الفهرس 
GENETICS AND DISEASEOnly 14 pages are availabe for public view
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Abstract
G
enetics has traditionally been viewed through the window of relatively rare single-gene diseases. It is, however, increasingly apparent that virtually every medical condition with the exception of simple trauma has a genetic component. Genetic medicine is changing the way diseases are classified, enhancing our understanding of pathophysiology, providing practical information concerning drug metabolism and therapeutic responses, and allowing for individualized screening and health care management programs.
The study of human disease genetics has recently undergone a dramatic revolution due to the coming of age of GWAS, the advent of which has been catalysed by a number of recent developments. First, advances in technology have enabled hundreds of thousands of SNPs to be economically genotyped in thousands of samples, thus allowing studies to achieve good coverage of common variation in the human genome. Second, there has been a recognition that only large, well-powered studies will be able to detect the genetic effects expected in complex diseases.
It is hypothesized that the presence and complex interplay of multiple, polymorphic genes predisposing to disease, along with the absence of genes protecting from disease in combination with the necessary and sufficient environmental exposures is responsible for the wide spectrum of phenotypic and pathogenetic variants associated with a particular autoimmune pathology.
The MHC or HLA region is the most polymorphic region of the genome. Polymorphisms in HLA have been linked to a number of autoimmune diseases including RA, SpA, SLE, scleroderma, IIM and many others.
The heritability of RA, defined as the extent to which variation in liability to disease in a population can be explained by genetic variation, has been estimated at between 50% and 60%. The strongest associations were identified with the HLA-DRB1 and PTPN22 genes.
Susceptibility to AS is overwhelmingly due to genetic factors. Variance modeling has indicated that genetic factors contributed more than 90% of susceptibility, with the remainder caused by random environmental effects. The most frequently documented of these genetic factors is HLA-B27. KIRs synergize with HLAs in order to generate compound genotypes which provide different levels of activation and inhibition on NK or T-cells and some of these, have been associated with some SpA.
SLE susceptibility is determined by multiple immunological abnormalities arising from genetic variation at multiple loci. Variation in the HLA region on chromosome 6 is the most strongly associated with this disease.
It currently is believed that scleroderma is a complex polygenic disease that occurs in genetically predisposed individuals who have encountered specific environment exposures and/or other stochastic factors. Based on these studies, a positive family history of scleroderma confers the strongest known relative risk for disease.
The IIMs, like other human AD, likely result from chronic immune activation in genetically susceptible individuals following specific environmental exposures. Multiple polymorphic, immune response genes have been associated with the IIMs. Most prominent among these are genes encoding antigen-presenting molecules of the human MHC and other genes which play important regulatory roles in immune activation.
Although individual common genetic variants confer a modest risk of gout, their combination resulted in a large association with uric acid and gout.
The contribution of genetic factors to osteoporosis is most important. Multiple gene polymorphisms have been tested in association studies with BMD and/or fractures.
The genetic contribution to risk of developing one of the vasculitides remains poorly understood, but recent progress has been made in confirming associations in multiple studies. The HLA region remains the best documented association for most vasculitides, which bolsters the ongoing investigation of other genes associated with immune responses and autoimmunity
The past decade has seen the introduction of many agents, especially biologics, which have allowed a more successful control of AD manifestations. However, the elusive aim of tolerance induction has not yet been achieved. It could be that through harnessing the complex and multifaceted potential of cellular-based therapies, especially HSCT, a ”resetting” of autoaggressive immune reactions while maintaining protective immunity will be possible. In addition, the anti-proliferative and immunomodulatory properties of MSCs combined with their immunological privilege and seemingly low toxicity may offer a new strategy for controlling and protecting vital organs from inflammatory, destructive autoimmune reactions.