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Research Article

Inflammation, Insulin Resistance, and Diabetes—Mendelian Randomization Using CRP Haplotypes Points Upstream

  • Eric J Brunner mail,

    To whom correspondence should be addressed. E-mail: e.brunner@ucl.ac.uk

    Affiliation: Department of Epidemiology and Public Health, Royal Free and University College London Medical School, London, United Kingdom

    X
  • Mika Kivimäki,

    Affiliation: Department of Epidemiology and Public Health, Royal Free and University College London Medical School, London, United Kingdom

    X
  • Daniel R Witte,

    Affiliation: Department of Epidemiology and Public Health, Royal Free and University College London Medical School, London, United Kingdom

    X
  • Debbie A Lawlor,

    Affiliation: Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom

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  • George Davey Smith,

    Affiliation: Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom

    X
  • Jackie A Cooper,

    Affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Royal Free and University College London Medical School, London, United Kingdom

    X
  • Michelle Miller,

    Affiliation: Clinical Sciences Research Institute, Warwick Medical School, Coventry, United Kingdom

    X
  • Gordon D. O Lowe,

    Affiliation: Division of Cardiovascular and Medical Sciences, University of Glasgow, Royal Infirmary, Glasgow, United Kingdom

    X
  • Ann Rumley,

    Affiliation: Division of Cardiovascular and Medical Sciences, University of Glasgow, Royal Infirmary, Glasgow, United Kingdom

    X
  • Juan P Casas,

    Affiliation: Non-communicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, United Kingdom

    X
  • Tina Shah,

    Affiliation: University College London Centre for Clinical Pharmacology, Division of Medicine, London, United Kingdom

    X
  • Steve E Humphries,

    Affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Royal Free and University College London Medical School, London, United Kingdom

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  • Aroon D Hingorani,

    Affiliation: Department of Epidemiology and Public Health, Royal Free and University College London Medical School, London, United Kingdom

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  • Michael G Marmot,

    Affiliation: Department of Epidemiology and Public Health, Royal Free and University College London Medical School, London, United Kingdom

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  • Nicholas J Timpson,

    Affiliation: Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom

    X
  • Meena Kumari

    Affiliation: Department of Epidemiology and Public Health, Royal Free and University College London Medical School, London, United Kingdom

    X
  • Published: August 12, 2008
  • DOI: 10.1371/journal.pmed.0050155

Reader Comments (1)

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The Upstream Link?

Posted by plosmedicine on 31 Mar 2009 at 00:28 GMT

Author: David Moskowitz
Position: MD, CEO, Chief Medical Officer,
Institution: GenoMed, Inc.
E-mail: dwmoskowitz@genomed.com
Submitted Date: August 21, 2008
Published Date: August 21, 2008
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

It could well be the ACE D/D genotype, which produces more ACE. C-reactive protein is a macrophage-derived protein with a TPA-response element (TRE) in its promoter. Angiotensin II, the product of ACE, is likely to be the physiologic phorbol ester (1-11). ACE (CD143) appears on the plasma membrane of macrophages early during autocrine and paracrine activation (see refs. in 5).

The ACE D/D genotype has already been associated with insulin resistance and type 2 diabetes (2). It is a likely component of "the African gene," the genetic reason why blacks have a 2-5-fold elevated incidence of diabetes, hypertension, renal failure, etc. vs. whites.

References

1: Moskowitz DW. From pharmacogenomics to improved patient outcomes: angiotensin I-converting enzyme as an example. Diabetes Technol Ther. 2002;4(4):519-32. PMID: 12396747.

2: Moskowitz DW. Is angiotensin I-converting enzyme a "master" disease gene? Diabetes Technol Ther. 2002;4(5):683-711. PMID: 12458570

3: Moskowitz DW. Is "somatic" angiotensin I-converting enzyme a mechanosensor? Diabetes Technol Ther. 2002;4(6):841-58. PMID: 12685804

4: Moskowitz DW. Pathophysiologic implications of angiotensin I-converting enzyme as a mechanosensor: diabetes. Diabetes Technol Ther. 2003;5(2):189-99. PMID: 12871609

5: Moskowitz DW, Johnson FE. The central role of angiotensin I-converting enzyme in vertebrate pathophysiology. Curr Top Med Chem. 2004;4(13):1433-54. PMID: 15379656

6: Moskowitz DW. Acute oxygen-sensing mechanisms. N Engl J Med. 2006 Mar 2;354(9):975-7. PMID: 16510756

7: Williams RM, Moskowitz DW. The prevention of pain from sickle cell disease using trandolapril. J Natl Med Assoc 2007 Mar; 99(3):276-8

8: ACE inhibitors and ARBs (angiotensin II receptor blockers) may turn out to be general viral antidotes, as described in Section 2151 of the Project BioShield II Act of April 28, 2005, reproduced below:

CHAPTER 5--REPORT AND ADMINISTRATION

SEC. 2151. REPORT TO CONGRESS.

Not later than 180 days after the date of enactment of this Act, the Director of the Centers for Disease Control and Prevention, in consultation with the Assistant Secretary for Medical Readiness and Response of the Department of Homeland Security and the Director of the National Institute for Allergy and Infectious Disease of the National Institutes of Health, shall submit a report to Congress that describes alternatives to traditional vaccines and anti-viral therapeutics for viral diseases, including negative immunomodulation compounds that partially suppress a macrophage-dependent innate immune response of an individual to viral pathogens, in order to decrease morbidity and mortality from an excessive immune response.

9. Moskowitz, DW. Promoting dialysis alternative. Letter. ACP Observer, Dec. 2006

10. Daily KC and Moskowitz DW. Unusually long MS remission with losartan. (Submitted).

11. Moskowitz DW. Hypertension, thermotolerance, and the "African gene": an hypothesis. Clin Exp Hypertens. 1996 Jan;18(1):1-19. PMID: 8822230

Competing interests declared: CEO of GenoMed, Inc. (www.genomed.com), a for-profit disease management company that is attempting to put the world's population on an ACE inhibitor or ARB (angiotensin II receptor blocker).