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Is Metabolic Syndrome a Novel Inheritable Trait?

Is Metabolic Syndrome a Novel Inheritable Trait?. Suh-Hang Hank Juo, MD, PhD Director Graduate Institute of Medical Genetics Kaohsiung Medical University. What I am going to say …. Brief background Epidemiological data Heritability analysis Factor analysis conclusions.

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Is Metabolic Syndrome a Novel Inheritable Trait?

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  1. Is Metabolic Syndrome a Novel Inheritable Trait? Suh-Hang Hank Juo, MD, PhD Director Graduate Institute of Medical Genetics Kaohsiung Medical University

  2. What I am going to say … • Brief background • Epidemiological data • Heritability analysis • Factor analysis • conclusions

  3. History of Metabolic Synd • 1923: Dr. Kylin described a clustering of H/T, hyperglycemia and gout (Zentralblatt Fuer Innere Medizin, 44:105-127) • 1947: Dr. Vague reported one obesity type associated with metab abnormalities often seen in DM or CVD Pts (In Medical Complications of obesity, Academic Press) • 1988: Dr. Reaven described a cluster of metab abnormalities with insulin resistance, called “syndrome X” (diabetes: 37:1595)

  4. Alternative names • Metabolic syndrome • Syndrome X • Insulin resistance syndrome • Deadly quartet

  5. Characteristics of Metab Synd • The metab synd is a constellation of abnormalities – essential components are glucose intolerance, obesity, dyslipidemia and H/T • The risk components co-occur in an individual more often than may be expected by chance  Is there a common underlying mechanism driving the co-existence of risk components ?

  6. Definition • Consensus definition for the synd was not available till 1998 • WHO definition: more complicated • NCEP ATPIII: simpler • EGIR (European Group for the Study of Insulin Resistance)

  7. Diagnosis criteria

  8. Issues for waist circumference • Waist circumference vs BMI • Waist circumference reflects abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). • VAT is the major determinant of metab and cardiovascular complication of obesity

  9. Issues for waist circumference (cont.)

  10. Age-Specific Prevalence of the Metab Synd in US Adults 1988-94.

  11. ATPⅢ Asian ATPⅢ Asian ATPⅢ JASSO def. ≧65 60~69 Mean 50 ≧60 Prevalence in diff countries

  12. ATPIII 4.3 CHD mortality 2.5 CVD mortality 2.0 total mortality WHO 3.3 CHD mortality 2.6 CVD mortality 1.8 total mortality (JAMA, 2002; 288:2709) Relative risk according to ATPIII vs WHO CHD: coronary heart disease CVD: cardiovascular disease

  13. Meta Synd for Clinical Implication • As a high risk marker for the development of type II diabetes, MI and stroke • More aggressive approach for not only glucose control, but also other risk factors including weight reduction, physical activity, diet, or drug (statin, anti-H/T, low dose aspirin)

  14. Is metab synd a unified novel trait • Prospective study suggests Metab Synd identify additional cardiovascular risk beyond the individual risk factors (Circulation; 2003;108:1546) • Question remains to be answered: is the cluster of risk components driven by a common mechanism? If so, can genetic mechanism play a role?

  15. Genetic studies of the components • Previous genetic studies showed significant heritabilities for the components • TG, HDL-C and other lipids • waist circumference, WHR, and obesity phenotypes • Blood pressure and H/T • Blood sugar, insulin level and DM

  16. What is Heritability ? • Statistical definition: Heritability is the proportion of phenotypic variance explained by overall genetic effects. • Non-statistical def: Heritability is the extent to which genetic variants contribute to individual differences of the phenotype

  17. Heritability estimation for metab synd • Two important needs to know whether metab synd can be treated as a novel genetic trait – 1. to support the synd is a novel disease rather than a combination of mild abnormalities 2. to justify the ongoing gene mapping endeavors

  18. Heritability Estimation • Twin Study • Family Study

  19. Twin study • MZ twins share 100% genetic factors; DZ 50% • If MZ twins have a higher concordance rate (both have disease) than DZ twins  genetic • For Mendelian diseases, MZ concordance rate = 100%, DZ = 50% and thus the heritability = (100%-50%) x2 = 100% • limitation: more adverse intrauterine environment among MZ compared to DZ twins, MZ twins are more prone to metabolic abnormalities. Therefore h2 estimation can be biased by the pre-natal condition

  20. Family Study for H2 Estimation • Using data from multiple family members, and sophisticated statistical tools to estimate the overall genetic contribution

  21. Family study to estimate heritability of the metabolic syndrome (Lin et al. Diabetologia. 48(10): 2006-12, 2005)

  22. Study Subjects • Northern Manhattan Family Study (NOMAFS) enrolls high-risk Caribbean Hispanic families. • 803 subjects with available information of metabolic syndrome from 89 families • Family size: 3 to 53 with mean of 9 subjects. The mean age = 47 (18 – 95 yr) • Metab synd (ATPIII) 26% (Lin et al. Diabetologia. 48(10): 2006-12, 2005)

  23. Methods • Statistical method: variance component implemented in a statistical software, SOLAR • SOLAR uses a threshold method: assuming an individual is affected if an underlying genetically determined risk (i.e., liability) exceeds a certain threshold. (Lin et al. Diabetologia. 48(10): 2006-12, 2005)

  24. Heritability estimates for the metab synd and its components (Lin et al. Diabetologia. 48(10): 2006-12, 2005)

  25. Interpretation of H2 for metab synd • A common set of genes cause abnormalities of several risk factors leading to the development of metab synd • Additional genes may have individual effects on each risk component

  26. Factor Analysis • Factor analysis consists of (1) principle component analysis, (2) a varimax rotation and (3) identification of the variables to facilitate interpretation. • Factor analysis is to discover if the observed variables can be explained largely or entirely in terms of a smaller number of variables called factors. • In this case, factors replace the metab synd as the phenotypes of interest (Lin et al. Diabetologia. 48(10): 2006-12, 2005)

  27. Factor analysis and h2 estimation *p<0.001 Factor1: lipids/glucose/obesity; Factor 2: Blood pressure

  28. Interpretation of Factor Analysis • Metab Synd can be caused (or replaced) two major factors: lipid/glucose/obesity and BP • Lipid/glucose/obesity factor may share a common genetic mechanism, and the BP factor is more likely influenced by another set of genes

  29. To test for familial aggregation of the synd according to its severity • Dividing the families into different severity subgroups according to the number of risk components in the most severely affected individual in each family. • “5-risk” family: the most severe family member had 5 risk components (ATPIII). • “4-risk” family: the most severe member had 4 risk components.

  30. Prevalence of the syndrome among severity subgroups

  31. Summary of family aggregation • increasing familial aggregation with the increase of load of the risk components. • An estimated heritability of 78% for a modified metabolic syndrome defined as ≥ 4 risk components.

  32. Hypothesis-testing approach to specify the metab synd underlying structure: Confirmatory factor analysis

  33. A hierarchical 4-factor model with 4 1st order factors, and a 2nd order factor reflecting the metab synd (Am J Epidemiol 2003;707-711)

  34. Each risk component independently contributes to the synd (Am J Epidemiol 2003;707-711)

  35. 4 major factors are correlated but not an unified disease (Am J Epidemiol 2003;707-711)

  36. Summary of confirmatory factor analysis • Metab synd was represented primarily by the insulin resistance and obesity factors, followed by the lipid factor and to a lesser extent, the blood pressure factor • Metab synd should be considered a unified disease (Am J Epidemiol 2003;707-711)

  37. Conclusions • The clustering of risk components in metab synd is driven by a common underlying mechanism • A set of genes is likely to cause clustering of several risk components leading to metab synd

  38. Conclusions (cont.) • The synd should be considered a unified novel trait and treated as a whole • Defining the synd w/ a higher load may increase power to detect susceptibility genes

  39. Acknowledgements • Dr. Hsiu-Fen Lin (KMU) • Dr. Ralph Sacco (Columbia Univ) • Dr. Tanja Rundek (Columbia Univ) • Dr. Bernadette Boden-Albala (Columbia Univ) • Dr. Rong Cheng (Columbia Univ) • Ms. Naeun Park (Columbia Univ)

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