative conditions (like the polyglutamine-expansion disorder spinocerebellar ataxia type 2, Parkinson's disease, the motor-neuron disease amyotrophic lateral sclerosis, and progressive supranuclear palsy), and finally longevity were reported. Now it is important to clarify, in which ways the loss or gain of function of the locally encoded proteins SH2B3/LNK and ataxin-2, respectively, contribute to these polygenic health problems. SH2B3/LNK is known to repress the JAK2/ABL1 dependent proliferation of white blood cells. Its null mutations in human and mouse are triggers of autoimmune traits and leukemia (acute lymphoblastic leukemia or chronic myeloid leukemia-like), while missense mutations were found in erythrocytosis-1 patients. Ataxin-2 is known to act on RNA-processing and trophic receptor internalization. While its polyglutamine-expansion mediated gain-of-function causes neuronal atrophy in human and mouse, its deletion leads to obesity and insulin resistance in mice. Thus, it is conceivable that the polygenic pathogenesis of type 1 diabetes is enhanced by an SH2B3-dysregulation-mediated predisposition to autoimmune diseases that conspires with an ATXN2-deficiency-mediated predisposition to lipid and glucose metabolism pathology.

Project description:BackgroundReports on the impact of electronic medical record (EMR) systems on clinicians are mixed. Currently, nurses' experiences of adopting a large-scale, multisite EMR system have not been investigated. Nurses are the largest health care workforce; therefore, the impact of EMR implementation must be investigated and understood to ensure that patient care quality, changes to nurses' work, and nurses themselves are not negatively impacted.ObjectiveThis study aims to explore Australian nurses' postimplementation experiences of an organization-wide EMR system.MethodsThis qualitative descriptive study used focus group and individual interviews and an open-ended survey question to collect data between 12 and 18 months after the implementation of an EMR across 6 hospital sites of a large health care organization in Victoria, Australia. Data were collected between November 2020 and June 2021, coinciding with the COVID-19 pandemic. Analysis comprised complementary inductive and deductive approaches. Specifically, reflexive thematic analysis was followed by framework analysis by the coding of data as barriers or facilitators to nurses' use of the EMR using the Theoretical Domains Framework.ResultsA total of 158 nurses participated in this study. The EMR implementation dramatically changed nurses' work and how they viewed their profession, and nurses were still adapting to the EMR implementation 18 months after implementation. Reflexive thematic analysis led to the development of 2 themes: An unintentional divide captured nurses' feelings of division related to how using the EMR affected nurses, patient care, and the broader nursing profession. This time, it's personal detailed nurses' beliefs about the EMR implementation leading to bigger changes to nurses as individuals and nursing as a profession than other changes that nurses have experienced within the health care organization. The most frequent barriers to EMR use by nurses were related to the Theoretical Domains Framework domain of environmental context and resources. Facilitators of EMR use were most often related to memory, attention, and decision processes. Most barriers and facilitators were related to motivation.ConclusionsNurses perceived EMR implementation to have a mixed impact on the provision of quality patient care and on their colleagues. Implementing technology in a health care setting was perceived as a complex endeavor that impacted nurses' perceptions of their autonomy, ways of working, and professional roles. Potential negative consequences were related to nursing workforce retention and patient care delivery. Motivation was the main behavioral driver for nurses' adoption of EMR systems and hence a key consideration for implementing interventions or organizational changes directed at nurses.

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The ATXN2-SH2B3 locus is associated with peripheral arterial disease: an electronic medical record-based genome-wide association study.

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