Genetic View on the Phenomenon of Combined Diseases in Man

Cover Page

Abstract


In clinical medicine, the phenomenon of polypathy, as a particular object of investigation, was first put forth by French clinicians at the end of the 19th century through the “arthritismus” doctrine. In the first half of the 20th century, German paediatricians singled out “syntropias,” which are combinations of diseases with common pathophysiological mechanisms, and “dystropias,” which are diseases that rarely co-occur in one individual. In the present paper, syntropy/dystropy is defined as a natural generic nonrandom phenomenon with an evolutionary-genetic basis. The genes involved in the development of syntropy are called “syntropic genes,” whereas the genes that co-participate in pathophysiological mechanisms and prevent the co-occurrence of particular phenotypes are called “dystropic genes.” Prospects for studying the genetic basis of this phenomenon are highlighted. The publicly available database Hu-EN et can be used in order to identify syntropic genes, as will be shown as examples in an analysis of cardiovascular diseases.

Global epidemiological studies of human diseases have yielded plenty of results, among which three observations deserve special attention when considering polypathy and the phenomenon of polymorbidity; that is, the situation in which an individual carries several diseases at the same time. First, only 30 chronic multifactor diseases account for 65 % of all the diseases human beings suffer from, accounting for morbidity and mortality rates in contemporary populations [1]. The risk of contracting such a multifactor disease in one’s lifetime is estimated at 60 % [2] in Western populations. Secondly, polypathy is typical of the clinical state of a contemporary patient. In patients over 65 years of age, it is common to observe more than ten related diseases in clinical practice; the co-occurrence of diseases in women is more frequent than in men (this is true for all age groups) [3]. Finally, genetic epidemiology studies of common multifactor diseases point to the importance of inherited factors in their appearance and development. The role of genetic or inherited factors in determining the common phenotype of different diseases can vary, but even with low heritability indices (h2 = 20-30 %), the genetic factors that affect vulnerability to infectious agents such as viruses, bacteria, helminths and parasites can be determined [4].

V P Puzyrev

Research Institute for Medical Genetics, Siberian Branch, Russian Academy of Medical Sciences

Email: valery.puzyrev@medgenetics.ru

M B Freidin

Research Institute for Medical Genetics, Siberian Branch, Russian Academy of Medical Sciences

  1. Czeizel A. The baseline data of the Hungarian Congenital Malformation 1. Register, 19701976. Acta Paediatr Acad Sci Hung, 1978,V. 19, P. 149-156.
  2. Baird P. A., Anderson T. W., Newcombe H. B., Lowry R. B. Genetic studies in children and young adults: population study. Am J Hum Genet, 1988, V. 42, P. 677-693.
  3. Krylov A. A. On the problem of disease association. Klin Med, 2000, V. 78, P. 56-58.
  4. Hill A. V. S. Aspects of genetic susceptibility to human infectious diseases. Annu Rev Genet, 2006, V. 40, P. 469-486.
  5. Pfaundler M., von Seht L. Weiteres uber Syntropie kindlicher Krankheitzustande. Z Kinderheilkd, 1921, V. 30, P. 298-313.
  6. Williams F. M. K., Cherkas L. F., Spector T. D., Mac-regor A. J. A common genetic factor underlines hypertension and other cardiovascular disorders. BMC Cardiovascular Disorders, 2004, V. 4, P. 20.
  7. Rzhetsky A., Wajngurt D., Park N., Zheng T. Probing genetic overlap among complex human phenotypes. Proc Natl Acad Sci USA, 2008, V. 104, P. 11694-11699.
  8. Torkamani A., Topol E. J., Schork N. J. Pathway analysis of seven common diseases assessed by genome-wide association. Genomics, 2008, V. 92, P. 265-272. Bouchard Ch. Lecons sur les maladies par ralentissement de la nutrition. 1 9. 890, Librairie F. Savy, Paris.
  9. Dzau V. J., Braundwald E. Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement. Am Heart J, 1991, V. 121, P. 1244-1263.
  10. Dzau V. J., Antman E. M., Black H. R. et al. The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes: part I: Pathophysiology and clinical trial evidence (risk factors through stable coronary artery disease). Circulation, 2006, V. 114, P. 2850-2870.
  11. Cookson W. The immunogenetics of asthma and eczema: a new focus on the epithelium. Nat Rev Immunol, 2004, V. 4, P. 978-988.
  12. Gregersen P. K., Behrens T. W. Genetics of autoimmune diseases-disorders of immune homeostasis. Nat Rev Genet, 2006, V. 7, P. 917-928.
  13. Wellcome Trust Case Control Consortium - The Australo-Anglo-American Spondylitis Consortium. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet, 2007, V. 39, P. 1329-1337.
  14. Hanukoglu A., Mizrachi A., Dalal I. et al. Extrapancreatic autoimmune manifestations in type 1 diabetes patients and their first-degree relatives. Diabetes Care, 2003, V. 26, P. 1235-1240.
  15. Doolan A., Donaghue K., Fairchild J., Wong M., Williams A. J. Use of HLA typing in diagnosing celiac disease in patients with type 1 diabetes. Diabetes Care, 2005, V. 28, P. 806-809.
  16. Harvey M., Belleau P., Barden N. Gene interactions in depression: pathways out of darkness. Trends Genet, 2007, V. 23, P. 547-556.
  17. Decker K. P., Ries R. K. Differential diagnosis and psychopharmacology of dual disorders. Psychiatr Clin North Am, 1993, V. 16, P. 703-718.
  18. Li M. D., Burmeister M. New insights into the genetics of addiction. Nat Rev Genet, 2009, V. 10, P. 225-231.
  19. Puzyrev V. P. Genomic investigations in genetic cardiology: status and prospects. Vestn Ross Akad Med Nauk, 2000, № 7, P. 28-33.
  20. Becker K. G., Simon R. M., Bailey-Wilson J. E. et al. Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases. Proc Natl Acad Sci USA, 1998, V. 95, P. 9979-9984.
  21. Niehrs C., Pollet N. Synexpression groups in eukaryotes. Nature, 1999, V. 402, P. 483487.
  22. Brunner H. G., van Driel M. A. From syndrome families to functional genomics. Nat Rev Genet, 2004, V. 5, P. 545-551.
  23. Epplen J. T. On genetic components in autoimmunity: a critical review based on evolutionarily oriented rationality. Hum Genet, 1992, V. 90, P. 331-341.
  24. Moffatt M. F. Genes in asthma: new genes and new ways. Curr Opin Allergy Clin Immunol, 2008, V. 8, P. 411-417.
  25. Postma D. S., Koppelman G. H. Genetics of asthma: where are we and where do we goProc Am Thorac Soc, 2009, V. 6, P. 283-287.
  26. Bowcock A. M. The genetics of psoriasis and autoimmunity. Annu Rev Genomics Hum. Genet, 2005, V. 6, P. 93-122.
  27. Bowcock A. M., Cookson W. O. C. M. The genetics of psoriasis, psoriatic arthritis, and atopic dermatitis. Hum Mol Genet, 2004, V. 13, Spec. № 1, R43-55.
  28. Yu W., Gwinn M., Clyne M., Yesupriya A., Khoury M. J. A Navigator for Human Genome epidemiology. Nat Genet, 2008, V. 40, P. 124-125.
  29. Bennet A. M., Di Angelantonio E., Ye Z. et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA, 2007, V. 298, P. 1300-1311.
  30. Ariyaratnam R., Casas J. P., Whittaker J. et al. Genetics of ischaemic stroke among persons of non-European descent: a meta-analysis of eight genes involving approximately,500 individuals. PloS Med, 2007, V.4, e131.
  31. Wu A. H., Tsongalis G. J. Correlation of polymorphisms to coagulation and biochemical risk factors for cardiovascular diseases. Am J Cardiol, 2001, V. 87, P. 1361-1366.
  32. Klerk M., Verhoef P., Clarke R. et al. MTHFR Studies Collaboration Group; MTHFR
  33. C - >T polymorphisms and risk of coronary heart disease: a meta-analysis. JAMA, 2002, V. 288, P. 2023-2031.
  34. Casas J. P., Hingorani A. D., Bautista L. E., Sharma P. Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol, 2004, V. 61, P. 1652-1661.
  35. Zintzaras E., Chatzoulis D. Z., Karabatsas C. H., Stefanidis I. The relationship between C677T methylenetetrahydrofolate reductase gene polymorphism and retinopathy in type 2 diabetes: a meta-analysis. J Hum Genet, 2005, V. 50, P. 267-275.
  36. Banerjee I., Gupta V., Ganesh S. Association of gene polymorphism with genetic susceptibility to stroke in Asian population: a meta-analysis. J Hum Genet, 2007, V. 52, P.205-219.
  37. Lewis S. J., Ebrahim S., Smith D. G. Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate- BMJ, 2005, V. 331, P. 1053.
  38. Qian X., Lu Z., Tan M., Liu H., Lu D. A meta-analysis of association between C677T polymorphism the methylenetetrahydrofolate reductase gene and hypertension. Eur J Hum Genet, 2007, V. 15, P. 1239-1245.
  39. Zintzaras E., Lau J. Trends in meta-analysis of genetic association studies. J Hum Genet, 2008, V. 53, P. 1-9.
  40. Kitsios G., Zintzaras E. Genetic variation associated with ischemic heart failure: a Hu-E review and meta-analysis. Am J Epidemiol, 2007, V. 166, P. 619-633.
  41. Navarro-Lopez F. Genes and coronary heart disease. Rev Esp Cardiol, 2002, V. 55, P. 413-431.
  42. Mondry A., Loh M., Liu P., Nagel M. Polymorphisms of the insertion/deletion ACE and M235T AGT genes and hypertension: surprising new findings and meta-analysis of data. BMC Nephrol, 2005, V. 6, P. 1.
  43. Hu Y., Lin W., Huang R., Zhang X. A systematic review and meta-analysis of the relationship between lipoprotein lipase Asn 291 Ser variant and diseases. J Lipid Res, 2006, V. 47, P. 1908-1914.
  44. Baum L., Ng H. K., Wong K. S. et al. Association of apolipoprotein E exon 4 and lipoprotein lipase S447X polymorphisms with acute ischemic stroke and myocardial infarction. Clin Chem Lab Med, 2006, V. 44, P. 274-281.
  45. Huth C., Heid I. M., Vollmert C. et al. IL6 gene promoter polymorphisms and type 2 diabetes: joint analysis of individual participants’ data from 21 studies. Diabetes, 2006, V. 55, P. 2915-2921.
  46. Qi L., van Dam R. M., Meigs J. B. et al. Genetic variation in IL6 gene and type 2 diabetes: tagging-SNP haplotype analysis in large-scale case-control study and metaanalysis. Hum Mol Genet, 2006, V. 15, P. 1914-1920.
  47. Sie M. P., Sayed-Tabatabaei F. A., Oei H. H. Interleukin 6 -174 g/c promoter polymorphism and risk of coronary heart disease: results from the Rotterdam study and a meta-analysis. Arterioscler Tromb Vasc Biol, 2006, V. 26, P. 212-217.
  48. Sookoian S. C., Gonzalez C., Pirola C. J. Meta-analysis on the G-308A tumor necrosis factor alpha gene variant and phenotypes associated with the metabolic syndrome. Obes Res, 2005, V. 13, P. 2122-2131.
  49. Pereira T. V., Rudnicki M., Franco R. F., Pereira A. C., Krieger J. E. Effect of the G308A polymorphism of tumor necrosis factor alpha gene on the risk of ischemic heart disease and ischemic stroke: a meta-analysis. Am Heart J, 2007, V. 153, P. 821-830.
  50. Reaven G. M. The insulin resistance syndrome. Curr Atherocler Rep, 2003, V. 5, P.364-371.
  51. Eckel R. H., Grundy S. M., Zimmet P. Z. The metabolic syndrome. Lancet, 2005, V. 365, P. 1415-1428.
  52. Freimer N., Sabatti C. The Human phenome project. Nat Genet, 2003, V. 34, P. 15-21.
  53. Goh K.-I., Cusick M. E., Valle D. et al. The human disease network. Proc Natl Acad Sci USA, 2007, V. 104, P. 8685-8690.
  54. Tyler A. L., Asselbergs F. W., Williams S., Moore J. H. Shadows of complexity: what biological networks reveal about epistasis and pleiotropy. BioEssays, 2009, V. 31, P. 220-227
  55. Cambien F., Tiret L. Genetic of cardiovascular diseases. From single mutation to whole genome. Circulation, 2007, V. 116, P. 1714-1724.
  56. Cambien F. About mega-studies, genetics and cardiovascular diseases. In: Prospects and limitations of very large cohort studies. Available via GeneCanvas. http://genecanvas. idf.inserm.fr/readarticle.php?article_id=265. 2006.

Views

Abstract - 277

PDF (English) - 139

PDF (Russian) - 91

Cited-By


Article Metrics

Metrics Loading ...

Metrics powered by PLOS ALM

PlumX

Dimensions

Refbacks

  • There are currently no refbacks.

Copyright (c) 2009 Puzyrev V.P., Freidin M.B.

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies