Genetics of rheumatoid arthritis: confronting complexity

The genetic basis for rheumatoid arthritis (RA) is likely to be extremely complex. Even the role of MHC genes remains to be fully defined, and may involve interactive genetic effects. The difficulty of precisely defining the clinical phenotype, as well as underlying genetic heterogeneity, complicates the problem. In addition, stochastic genetic or physiologic events may contribute to the low penetrance of susceptibility genes. This situation parallels developing paradigms for other autoimmune disorders, in which many different genes each appear to contribute a small amount to overall risk for disease, and where severity and specific phenotypic subtypes are subject to genetic effects. The completion of the human genome project, along with advances in informatics, will be required to reach a deeper understanding of RA. It is likely that this will involve an iterative and interactive process between several different scientific disciplines.     

Genetics of human cardiovascular disease

Cardiovascular disease encompasses a range of conditions extending from myocardial infarction to congenital heart disease, most of which are heritable. Enormous effort has been invested in understanding the genes and specific DNA sequence variants that are responsible for this heritability. Here, we review the lessons learned for monogenic and common, complex forms of cardiovascular disease. We also discuss key challenges that remain for gene discovery and for moving from genomic localization to mechanistic insights, with an emphasis on the impact of next-generation sequencing and the use of pluripotent human cells to understand the mechanism by which genetic variation contributes to disease.     

Genetics of common disease: implications for therapy,screening and redefinition of disease.

Susceptibility to most common human diseases is, at least in part, determined by genetic factors. Rapid progress is being made in defining these genetic determinants for a range of diseases including breast cancer, colon cancer, diabetes, arthritis and dementia. The ability to define susceptibility in genetic terms has already led to a reclassification of some of these diseases on genetic and mechanistic grounds. This information is likely to have a profound effect on our approach to human diseases as it will allow a better definition of these disorders, permitting more effective therapeutic intervention, and will lead to both a more precise understanding of the natural history of these diseases and the possibility of identifying populations at risk. An understanding of the mechanisms underlying disease susceptibilty will also improve our ability to develop rational therapeutic interventions for many of these diseases. The role of genetic screening in these common diseases will be discussed, particularly in regard to the application of health care in populations.     

Genetics of human behavior: problems, results and prospects

In this paper, the main problems of modern behaviour genetics of man are formulated and methods for their study proposed. As a result of the Mendelian analysis of some psychometric scales of personality inventories, a major-gene mode of inheritance is found for 20% of scales of three questionnaires: MMPI, 16 PF and the Pathocharacterologic Diagnostic Inventory (PDI). Perspectives of further studies in the field of human behaviour genetics are outlined.     

Autosomal dominant polycystic kidney disease: Genetics, mutations and microRNAs

Autosomal dominant polycystic kidney disease (ADPKD) is a common, monogenic multi-systemic disorder characterized by the development of renal cysts and various extrarenal manifestations. Worldwide, it is a common cause of end-stage renal disease. ADPKD is caused by mutation in either one of two principal genes, PKD1 and PKD2, but has large phenotypic variability among affected individuals, attributable to PKD genic and allelic variability and, possibly, modifier gene effects. Recent studies have generated considerable information regarding the genetic basis and molecular diagnosis of this disease, its pathogenesis, and potential strategies for targeted treatment. The purpose of this article is to provide a comprehensive review of the genetics of ADPKD, including mechanisms responsible for disease development, the role of gene variations and mutations in disease presentation, and the putative role of microRNAs in ADPKD etiology. The emerging and important role of genetic testing and the advent of novel molecular diagnostic applications also are reviewed. This article is part of a Special Issue entitled: Polycystic Kidney Disease.     

Genetics of the P2X7 receptor and human disease

The P2RX7 gene is highly polymorphic, and many single nucleotide polymorphisms (SNPs) underlie the wide variation observed in P2X7 receptor responses. We review the discovery of those non-synonymous SNPs that affect receptor function and compare their frequencies in different ethnic populations. Analysis of pairwise linkage disequilibrium (LD) predicts a limited range of haplotypes. The strong LD between certain functional SNPs provides insight into published studies of the association between SNPs and human disease.     

Nonlinearity,coherence and complexity: Biophysical aspects related to health and disease

Biological organisms are complex open dissipative systems whose dynamical stability is sustained due to the exchange of matter, energy and information. Dynamical stability occurs through a number of mechanisms that sustain efficient adaptive dynamics. Such properties of living matter can be the consequence of a self-consistent state of matter and electromagnetic field (EMF). Based on the soliton model of charge transport in redox processes, we describe a possible mechanism of the origin of endogenous EMF and coherence. Solitons are formed in polypeptides due to electron–lattice interaction. Solitons experience periodical potential barrier, as a result of which their velocity oscillates in time, and, hence, they emit electromagnetic radiation (EMR). Under the effect of such radiation from all other solitons, the synchronization of their dynamics takes place, which significantly increases the intensity of the general EMF. The complex structure of biological molecules, such as helical structure, is not only important for “structure-function” relations, but also the source of the stability of biophysical processes, e.g. effectiveness of energy and charge transport on macroscopic distances. Such a complex structure also provides the framework for the spatiotemporal structure of the endogenous EMF. The highly hierarchical organization of living organisms is a manifestation of their complexity, even at the level of simple unicellular organisms. This complexity increases the dynamical stability of open systems and enhances the possibility of information storage and processing. Our findings provide a qualitative overview of a possible biophysical mechanism that supports health and disease adaptive dynamics.     

Organismal complexity, cell differentiation and gene expression: human over mouse

We present a molecular and cellular phenomenon underlying the intriguing increase in phenotypic organizational complexity. For the same set of human–mouse orthologous genes (11 534 gene pairs) and homologous tissues (32 tissue pairs), human shows a greater fraction of tissue-specific genes and a greater ratio of the total expression of tissue-specific genes to housekeeping genes in each studied tissue, which suggests a generally higher level of evolutionary cell differentiation (specialization). This phenomenon is spectacularly more pronounced in those human tissues that are more directly involved in the increase of complexity, longevity and body size (i.e. it is reflected on the organismal level as well). Genes with a change in expression breadth show a greater human–mouse divergence of promoter regions and encoded proteins (i.e. the functional genomics data are supported by the structural analysis). Human also shows the higher expression of translation machinery. The upstream untranslated regions (5′UTRs) of human mRNAs are longer than mouse 5′UTRs (even after correction for the difference in genome sizes) and contain more uAUG codons, which suggest a more complex regulation at the translational level in human cells (and agrees well with the augmented cell specialization).