http://www.dspace.cam.ac.uk:80/handle/1810/221737 Thu, 23 May 2013 19:34:06 GMT 2013-05-23T19:34:06Z http://www.dspace.cam.ac.uk:80/handle/1810/243860 Title: Risk assessment for osteoporotic fractures among men and women from a prospective population study: the EPIC-Norfolk study Authors: Moayyeri, Alireza Abstract: Osteoporotic fractures are a major and increasing clinical and public health concern internationally. Identification of individuals at high risk for fragility fractures may enable us to target preventive interventions more effectively. In this thesis, I aimed to evaluate novel risk factors for osteoporosis and develop a fracture risk assessment model among the middle-aged and older people. I used data from the European Prospective Investigation into Cancer (EPIC)-Norfolk study, which is a large population-based prospective study started in 1993. About 25,000 men and women were assessed at baseline and about 15,000 of them returned for a second examination 4 years later. All participants are followed up to the present for clinical events including fractures. My work is in two parts. For the first part, I examined the risk of fracture associated with some novel or less well studied risk factors. These risk factors included change in height over time, respiratory function, physical activity and body fat mass. We found that men and women with annual height loss >0.5 cm are at increased risk of hip and any fracture (relative risk=1.9 (95% CI 1.3-2.7) per cm/year height loss). One litre lower forced expiratory volume in 1 second (FEV1) was associated with a 2-fold risk of hip fracture in men and women. We also observed a non-linear association, independent of body mass index, between increasing body fat mass and lower fracture risk in women but not in men. I performed a systematic review and meta-analysis of studies evaluating the association between physical activity and hip fractures. Using a new validated questionnaire in EPIC-Norfolk, we observed varying relationships between physical activity in different domains of life and fracture risk in men and women. For the second part of the thesis, I developed a biostatistical model to calculate 10-year risk of developing a fracture among EPIC-Norfolk study participants. This model incorporates clinical and radiological assessments known to be associated with fractures and can be extended to other risk factors assessed in other prospective cohorts. This helps clinicians to achieve a better estimate of the prospective risk of fracture in their patients. I applied this model to compare the predictive value of two different clinical assessment methods for osteoporosis, namely dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS). We found that that the predictive power of QUS is comparable to, and independent of, predictive power of DXA. In summary, my studies have added to our knowledge about some novel and easy-to-use risk factors of osteoporosis and proposed a practical method to merge and utilise data from different risk factors for estimation of fracture risk in individuals. Description: For appendices see hardbound copy deposited in the Manuscripts Reading Room, Cambridge University Library. Tue, 06 Mar 2012 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/243860 2012-03-06T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/225182 Title: Lipoprotein(a) and the risk of vascular disease Authors: Erqou, Sebhat Abstract: Background: Lipoprotein(a) [Lp(a)] is composed of a low density-lipoprotein (LDL) particle and a glycoprotein molecule known as apolipoprotein(a) [apo(a)]. Apo(a) exists in several differently-sized isoforms and is responsible for the unique properties of Lp(a). Although Lp(a) has been known for the past 40 years its relationship with coronary heart disease (CHD) has not been characterized in sufficient detail. Whether Lp(a) causes CHD is not clear. Furthermore, the role of apo(a) isoform variation and other sources of Lp(a) heterogeneity (e.g., level of oxidized phospholipids) in Lp(a)-disease association has not been determined. Objectives: To characterize in detail the association of circulating Lp(a) levels with the risk CHD To assess the nature of Lp(a)-CHD association using an integrative genetic study To explore the role of Lp(a) heterogeneity in its association with CHD Data sources: 1. The Emerging Risk Factors Collaboration (ERFC) database (36 studies, 127,000 participants) 2. The European Prospective Investigation of Cancer – Norfolk (EPIC-Norfolk) study (2200CHD cases, 2200 controls) 3. The Pakistani Risk of Myocardial Infarction Study (PROMIS) (1800 MI cases and 1800 controls) 4. Systematic quantitative reviews of published epidemiological studies Results: ERFC data - Analyses of cross-sectional data on up to 127,000 participants (predominantly of European descent) demonstrated that Lp(a) is generally not strongly correlated with known CHD risk factors. Weakly positive correlations were observed with LDL-cholesterol, apolipoprotein B100 and fibrinogen. Levels were over 2-fold higher in Blacks compared to Whites. Analyses of available data on repeat measurements in 6600 participants demonstrated that Lp(a) values have very high long-term within-person consistency (regression dilution ratio ~ 0.9). Outcome data involved 9300 incident CHD events, 1900 ischaemic strokes and 8100 nonvascular deaths. The risk ratio for CHD per 1SD higher Lp(a) concentration, adjusted for age, sex, lipids and other conventional vascular risk factors, was 1.13 (95% CI, 1.09-1.18). The corresponding risk ratios for ischaemic stroke and nonvascular death were 1.10 (1.02 – 1.18) and 1.01 (0.98-1.05), respectively. Data were too limited to assess association in nonwhites. PROMIS data – the adjusted odds ratio for MI in South Asians was comparable to that of Europeans. EPIC-Norfolk genetic data - The odds ratio for CHD per 1-SD higher Lp(a) concentration, after adjustment for cardiovascular risk factors, was 1.37 (1.20-1.56). Tagging SNPs rs10455872 and rs11751605 (minor allele frequency: 8% and 18%, respectively) were associated with 207% (95% CI, 188 - 227%) and 38% (31 - 46%) higher Lp(a) concentrations per copy of minor allele, respectively. These SNPs accounted for 35% and 5% of the variation in circulating Lp(a) levels, respectively, and were associated with an odds ratio for CHD of 1.34 (1.14-1.58) and 1.17 (1.04-1.33), respectively. The observed SNP-CHD associations were consistent with expected odds ratios corresponding to the Lp(a) effect of the SNPs. Systematic reviews – meta-analysis of published data from 40 studies (11,300 cases, 47,000 controls) demonstrated that people with smaller apo(a) isoforms have about a 2-fold higher risk of CHD or ischemic stroke than those with larger isoforms. Meta-analysis of published data from 10 studies (1500 cases, 10,200 controls) showed that people in the top third of baseline distribution of oxidized LDL levels have a 1.8-fold higher risk of CHD than those in bottom third. EPIC-Norfolk biomarker data – Levels of oxidized phospholipids were strongly correlated with Lp(a) concentration (r = 0.7, p-value < 0.0001). One SD higher concentration of oxidized phospholipids was associated with an adjusted odds ratio for CHD of 1.31 (1.15-1.49). The risk ratio was no longer significant after adjustment for Lp(a) concentration (1.08; 95% CI, 0.91-1.29). Conclusion: Lp(a) concentration is specifically, continuously and independently associated with the risk of ischaemic vascular outcomes. Available evidence supports the causal role of the particle in CHD. Lp(a) appears to induce vascular damage through causal mechanisms that involve apo(a) isoforms and oxidized phospholipids. A comprehensive study of markers of Lp(a) heterogeneity should help to understand the full impact of Lp(a) on cardiovascular diseases. In addition, further study is needed in nonwhites to assess the relevance of the factor to vascular disease risk in these populations. Mon, 03 May 2010 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/225182 2010-05-03T23:00:00Z