Functional polymorphisms

Protein Polymorphism Function Therapy Clinical Significance... 

Limited by our current knowledge of gene and polymorphism function and drag pathways which may miss the true candidate genes and polymorphisms low predictive power for polygenic traits no consideration of gene-gene interaction... 

TNF +489G/G Intronic polymorphism— function unknown No effect on response toETN [99]... 

Brambila-Tapia, A.J.-L., 2013. MDRl (ABCBl) polymorphisms functional effects and clinical implications. Revista de Investigacidn Clinica, 65(5), pp. 445-454. 

Stenstedt K, Travica S, Guo J, Barragan I, Pors K, Patterson L, Edler D, Mkrtchian S, Johansson I, Ingelman-Sundberg M (2013) CYP2W1 polymorphism functional aspects and relation to risk for colorectal cancer. Pharmacogenomics 14 1615-1622... 

Veltkamp M, Wijnen PA, van Moorsel CH, et al. Linkage between toll-like receptor (TLR) 2 promotor and intron polymorphisms functional effects and relevance to sarcoidosis. Clin Exp Immunol 2007. 

DCPA inhibits the growth of grass species by dismpting the mitotic sequence, probably at entry (190). DCPA influences spindle formation and function (181) and causes root-tip swelling (182) and britde shoot tissue (191). It has been reported that DCPA, like colchicine and vinblastine, attests mitosis at prometaphase and is associated with formation of polymorphic nuclei after mitotic arrest (192). Pronamide also inhibits root growth by dismpting the mitotic sequence in a manner similar to the effect of colchicine and the dinitroanilines (193,194). Cinmethylin and bensuhde prevent mitotic entry by unknown mechanisms (194). 

Fig. 18.2 Polymorphism and dimensional changes in silica as a function of temperature...

Based on their physiological function it is not surprising that genetic polymorphisms affecting expression and... 

As yet, no human diseases have been identified as a result of FATPl mutations. However, genetic polymorphisms in the human FATPl gene have been linked to dyslipidemia. An A/G exchange at position +48 in intron 8 of the FATPl gene has been shown to result in increased TG concentrations in female but not in male subjects. In a second study, the same polymorphism was linked to increased postprandial TG concentrations and smaller low density lipoprotein (LDL) particles. To date, it is still unknown if this polymorphism is associated with altered levels of FATPl expression and/or function. 

In vivo azathioprine is rapidly converted into its active metabolite 6-mercaptopurine by the enzyme thiopurine methyltransferase (TPMT). The active agent inhibits IMPDH function. Furthermore, it also acts as antimetabolite of the RNA and DNA synthesis particularly in T-lymphocytes leading to cell death. Due to genetic polymorphism of TPMT, therapy may fail, thus it is currently discussed whether individual patients should be monitored before the use of azathioprine. 

Moreover, there exist polymorphic MOP variants. An Asn40Asp polymorphism has been found with a high abundance in the Caucasian and Asian population. This receptor variant is less expressed in the brain and carrier of this polymorphism appears to need more opioids for analgesic treatment. There are many additional MOP polymorphisms with unknown functional significance. In spite of many studies there appears to exist no significant association of polymorphisms in the MOP gene and drug addiction [5]. 

CYP2J2 is abundant in cardiovascular tissue and active in the metabolism of arachidonic acid to eicosanoids that possess potent anti-inflammatory, vaso-dilatory, and fibrinolytic properties. Polymorphic alleles with reduced function are known. Some other CYP2 subfamilies and isozymes listed in Table 1 are still not well characterized, in part because most of them were discovered in the course of the human genome project. 

There are only very few genes which do not carry any polymorphisms. And there exists even a significant number of polymorphic genes that are not expressed at all in part of the population due to genetic polymorphisms. Table 1 summarizes a few selected polymorphisms with their functional and medical impact. 

Enzyme Functional effects of polymorphism and frequency Examples for the medical impact... 

Eight exons of the AR gene encode a protein of around 917 aa depending on two polymorphic regions of polyglutamines (CAG) and polyglycines (GGN) in the N-terminal activation domain. Two isoforms are detected in tissues the predominant (80%) 110 kD (B isoform) and 87 kD (A isoform). It is not clear whether the two isoforms also serve different functions. 

The polymorphic behavior of PVDF has been found to be changed also in the presence of functionalized ethylene-propylene copolymers, for the case of samples isothermally crstallized from the melt [103]. 

Chen CC, Lu RB, Chen YC, et al Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism. Am J Hum Genet 65 795-807, 1999... 

There is a normal variation of DNA sequence just as is true of more obvious aspects of human structute. Variations of DNA sequence, polymorphisms, occur approximately once in evety 500 nucleotides, or about 10 times per genome. There are without doubt deletions and insertions of DNA as well as single-base substitutions. In healthy people, these alterations obviously occur in noncoding regions of DNA or at sites that cause no change in function of the encoded protein. This heritable polymorphism of DNA structure can be associated with certain diseases within a large kindred and can be used to search for the specific gene involved, as is illustrated below. It can also be used in a variety of applications in forensic medicine. 

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