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Introduction

Introduction. Lipoprotein(a) [Lp(a)] LDL particle with apoB-100 linked with apo(a) Lp(a) concentration dependent on apo(a) size, highly dependent on genetics Biologic function uncertain; thought to be thrombogenic given

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Introduction

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  1. Introduction • Lipoprotein(a) [Lp(a)] • LDL particle with apoB-100 linked with apo(a) • Lp(a) concentration dependent on apo(a) size, highly dependent • on genetics • Biologic function uncertain; thought to be thrombogenic given homology to plasminogen and/or to be atherogenic given homology with LDL • Commercial assays not well standardized and sensitive to size of apo(a)

  2. Epidemiology • Lp(a) and CVD Consistent positive association of Lp(a) and CVD: the odds ratios below are minimal estimates because of the aforementioned variability in assays from study to study. Meta-analysis • 126,634 participants, 36 prospective studies • Odds ratio for coronary disease 1.13 per 1-SD increase in Lp(a) • Odds ratio for ischemic stroke 1.10 per 1-SD increase in Lp(a) Emerging Risk Factors Collaboration JAMA 2009;302:412-423

  3. Epidemiology (cont) • Lp(a) and CVD for Extreme Levels of Lp(a) In Women’s Health Study (WHS) Lp(a) levels ≥ 90th and ≥ 95th percentile (vs. <90th and <95th) had hazard ratios for CVD events of 1.7 and 1.9 Suk Danik et al. JAMA 2006;296: 1363-1370

  4. Epidemiology (cont) • Lp(a) and MI for Extreme Levels of Lp(a) In the Copenhagen City Heart Study (CCHS) Lp(a) levels >95th vs. <22nd percentile had hazard ratio for myocardial infarction of 2.6 Kamstrup et al. JAMA 2009;301: 2331-2339

  5. Lp(a) and Type 2 Diabetes • Common Soil” HypothesisCommon genetic and environmental antecedents for CVD and type 2 diabetes • Prior Studies Small case-control studies inconsistent Case-control studies susceptible to bias since the disease may alter Lp(a) concentrations Prospective studies are better for determining risk factor associations Stern Diabetes 1995;44:369-374 Haffner SM et al Diabetes 1992;41:267-72

  6. Question • Given prior positive association of Lp(a) with CVD and the “common soil” hypothesis, what would be the expected association of Lp(a) with type 2 diabetes?

  7. Materials and Methods • Women’s Health Study (WHS) • Prospective study • Apparently healthy U.S. women • N=26 746 • Baseline Lp(a): immunoturbidimetric assay (Denka Seiken) not affected by number of kringle-IV type 2 repeats • Follow-up 13.3 years • Outcome: Incident clinical diagnosis of type 2 diabetes N=1670 cases

  8. Materials and Methods (cont) • Copenhagen City Heart Study (CCHS) • Replication study, cross-sectional design • General population of Danish men and women • N=9652 • Baseline Lp(a): immunoturbidimetric assay (Dako) • Outcome: Prevalent diagnosis of type 2 diabetes • N=419 cases

  9. Question • How does the number of kringle-IV type 2 repeats affect the accuracy of laboratory measurement of Lp(a) concentration? How may the size of apo(a) affect the measurement of Lp(a)?

  10. Results: Baseline Characteristics • Lp(a) concentrations were lowerin cases compared with non-cases • Weak correlations of Lp(a) with other risk factors

  11. Results (cont) • Lp(a) was inversely associated with diabetes in the WHS • In fasting individuals, threshold effect of ≈20% lower relative risk in quintiles 2–5 vs quintile 1 • Stronger association in non-fasting individuals Up to 50% lower risk for quintile 5 vs 1, more linear effect

  12. Lp(a) added predictive information to standard risk factors and HbA1c concentrations within the normal range Lp(a), mg/L <10 ≥10 5.36* P for trend <0.001 3.50* Adjusted Hazard Ratio 1.62 Ref. 5 to <6.5 HbA1c, % Figure 2. Additive association of Lp(a) (mg/L) and HbA1c (%) concentrations with incident type 2 diabetes in WHS. * P < 0.001 compared with reference (Ref.).

  13. CCHS Confirmed WHS Findings • Lp(a) (mg/dL) was also inversely associated with diabetes in the CCHS • No significant interaction by sex

  14. Question • What may be the mechanism(s) for the inverse association of Lp(a) with type 2 diabetes? What are possible explanations for why the association of Lp(a) with type 2 diabetes differs from its association with CVD?

  15. Discussion • Predicting risk of type 2 diabetes has mostlyfocused on glycemic factors This prospective study demonstrates independent and additive predictive value for Lp(a) in association with diabetes • Predicting type 2 diabetes vs CVD While there is overlap in risk factors, not all risk factors for CVD are risk factors for type 2 diabetes • LDL cholesterol is risk factor for CVD but not diabetes • Family history of diabetes is risk factor for diabetes but not CVD

  16. Discussion (cont) • Potential Mechanisms? Less likely to be related to insulin resistance, inflammation, or other standard risk factors for diabetes Possible mechanisms include hormonal regulation (insulin-like growth factors), post-transcriptional effects on apo(a), other effects Deserves further investigation

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