Research Article: Genetic View on the Phenomenon of Combined Diseases in Man

Date Published: October , 2009

Publisher: A.I. Gordeyev

Author(s): V.P. Puzyrev, M.B. Freidin.



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 HuGENet can be used in order to identify syntropic genes, as will be shown as examples in an analysis of cardiovascular diseases.

Partial Text

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].

The term «polypathy» refers to any manner of combinations of diseases and syndromes in a single patient, including accidental maladies (traumas, iatrogenic illness, etc.). However, special forms of polypathy do exist and were combined under the term “syntropy” offered by German paediatricians M. Pfaundler and L. von Seht. They defined syntropy as the “mutual disposition, attraction” of two disease conditions, whereas they refer to “mutual repulsion” as dystropy [5]. In the same authors’ opinion, a “syndrome” can also be regarded as syntropy, because it includes selective affinity of the traits it is made of. Another feature of the affinity of pathological conditions is synchrony, the appearance of at least two diseases simultaneously.

Epidemiological studies of complex diseases in humans provide good examples of syntropias (cardiovascular diseases continuum, allergic diseases, autoimmune diseases). Yet, for all syntropias it is important to identify the groups of genes that will determine one or the other pathophysiological pathways and can help predict the risk of syntropy among carriers of one or other combinations of those genes. Physical clustering of susceptibility genes in the human genome has been shown for a number of diseases and traits [21-23]. However, syntropic genes do not necessarily belong to a cluster of physically linked genes, but rather represent a set of functionally interacting genes dispersed throughout the human genome, co-regulated and involved in a common biochemical or physiological pathway.

Based on the concepts and definitions presented above, we aimed to define syntropic genes for a well-known group of syntropic diseases – cardiovascular disease continuum (CDC), including coronary artery disease (CAD), arterial hypertension (AH), stroke, metabolic syndrome (MS), dislipidemia (DL), obesity, and noninsulin-dependent diabetes-mellitus (NIDDM).

“Phenome” by analogy with the term “genome” is defined as the exact phenotypic representation of a species [52]. It includes the morphological, biochemical, physiological, and ontogenetic characteristics of an organism. Phenomics seeks to define the extent of variability in the phenome but represents a major challenge. The view of a pathological phenotype from the point of view of nonrandom combination of morbid traits (syntropy) does not coincide with the clinical tradition of paying primary attention to a particular diagnosis, a nosology. In the syntropic approach, from the infinite number of traits of the phenome, a sampling of interrelated traits controlled by common genes is assumed. The way to identify such syntropic genes is not significantly different from what is done for the genetic analysis of any non-Mendelian trait. However, substantially larger population sample sizes will be required to achieve confidence in a gene-phene link. Moreover, unification (standardisation) of a phenotype is critical, if very time-consuming, and dependent on the clinicians and epidemiologists involved in ongoing epidemiological studies in different regions of the world.

This work was supported in part by the Russian Foundation for Basic Research, (grants 07-04-01613, 07-04-01526, 08-04-01814).