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Biomedical subjects

Andrew D Morris

Publications and source records attributed to Andrew D Morris.

At least 19 recordsLinked to original sources
PubMed2006

Generation Scotland: the Scottish Family Health Study; a new resource for researching genes and heritability.

BACKGROUND: Generation Scotland: the Scottish Family Health Study aims to identify genetic variants accounting for variation in levels of quantitative traits underlying the major common complex diseases (such as cardiovascular disease, cognitive decline, mental illness) in Scotland. METHODS/DESIGN: Generation Scotland will recruit a family-based cohort of up to 50,000 individuals (comprising siblings and parent-offspring groups) across Scotland. It will be a six-year programme, beginning in Glasgow and Tayside in the first two years (Phase 1) before extending to other parts of Scotland in the remaining four years (Phase 2). In Phase 1, individuals aged between 35 and 55 years, living in the East and West of Scotland will be invited to participate, along with at least one (and preferably more) siblings and any other first degree relatives aged 18 or over. The total initial sample size will be 15,000 and it is planned that this will increase to 50,000 in Phase 2. All participants will be asked to contribute blood samples from which DNA will be extracted and stored for future investigation. The information from the DNA, along with answers to a life-style and medical history questionnaire, clinical and biochemical measurements taken at the time of donation, and subsequent health developments over the life course (traced through electronic health records) will be stored and used for research purposes. In addition, a detailed public consultation process will begin that will allow respondents' views to shape and develop the study. This is an important aspect to the research, and forms the continuation of a long-term parallel engagement process. DISCUSSION: As well as gene identification, the family-based study design will allow measurement of the heritability and familial aggregation of relevant quantitative traits, and the study of how genetic effects may vary by parent-of-origin. Long-term potential outcomes of this research include the targeting of disease prevention and treatment, and the development of screening tools based on the new genetic information. This study approach is complementary to other population-based genetic epidemiology studies, such as UK Biobank, which are established primarily to characterise genes and genetic risk in the population.

Adolescent↗
PubMed2006

Mortality in people diagnosed with type 2 diabetes at an older age: a systematic review.

OBJECTIVES: To review all published observational studies reporting on all-cause mortality in patients with type 2 diabetes to determine the degree of increased mortality when diagnosed at an older age. DESIGN: Systematic literature search. SETTING: The review included studies carried out in populations from Germany, United Kingdom, United States, Japan, Italy, Western Australia, Netherlands and Sweden. MEASUREMENTS: Medline, CINAHL, EMBASE, National Research Register and Cochrane Reviews were systematically searched from 1975 to 2004. We identified observational studies that reported overall mortality for people diagnosed with type 2 diabetes when they were over the age of 60, compared with a non-diabetic population. Outcome measures were expressed as risk ratios or relative risks. RESULTS: Among 14 eligible studies, one study reported reduced mortality for patients diagnosed with type 2 diabetes over the age of 60, whereas another found virtually no increased risk of mortality. However, 7 of the 14 studies reported increased mortality in all patients diagnosed when older, and 5 studies for certain subgroups only. A meta-analysis showed the combined relative risks (with 95% CI) of increased mortality for men diagnosed between the ages of 60 and 70 to be 1.38 (1.08-1.76) and 1.13 (0.88-1.45) for men diagnosed aged 70 years or older. A similar pattern was found for the same age groups for women, with combined relative risks of 1.40 (1.10-1.79) and 1.19 (0.93-1.52) respectively. CONCLUSION: Increased mortality associated with a diagnosis of type 2 diabetes at an older age is lower than that reported for the general older diabetic population.

Age Factors↗
PubMed2006

Derivation and validation of a prediction score for major coronary heart disease events in a U.K. type 2 diabetic population.

OBJECTIVE: To derive and validate an absolute risk algorithm for major coronary heart disease (CHD) events in the U.K. population with type 2 diabetes. RESEARCH DESIGN AND METHODS: A population cohort with type 2 diabetes was constructed in Tayside, Scotland, U.K., and longitudinally followed-up to June 2004. Participants were all people with type 2 diabetes registered with general practices and the Diabetes Audit and Research in Tayside, Scotland, database (97% sensitive) with no previous CHD event and with complete measurements (n = 4,569). The main outcome measure was risk of CHD defined as fatal or nonfatal myocardial infarction or CHD death, derived from the Weibull accelerated failure-time model. Validation of the algorithm was performed on an independent dataset from Salford, England, U.K. RESULTS: There were a total of 243 subjects (5.3%) with a fatal or nonfatal myocardial infarction or CHD death over the follow-up period from 1 January 1995 to 30 June 2004 (maximum follow-up 9.5 years). The final Weibull model included the significant predictors of age at diagnosis, duration of diabetes, HbA(1c), smoking (current, past, never), sex, systolic blood pressure, treated hypertension, total cholesterol, and height. Assessment of discrimination and calibration in the Salford validation dataset demonstrated a good fit (c = 0.71 [95% CI 0.63-0.79]). CONCLUSIONS: This study provides the first validated, population-derived model for prediction of absolute risk of CHD in people with type 2 diabetes. It provides a useful additional decision aid for the clinician treating type 2 diabetes by indicating appropriate early action to decrease the risk of adverse outcomes.

Adult↗
PubMed2006

Mortality and hospitalization in patients after amputation: a comparison between patients with and without diabetes.

OBJECTIVE: We sought to compare the risk of mortality and hospitalization between patients with and without diabetes following incident lower-extremity amputation (LEA). RESEARCH DESIGN AND METHODS: We performed a retrospective data-linkage review of all incident amputations between 1 January 1992 and 31 December 1995. Patients were categorized according to their diabetes status. Follow-up for mortality was until 1 January 2005 and until 31 March 1996 for hospitalization. RESULTS: Of 390 major-incident LEAs performed during the study period, 119 (30.5%) were in patients with diabetes and 271 (69.5%) were in nondiabetic subjects. The median time to death was 27.2 months in patients with diabetes compared with 46.7 months for patients without (P = 0.01). Diabetic subjects had a 55% greater risk of death than those without diabetes. The risk of developing congestive cardiac failure with diabetes was 2.26 (95% CI 1.12-4.57) and of further amputation was 1.95 (1.14-3.33) times that of a patient without diabetes after incident LEA. CONCLUSIONS: After LEA, patients with diabetes have an increased risk of death compared with nondiabetic patients. Efforts should be made to minimize these risks with aggressive treatment of cardiovascular risk factors and management of cardiac failure.

Aged↗
PubMed2005

A novel regulation of IRS1 (insulin receptor substrate-1) expression following short term insulin administration.

Reduced insulin-mediated glucose transport in skeletal muscle is a hallmark of the pathophysiology of T2DM (Type II diabetes mellitus). Impaired intracellular insulin signalling is implicated as a key underlying mechanism. Attention has focused on early signalling events such as defective tyrosine phosphorylation of IRS1 (insulin receptor substrate-1), a major target for the insulin receptor tyrosine kinase. This is required for normal induction of signalling pathways key to many of the metabolic actions of insulin. Conversely, increased serine/threonine phosphorylation of IRS1 following prolonged insulin exposure (or in obesity) reduces signalling capacity, partly by stimulating IRS1 degradation. We now show that IRS1 levels in human muscle are actually increased 3-fold following 1 h of hyperinsulinaemic euglycaemia. Similarly, transient induction of IRS1 (3-fold) in the liver or muscle of rodents occurs following feeding or insulin injection respectively. The induction by insulin is also observed in cell culture systems, although to a lesser degree, and is not due to reduced proteasomal targeting, increased protein synthesis or gene transcription. Elucidation of the mechanism by which insulin promotes IRS1 stability will permit characterization of the importance of this novel signalling event in insulin regulation of liver and muscle function. Impairment of this process would reduce IRS1 signalling capacity, thereby contributing to the development of hyperinsulinaemia/insulin resistance prior to the appearance of T2DM.

Adult↗
PubMed2005

Association of common variation in the PPARA gene with incident myocardial infarction in individuals with type 2 diabetes: a Go-DARTS study.

BACKGROUND: Common variants of the PPARA gene have been found to associate with ischaemic heart disease in non diabetic men. The L162V variant was found to be protective while the C2528G variant increased risk. L162V has also been associated with altered lipid measures. We therefore sought to determine the effect of PPARA gene variation on susceptibility to myocardial infarction in patients with type 2 diabetes. 1810 subjects with type 2 diabetes from the prospective Go-DARTS study were genotyped for the L162V and C2528G variants in the PPARA gene and the association of the variants with incident non-fatal myocardial infarction was examined. Cox's proportional hazards was used to interrogate time to event from recruitment, and linear regression for analysing association of genotype with quantitative clinical traits. RESULTS: The V162 allele was associated with decreased risk of non-fatal myocardial infarction (HR = 0.31, 95%CI 0.10-0.93 p = 0.037) whereas the C2528 allele was associated with increased risk (HR = 2.77 95%CI 1.34-5.75 p = 0.006). Similarly V162 was associated with a later mean age of diagnosis with type 2 diabetes and C2582 an earlier age of diagnosis. C2528 was also associated with increased total cholesterol and LDL cholesterol, which did not account for the observed increased risk. Haplotype analysis demonstrated that when both rare variants occurred on the same haplotype the effect of each was abrogated. CONCLUSION: Genetic variation at the PPARA locus is important in determining cardiovascular risk in both male and female patients with diabetes. This genotype associated risk appears to be independent of the effect of these genotypes on lipid profiles and age of diagnosis with diabetes.

Journal Article↗
PubMed2005

B-type natriuretic peptide as an alternative way of assessing total cardiovascular risk in patients with diabetes mellitus.

Cardiovascular risk scores are available but are often not calculated in busy clinics for numerous practical reasons. B-type natriuretic peptide (BNP) may be an alternative way of identifying subjects who have a high total cardiovascular risk score. We compared BNP level with Framingham 10-year Risk Scores for coronary heart disease and stroke and New Zealand Cardiovascular Risk Scores in 231 patients who had type 2 diabetes and no preexisting coronary heart disease or stroke. There was a significant correlation between log BNP and 10-year risk for coronary heart disease and stroke, and there were significantly higher BNP levels in those who had high cardiovascular risk as assessed by the New Zealand Risk Score. BNP may be a useful way of measuring total cardiovascular risk, thus having the potential to better target the most aggressive primary preventive therapies toward the most needy.

Adult↗
PubMed2005

Increased cardiovascular morbidity and mortality in type 2 diabetes is associated with the glutathione S transferase theta-null genotype: a Go-DARTS study.

BACKGROUND: Glutathione S-transferases (GSTs) modulate oxidative stress, and variation in GST genes has been associated with cardiovascular disease risk. We prospectively determined smoking-related cardiovascular morbidity by GST genotype in a large cohort of individuals with type 2 diabetes using a population-based diabetes research database (DARTS). METHODS AND RESULTS: We performed a cohort study of 2015 individuals with type 2 diabetes. Individuals were genotyped for the Ile105Val variant of GSTP1 and the deleted variants of GSTT1 and GSTM1. Clinical characteristics, smoking status, and incidence of subsequent cardiovascular events were obtained by examining the DARTS databases. Variation in the GSTP1 and GSTM1 genes was not associated with smoking-related risk of death or cardiovascular events. There was an increase in the rate of cardiovascular events in smokers lacking the GSTT1 gene compared with smokers with the GSTT1 gene intact (hazard ratio [HR], 1.96; P=0.001). This excess of cardiovascular events was due to both strokes (HR, 2.7; P=0.008) and myocardial infarctions (HR, 1.9; P=0.006). The rate of death as a result of a cardiovascular event was even more markedly increased in the GSTT1-null smokers (HR, 2.7; P=0.001), with a 2-fold increase in myocardial infarction fatality ratio. These effects translated into an increase in overall death and a decrease in age at death. We also found that the GSTT1- genotype was associated with progression of both diabetic retinopathy and nephropathy (P=0.005 and P=0.01, respectively), although we found little evidence for an interaction with smoking. CONCLUSIONS: Genetic absence of the GSTT1 enzyme is an independent and powerful predictor of premature vascular morbidity and death in individuals with type 2 diabetes.

Aged↗
PubMed2005

B-type natriuretic Peptide is associated with both augmentation index and left ventricular mass in diabetic patients without heart failure.

BACKGROUND: B-type natriuretic peptide (BNP) increases the risk of death and cardiovascular events in patients without heart failure, even at BNP values within the "normal" range. The reasons for this are unclear. METHODS: We performed two separate studies (n = 33 and n = 129) on subjects with type 2 diabetes mellitus in whom frank left ventricular systolic dysfunction had been excluded to ascertain whether a high-normal BNP could be identifying either greater augmentation of the ascending aortic pressure wave, increased left ventricular mass, or a subtly lower left ventricular ejection fraction (but within the normal range). RESULTS: Our results demonstrate that an increased augmentation index is an independent predictor of BNP levels even when BNP levels are within the normal range (P = .006 in study one and P = .007 in study two). A high-normal BNP also correlated with increased left ventricular mass and (P = .021) with a subtly lower left ventricular ejection fraction (P < .001). CONCLUSIONS: We found that high-normal BNP levels identified increased augmentation of the ascending aortic pressure wave as well as subtle left ventricular abnormalities.

Aged↗
PubMed2004

Cardiovascular risk in type 2 diabetes is associated with variation at the PPARG locus: a Go-DARTS study.

OBJECTIVE: The Pro12Ala polymorphism of PPARG modulates risk of developing type 2 diabetes. The Ala allele has also been associated with a reduced risk of cardiovascular events. We have shown previously that the linked T allele of the C1431T polymorphism influences Ala12-associated diabetes risk and that the 2 polymorphisms have opposing associations with body weight. We therefore investigated the association of these 2 variants with cardiovascular events in people with type 2 diabetes. METHODS AND RESULTS: We performed a cohort study of 2016 individuals and used Cox proportional hazards to analyze risk of myocardial infarction or death by PPARG Pro12Ala and C1431T genotypes, adjusting for age, sex, and smoking status. In individuals enrolled <70 years of age, the hazard for a first nonfatal event associated with the Ala12 allele was 0.21 (CI, 0.06 to 0.69; P=0.01) and the T1431 allele 9.9 (CI, 1.90 to 51.29; P=0.007). These opposing associations remained significant after correction for other conventional risk factors. The T1431 allele was also associated with all-cause mortality. CONCLUSIONS: This study confirms the association of the Ala12 allele with reduced risk of myocardial infarction in a type 2 diabetic population and demonstrates that the T allele independently associates with an increased risk.

Age Factors↗
PubMed2004

How much echo left ventricular hypertrophy would be missed in diabetics by applying the Losartan Intervention For Endpoint Reduction electrocardiogram criteria to select patients for angiotensin receptor blockade?

OBJECTIVE: The Losartan Intervention For Endpoint Reduction (LIFE) study demonstrated a clear mortality benefit in treating hypertensive patients with electrocardiogram (ECG) evidence of left ventricular hypertrophy (LVH) with losartan rather than atenolol. Previous studies have also shown that identifying and treating echo LVH is associated with prognostic benefits in hypertensive subjects, and is independent of the presence of ECG LVH. We sought to determine how many cases of echo LVH would be missed by applying the ECG criteria for LVH used in the LIFE study. DESIGN: A prospective study of 219 patients with type 2 diabetes recruited from the hospital diabetic clinic. METHODS: Fifteen ECG criteria were assessed on each subject and compared with the presence or absence of LVH on echocardiography. RESULTS: All the proposed ECG criteria are poor at identifying echo LVH in people with diabetes. CONCLUSION: Using ECG LVH to select patients for angiotensin receptor blockade would lead to many diabetics with echo LVH missing out on the benefits of treatment. This assumes that the benefits seen in the LIFE study would also occur if the LIFE strategy were extended to echo LVH patients as well as to ECG LVH patients.

Aged↗
PubMed2004

The Walker Project: a longitudinal study of 48,000 children born 1952-1966 (aged 36-50 years in 2002) and their families.

The Walker cohort is a database of over 48,000 birth records that has recently become available. It contains meticulously recorded details of pregnancy, labour, birth and care before discharge for babies born in hospital in Dundee, Scotland between 1952 and 1966. These babies accounted for 75% of all births in Dundee at this time. Over 34,000 (73%) of these subjects can be identified and this presents the opportunity to link this birth information with a large number of current health-outcome databases covering both primary and secondary care. Further, it allows linkage of records across siblings and over two and, in future, three generations. The number of birth records available and linkage to current databases make this a unique birth cohort with huge potential for the investigation of the fetal origins of adult disease.

Adult↗
PubMed2004

Diagnosis of type 2 diabetes at an older age: effect on mortality in men and women.

OBJECTIVE: To compare the mortality of people who were diagnosed with type 2 diabetes over 65 years of age with that of nondiabetic individuals. RESEARCH DESIGN AND METHODS: Using a population-based diabetes information system for an observational cohort study in Tayside, Scotland, people who were diagnosed with type 2 diabetes over the age of 65 years between 1993 and 2002 were identified. Nondiabetic comparators, matched for age and sex, were identified from the nondiabetic population. The two cohorts were followed up for mortality and cardiovascular mortality according to death certification records. RESULTS: There were 3,594 people with type 2 diabetes (48% male) and 7,188 matched comparators identified in the study. Over a mean follow-up period of 4.6 +/- 2.9 years for 3,594 people with type 2 diabetes and 7,188 comparators, 909 (25.3%) patients in the diabetic cohort and 1,651 (23.0%) in the nondiabetic cohort died. The adjusted relative risk for mortality in the diabetic cohort compared with the nondiabetic cohort was 1.06 (95% CI 0.94-1.19) for men and 1.29 (1.15-1.45) for women. Cardiovascular deaths accounted for 49.4% of the deaths in people with and 45.2% in those without diabetes (adjusted relative risk 1.01 [0.93-1.10]). CONCLUSIONS: Men diagnosed with type 2 diabetes over the age of 65 years have no excess mortality compared with their nondiabetic counterparts, a finding that was not replicated for women.

Aged↗
PubMed2003

Male preponderance in early diagnosed type 2 diabetes is associated with the ARE insertion/deletion polymorphism in the PPP1R3A locus.

BACKGROUND: The ARE insertion/deletion polymorphism of PPP1R3A has been associated with variation in glycaemic parameters and prevalence of diabetes. We have investigated its role in age of diagnosis, body weight and glycaemic control in 1,950 individuals with type 2 diabetes in Tayside, Scotland, and compared the ARE2 allele frequencies with 1,014 local schoolchildren. RESULTS: Men homozygous for the rarer allele (ARE2) were younger at diagnosis than ARE1 homozygotes (p = 0.008). Conversely, women ARE2 homozygotes were diagnosed later than ARE1 homozygotes (p = 0.036). Thus, men possessing the rarer (ARE2) allele were diagnosed with type 2 diabetes earlier than women (p < 0.000001). In contrast, there was no difference in age of diagnosis by gender in those individuals carrying only the common ARE1 variant. Furthermore, although there was no difference in the frequency between the children and the type 2 diabetic population overall, marked differences in allele frequencies were noted by gender and age-of diagnosis. The ARE2 allele frequency in early diagnosed males (diagnosed earlier than the first quartile of the overall ages at diagnosis) was higher than that found in both later diagnosed males and healthy children (p = 0.021 and p = 0.03 respectively). By contrast, the frequency in early diagnosed females was significantly lower than later diagnosed females and that found in children (p = 0.021 and p = 0.037). Comparison of the male to female ratios at different ages-diagnosed confirms a known phenomenon that men are much more prone to early type 2 diabetes than women. When this feature was examined by the common ARE 1/1 genotype we found that the male to female ratio remained at unity with all ages of diagnosis, however, carriers of the ARE2 variant displayed a marked preponderance of early male diagnosis (p = 0.003). CONCLUSION: The ARE2 allele of PPP1R3A is associated with a male preponderance to early diagnosed type 2 diabetes. Susceptibility to type 2 diabetes in later life is not modulated by the ARE2 allele in either sex.

AT Rich Sequence↗