Is TNFA-376A SNP a population specific genetic risk marker of the susceptibility to develop multiple sclerosis?

KAUFFMAN MARCELO; GONZALEZ MORON DOLORES; FERNANDEZ LIGUORI NORA; SANDOVAL GUSTAVO; GARCEA ORLANDO; VILLA ANDRES MARIA

Madrid

Congreso; European Committe for Treatment and Research in Multiple Sclerosis; 2006

Background and aims: Multiple sclerosis (MS) is a complex genetic disorder in which only alleles of the major histocompatibility complex has reproducibly been associated with the disease in molecular epidemiology studies. There have been a huge number of initial positive reports of association between variants in different genes and MS that subsequently failed to be reproduced in independent populations. A single nucleotide polymorphism at the /376 position of the promoter of TNF A gene was associated with susceptibility to MS in Spain, but it could not be reproduced in studies performed in USA and Holland. Our aim was to investigate the association between TNFA /376A SNP and MS susceptibility in a cohort of Argentinean MS patients. Methods: 90 patients with MS relapsing-remitting (McDonald’s criteria) were consecutively recruited at the MS clinic of Ramos Mejia Hospital, Buenos Aires, Argentina from March 2005 to January 2006. Control group consisted of 84 healthy subjects matched for ethnic background, gender and age. TNFA /376A SNP was blindly to clinical status determined by PCR-RFLP assay. Hardy-Weimberg equilibrium was tested by exact test. x2 was used to test for differences in allele distribution between groups. The odds ratio (OR) was calculated along its 95% CI from contingency tables. Results: The genotype count in controls was in Hardy-Weinberg equilibrium (p/1). The A/G genotype was found in 4.44% of the patients and in 4.76% of the controls (p/0.92, OR/0.930 CI/0.225  3.84). Thus, no significant differences in genotypic and allele frequencies were found between healthy controls and MS patients. Discussion and conclusion: In contrast to both Spanish reports, results of the current study fail to find an association between the TNFA /376A SNP and MS susceptibility. Our failure to replicate it could be due to several factors: genotyping errors and chance seems very unlikely. Population stratification in the original report or population differences in susceptibility alleles or allele heterogeneity might be other reasons for non-replication if different diseasecausing alleles predominate in different study populations or allele frequencies are similar but heterogeneity in the size of the effect of the disease gene between study settings is present because of geneenvironment interaction. TNFA /376A SNP could be a populationspecific risk factor as a consequence of particular and restricted geneenvironment interaction acting in Spain.Multiple sclerosis (MS) is a complex genetic disorder in which only alleles of the major histocompatibility complex has reproducibly been associated with the disease in molecular epidemiology studies. There have been a huge number of initial positive reports of association between variants in different genes and MS that subsequently failed to be reproduced in independent populations. A single nucleotide polymorphism at the /376 position of the promoter of TNF A gene was associated with susceptibility to MS in Spain, but it could not be reproduced in studies performed in USA and Holland. Our aim was to investigate the association between TNFA /376A SNP and MS susceptibility in a cohort of Argentinean MS patients. Methods: 90 patients with MS relapsing-remitting (McDonald’s criteria) were consecutively recruited at the MS clinic of Ramos Mejia Hospital, Buenos Aires, Argentina from March 2005 to January 2006. Control group consisted of 84 healthy subjects matched for ethnic background, gender and age. TNFA /376A SNP was blindly to clinical status determined by PCR-RFLP assay. Hardy-Weimberg equilibrium was tested by exact test. x2 was used to test for differences in allele distribution between groups. The odds ratio (OR) was calculated along its 95% CI from contingency tables. Results: The genotype count in controls was in Hardy-Weinberg equilibrium (p/1). The A/G genotype was found in 4.44% of the patients and in 4.76% of the controls (p/0.92, OR/0.930 CI/0.225  3.84). Thus, no significant differences in genotypic and allele frequencies were found between healthy controls and MS patients. Discussion and conclusion: In contrast to both Spanish reports, results of the current study fail to find an association between the TNFA /376A SNP and MS susceptibility. Our failure to replicate it could be due to several factors: genotyping errors and chance seems very unlikely. Population stratification in the original report or population differences in susceptibility alleles or allele heterogeneity might be other reasons for non-replication if different diseasecausing alleles predominate in different study populations or allele frequencies are similar but heterogeneity in the size of the effect of the disease gene between study settings is present because of geneenvironment interaction. TNFA /376A SNP could be a populationspecific risk factor as a consequence of particular and restricted geneenvironment interaction acting in Spain.