Article Review: Risk of Development and Progression

Pages: 10 (3037 words)  ·  Bibliography Sources: 10  ·  Level: College Junior  ·  Topic: Genetics  ·  Buy This Paper

SAMPLE EXCERPT:

[. . .] (D Otaegui1, A Sa'enz1, P Caman "o1, 2006)

Pearson's chi square test was used to perform the homogeneity test between the two distributions of the genotypes. Yate's chi square test was utilized to perform tests to compare frequencies of the CD 24 V/V genotype between cases and controls. (D Otaegui1, A Sa'enz1, P Caman "o1, 2006)

Patients with an EDDS classification of 6.0 were classified into three groups according to their genotypes: V/V, V/A, A/A. To assess differences in MS progression, the Kaplan Meier method was used to estimate the survival curve. This was compared with the log- rank test. Here survival was taken to mean that a patient had not reached EDDS 6.0 yet, and the time span was measured by the number of years that had lapsed since the first symptom. (D Otaegui1, A Sa'enz1, P Caman "o1, 2006)

RESULTS:

In the first study, the CD 24 V/V SNP was observed to occur more in the MS group compared to the control group. There was no significant difference between these groups in the other two variations, the CD 24 A/V and the CD 24 A/A SNP. In addition, there was also no relationship between age, gender and ethnic group (Basque and Caucasians) regarding the presence of the CD 24 V/V SNP. The average MSSS in patients with CD 24 V/V was 6.1613 compared to CD 24 V/V non-carriers. The MSSS test program yielded a P. value of 0.123791. (Zhou, Rammohan, Lin, Robinson, & Li, 2005)

The second paper was a much more extensive study, which tested the effects of the CD24 genotypes in relation to the progression of the disease and the efficiency of the three CD 24 genotypes that were expressed on the cell surface. In their population study, the samples were obtained from central Ohio. Most of the patients with MS were Caucasians indicating the high incidence of MS in this particular ethnic group. After PCR was conducted, it was observed that the CD 24 A/A and A/V genotypes in both the normal and effected population were nearly the same. However 6.3% of the normal individuals and 13.2% of the effected individuals had the CD 24 V/V genotype indicating a double risk of acquiring multiples sclerosis with this genotype. (D Otaegui1, A Sa'enz1, P Caman "o1, 2006)

A family study was carried out using TDT analysis to check the association of MS with CD 24 'V' allele. In the type 1 families the Xtdt value was 13 compared to the expected 7.5. In the type 2 families the TDT value was 20 compared to the expected 18.57. The total observed TDT values for both family types was 33 which yielded a P. value of 0.017 which indicates significant results. Thus the population and family study both suggest that there is a link between allele CD 24 V/V and its preferential transmission to MS patients as compared to non-MS individuals. (D Otaegui1, A Sa'enz1, P Caman "o1, 2006)

The effect of CD 24 genotype and disease progression was also evaluated with the help of the EDSS score. All patients with an EDDS score of 6 (indicating a loss of ability to walk without aid) were interviewed or followed up. The patients with each genotype were asked how many years it took to reach an EDDS value of 6. 50% of patients with CD24 V/V reached EDSS in 5 years, compared to 13 and 16 years in CD 24 A/A and CD24 A/V respectively. This indicates a relationship between CD24 V/V and progression of MS, concluding that homozygous patients have an increased risk of a more rapid disease progression. (D Otaegui1, A Sa'enz1, P Caman "o1, 2006)

The expression of the three alleles and how efficiently they are expressed on the cell surface was also determined. The expression of CD24 on peripheral blood leukocytes of age, sex and disease status matched CD24 A/A and V/V by two color flow cytometry. CD24 is expressed in both T cells and non- T cells of all the genotypes, however, there is a greater expressivity, on T cells, in patients with CD 24 V/V genotype. Also, the CD 3+ cells expressed 6 times more cell surface receptors in CD 24 V/V patients compared to AA patients. The intensity of expression was higher amongst the peripheral blood leukocytes of CD 24 V/V patient. CD 24 A/A and A/V were also compared for difference in expressivity. CD 24 A/V shows less than two fold increase in expressivity compared to CD A/A which shows that it does not have a significant effect on the progression of MS. To directly check for expressivity CD 24 'A' and 'V', cDNA were cloned and transfected in Chinese Hamster Ovary cells with different concentrations of plasmids. Three days later, the expression of the CD 24 genes were analyzed with flow cytometry revealing that CD 'V' showed 30-40% more expressivity than CD 'A' c DNA. The increased expressivity of the homozygous Valine gene could be a reason for its more rapid disease progression. (D Otaegui1, A Sa'enz1, P Caman "o1, 2006)

DISCUSSION:

Existing evidence associates CD 24 to multiple sclerosis, as a factor, modifying disease progression. The lesions of ms are mimicked by those of EAE, an autoimmune disease induced in animals by immunization with myelin. This happens when t lymphocytes are sensitized to myelin antigens. However, in MS, sensitivity to myelin has not been demonstrated. The interest of this research was based on establishing an association with the CD 24 receptor polymorphism with MS susceptibility. (D.A, 1996)

In both studies, the size of the proteins containing alanine or valine had been clearly demonstrated, indicating that these amino acids could influence the cleavage efficiency and anchor attachment of this region of CD 24 peptide, which is a co-stumulatory molecule that functions independently of CD 28 and that may regulate the recruitment of autoreactive T cells to the CNS. (Zhou, Rammohan, Lin, Robinson, & Li, 2005)

The studies also analyzed the difference of the presence of C/C, V/C and V/V in MS and non-MS patients. Since differences were only observed with the homozygous valine allele, occurrence of which was considerably high amongst MS patients, it is likely that the association is based on the absence of alanine rather than with the presence of valine. (D Otaegui1, A Sa'enz1, P Caman "o1, 2006)

The first study also noted that the average MSSS was higher amongst the homozygous individuals, also concluding that the gene could be responsible in disease progression. This is in accordance with results from animal models, where the same homozygous gene was found responsible for the induction of Experimental Autoimmune Encephalomyelitis, and results from the second study. This conclusion was additionally aided with the second study that checked expressivity efficiency of the different genes, revealing a greater expressivity capability of valine. This might be a reason for its more rapid progression. (Zhou, Rammohan, Lin, Robinson, & Li, 2005)

The first study did not find any differences in the frequency distribution of Multiple Sclerosis in between the different ethnic groups, which is inconsistent with other studies done on ethnic predisposition of Multiple Sclerosis. This reveals a similar preponderance in the development of Multiple Sclerosis amongst the Basque Natives with the Caucasians. The similarity could also have been due to an error in the classification method of the control groups. They were divided on the basis of their surnames. Global mixing of the different ethnic groups with each other could have led to a misapprehension of results, under or over estimating the ratio of Caucasians to Basque Natives. (Zhou, Rammohan, Lin, Robinson, & Li, 2005)

On the other hand, the second study observed a dramatic difference in the ethnic predisposition, of Caucasians, towards the disease. (D Otaegui1, A Sa'enz1, P Caman "o1, 2006) There could have been several factors that might have led to this conclusion.

1) The selection criteria was non-selective in terms of ethnicity. An equal number of Caucasians and other ethnic groups, amongst the control and subject population, were not selected.

2) The groups selected reflected the Ohio Population, demographic data of which, reveals more Caucasians living in the area. Therefore, it would be rational to base the difference, of prevalence in between the different ethnic groups, using this data. The author, too, made this clear, that the results inferred reflected only the Ohio population and not Multiple Sclerosis patients worldwide.

CONCLUSION:

The aim of these two studies was to find a link between Multiple sclerosis and CD 24 polymorphism. It was observed that the V/V allele posed twice the risk of developing Multiple Sclerosis in patients, as compared to those who were either heterozygous for the gene, or homozygous for the amino acid, alanine. Moreover, it was concluded that the V/V gene was quicker in reaching EDS 6.0, indicating a faster disease progression. The reason for the greater tendency for this gene to cause Multiple Sclerosis was due… [END OF PREVIEW]

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