Investigation of mutations in Fanconi anemia genes and malignancy predisposition in Brazilian patients.

INTRODUCTION: This study proposed to identify Fanconi anemia (FA) mutations in Brazilian patients and to investigate their impact on clinical manifestations and malignancies onset. METHODS: A total of 116 patients were screened for nine mutations in FANCA, FANCC, FANCG. Those with no mutations were investigated by multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing for FANCA, FANCC, FANCE, FANCF, FANCG, FANCD1/BRCA2. RESULTS: Genetic subtype was identified in 107/116 (78 FA-A, 8 FA-C, 13 FA-G, 8 FA-E), with only one mutation in 1/116, and no mutations in 9/116 patients. Before hematopoietic cell transplantation (HCT), malignancies were detected in 16/116 patients (14/78 FA-A, 01/08 FA-C, 01/08 FA-E), and 12 of them were hematological. Observed to expected ratio (O/E) of hematologic malignancy was 303.7 (95% CI = 148.6-458.7). CONCLUSION: This study allowed the identification of biallelic mutations in 91.4% of patients. FANCG and FANCC mutations had significantly earlier bone marrow failure onset, and FANCG severe cytopenia at diagnosis. Despite the inherent limitations of the small number of malignancy events in each genetic subtype, the hematologic malignancies O/E ratio was very high. Cumulative incidence of malignancy before HCT was higher in the third and fourth decades of life, considering HCT and death as competing risks. The cumulative incidence of HCT increased during the first decade, competing with malignancy development.

Both qualitative and quantitative genetic variation of MHC class II molecules may influence susceptibility to autoimmune diseases: the case of endemic pemphigus foliaceus.

The MHC class II transactivator (CIITA) is a key regulator in expression of the HLA class II genes. It is well known that HLA-DRB1 genotypes have a strong influence on the risk of multifactorial autoimmune diseases, but the effect of CIITA genotypes remains controversial. We tested in a case-control study whether CIITA polymorphisms influence the risk of developing endemic pemphigus foliaceus (EPF) and whether CIITA and HLA-DRB1 interact as regards susceptibility to the disease. The rs4774 SNP is not associated to EPF, while rs3087456 in the CIITA gene promoter is associated with susceptibility [odds ratio (OR) = 2.6, p < 0.001 and OR = 2.0 p = 0.003 for genotypes G/G and G/A, respectively]. We suggest that the associations result from the effect of genetically controlled levels of CIITA on expression of the susceptible and protective HLA class II molecules. Remarkably, the interaction between CIITA and HLA-DRB1 genotypes is strong and additive. The OR for individuals having two susceptible HLA-DRB1 alleles is 14.1 in presence of the susceptible CIITA G/G or G/A genotypes and much lower (2.2) in presence of the protective CIITA A/A genotype. We conclude that quantitative as well as qualitative variation of HLA class II molecules have an effect on the risk of an individual developing EPF.

KIR gene content in amerindians indicates influence of demographic factors.

Although the KIR gene content polymorphism has been studied worldwide, only a few isolated or Amerindian populations have been analyzed. This extremely diverse gene family codifies receptors that are expressed mainly in NK cells and bind HLA class I molecules. KIR-HLA combinations have been associated to several diseases and population studies are important to comprehend their evolution and their role in immunity. Here we analyzed, by PCR-SSP (specific sequencing priming), 327 individuals from four isolated groups of two of the most important Brazilian Amerindian populations: Kaingang and Guarani. The pattern of KIR diversity among these and other ten Amerindian populations disclosed a wide range of variation for both KIR haplotypes and gene frequencies, indicating that demographic factors, such as bottleneck and founder effects, were the most important evolutionary factors in shaping the KIR polymorphism in these populations.