Evidence of a causal relationship between high serum adiponectin levels and increased cardiovascular mortality rate in patients with type 2 ... View Full Text


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Article Info

DATE

2016-01-27

AUTHORS

Lorena Ortega Moreno, Massimiliano Copetti, Andrea Fontana, Concetta De Bonis, Lucia Salvemini, Vincenzo Trischitta, Claudia Menzaghi

ABSTRACT

BACKGROUND: Despite its beneficial role on insulin resistance and atherosclerosis, adiponectin has been repeatedly reported as an independent positive predictor of cardiovascular mortality. METHODS: A Mendelian randomization approach was used, in order to evaluate whether such counterintuitive association recognizes a cause-effect relationship. To this purpose, single nucleotide polymorphism rs822354 in the ADIPOQ locus which has been previously associated with serum adiponectin at genome-wide level, was used as an instrument variable. Our investigation was carried out in the Gargano Heart Study-prospective design, comprising 356 patients with type 2 diabetes, in whom both total and high molecular weight (HMW) adiponectin were measured and cardiovascular mortality was recorded (mean follow-up = 5.4 ± 2.5 years; 58 events/1922 person-year). RESULTS: The A allele of rs822354 was associated with both total and HMW adiponectin [β (SE) = 0.10 (0.042), p = 0.014 and 0.17 (0.06), p = 0.003; respectively]. In a Poisson model comprising age, sex, smoking habits, BMI, HbA1c, total cholesterol, HDL-cholesterol, triglycerides, insulin therapy and hypertension, both rs822354 (IRR = 1.94, 95 % CI 1.23-3.07; p = 0.005), as well as the genetic equivalent of total adiponectin change (IRR = 1.07, 95 % CI 1.02-1.12; p = 0.003) were significantly associated with cardiovascular mortality. The observed genetic effect was significantly greater than that exerted by the genetic equivalent change of serum adiponectin (p for IRR heterogeneity = 0.012). In the above-mentioned adjusted model, very similar results were obtained when HMW, rather than total, adiponectin was used as the exposure variable of interest. CONCLUSIONS: Our data suggest that the paradoxical association between high serum adiponectin levels and increased cardiovascular mortality rate is based on a cause-effect relationship, thus pointing to an unexpected deleterious role of adiponectin action/metabolism on atherosclerotic processes. More... »

PAGES

17

References to SciGraph publications

  • 2014-06-23. Adiponectin: a manifold therapeutic target for metabolic syndrome, diabetes, and coronary disease? in CARDIOVASCULAR DIABETOLOGY
  • 2015-02-10. Role of adiponectin and free fatty acids on the association between abdominal visceral fat and insulin resistance in CARDIOVASCULAR DIABETOLOGY
  • 2015-09-18. Relationship of YKL-40 and adiponectin and subclinical atherosclerosis in asymptomatic patients with type 1 diabetes mellitus from a European Mediterranean population in CARDIOVASCULAR DIABETOLOGY
  • 2015-04-29. Mucus mediated protection against acute colitis in adiponectin deficient mice in JOURNAL OF INFLAMMATION
  • 2009-01-22. Association of adiponectin with mortality in older adults: the Health, Aging, and Body Composition Study in DIABETOLOGIA
  • 2007-11-23. Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology? in HUMAN GENETICS
  • 2011-07-17. High-intensity endurance training improves adiponectin mRNA and plasma concentrations in EUROPEAN JOURNAL OF APPLIED PHYSIOLOGY
  • 2014-06-07. Adiponectin Induces Breast Cancer Cell Migration and Growth Factor Expression in CELL BIOCHEMISTRY AND BIOPHYSICS
  • 2014-09-10. Circulating adiponectin and cardiovascular mortality in patients with type 2 diabetes mellitus: evidence of sexual dimorphism in CARDIOVASCULAR DIABETOLOGY
  • 2012-06-12. Adiponectin: mechanistic insights and clinical implications in DIABETOLOGIA
  • 2011-01-13. Relationship between ADIPOQ gene, circulating high molecular weight adiponectin and albuminuria in individuals with normal kidney function: evidence from a family-based study in DIABETOLOGIA
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    DIMENSIONS

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    PUBMED

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    36 schema:description BACKGROUND: Despite its beneficial role on insulin resistance and atherosclerosis, adiponectin has been repeatedly reported as an independent positive predictor of cardiovascular mortality. METHODS: A Mendelian randomization approach was used, in order to evaluate whether such counterintuitive association recognizes a cause-effect relationship. To this purpose, single nucleotide polymorphism rs822354 in the ADIPOQ locus which has been previously associated with serum adiponectin at genome-wide level, was used as an instrument variable. Our investigation was carried out in the Gargano Heart Study-prospective design, comprising 356 patients with type 2 diabetes, in whom both total and high molecular weight (HMW) adiponectin were measured and cardiovascular mortality was recorded (mean follow-up = 5.4 ± 2.5 years; 58 events/1922 person-year). RESULTS: The A allele of rs822354 was associated with both total and HMW adiponectin [β (SE) = 0.10 (0.042), p = 0.014 and 0.17 (0.06), p = 0.003; respectively]. In a Poisson model comprising age, sex, smoking habits, BMI, HbA1c, total cholesterol, HDL-cholesterol, triglycerides, insulin therapy and hypertension, both rs822354 (IRR = 1.94, 95 % CI 1.23-3.07; p = 0.005), as well as the genetic equivalent of total adiponectin change (IRR = 1.07, 95 % CI 1.02-1.12; p = 0.003) were significantly associated with cardiovascular mortality. The observed genetic effect was significantly greater than that exerted by the genetic equivalent change of serum adiponectin (p for IRR heterogeneity = 0.012). In the above-mentioned adjusted model, very similar results were obtained when HMW, rather than total, adiponectin was used as the exposure variable of interest. CONCLUSIONS: Our data suggest that the paradoxical association between high serum adiponectin levels and increased cardiovascular mortality rate is based on a cause-effect relationship, thus pointing to an unexpected deleterious role of adiponectin action/metabolism on atherosclerotic processes.
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    44 BMI
    45 Gargano Heart Study-prospective design
    46 HDL cholesterol
    47 HMW
    48 HMW adiponectin
    49 HbA1c
    50 Heart Study-prospective design
    51 Mendelian randomization approach
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    55 adiponectin
    56 adiponectin action
    57 adiponectin changes
    58 adiponectin levels
    59 adjusted model
    60 age
    61 allele of rs822354
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    64 association
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    68 cardiovascular mortality
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    81 equivalent changes
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    83 exposure variables
    84 genetic effects
    85 genetic equivalent
    86 genetic equivalent change
    87 genome-wide level
    88 habits
    89 high molecular weight adiponectin
    90 higher serum adiponectin levels
    91 hypertension
    92 independent positive predictors
    93 instrument variables
    94 insulin resistance
    95 insulin therapy
    96 interest
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    98 levels
    99 loci
    100 metabolism
    101 model
    102 molecular weight adiponectin
    103 mortality
    104 mortality rate
    105 nucleotide polymorphism rs822354
    106 observed genetic effect
    107 order
    108 paradoxical association
    109 patients
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    111 positive predictor
    112 predictors
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    115 randomization approach
    116 rate
    117 relationship
    118 resistance
    119 results
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    121 rs822354
    122 serum adiponectin
    123 serum adiponectin levels
    124 sex
    125 similar results
    126 single nucleotide polymorphism rs822354
    127 smoking habits
    128 such counterintuitive association
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    131 total adiponectin change
    132 total cholesterol
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    138 schema:name Evidence of a causal relationship between high serum adiponectin levels and increased cardiovascular mortality rate in patients with type 2 diabetes
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