ABSTRACT
Polymorphisms in NFKBIA may be important in pre-disposition to and outcome after treatment, of multiple myeloma (MM). The NFKBIA gene product, IkappaBalpha, binds to NF-kappaB preventing its activation and is important in mediating resistance to apoptosis in B-cell lymphoproliferative diseases. This study investigates eight polymorphisms across the NFKBIA gene in large patient and control populations. Significant differences in the frequency of particular polymorphisms were noted between patients and controls. A risk haplotype [GCCTATCA] for MM was also identified (P=0.006). Analysis of the genetics of NFKBIA may lead to associations with disease progression and survival and thus more personalized therapy.
Subject(s)
Haplotypes , I-kappa B Proteins/genetics , Multiple Myeloma/genetics , Polymorphism, Single Nucleotide , Adult , Alleles , Base Sequence , Gene Frequency , Genotype , Humans , Linkage Disequilibrium , Molecular Sequence Data , Sequence Homology, Nucleic AcidABSTRACT
The cytokines tumour necrosis factor-alpha (TNFalpha) and lymphotoxin-alpha (LTalpha) are known to play key roles in B-cell growth, differentiation and maturation. Genetic polymorphism within regulatory regions of these cytokine genes can alter expression levels and may be important in development of lymphoid malignancy. This study investigates a number of single nucleotide polymorphisms (SNPs) and microsatellite variants present within these genes in a large cohort of non-Hodgkin lymphoma (NHL) cases including 211 cases of follicular lymphoma (FL) and 281 cases of diffuse large B-cell lymphoma (DLBCL), and 478 unaffected controls. The study investigated whether particular alleles at these loci, or their combination across the TNF region in the form of haplotypes, may act as markers for predisposition and development of NHL. The study provided evidence for an influence of the TNF region in the susceptibility to NHL, whereby the loci -863, -857, TNFe and TNFd categorised five haplotype groups over which risk of both FL and DLBCL varied significantly. Prediction of disease risk was improved by the addition of loci to the haplotype, demonstrating the importance of considering the haplotype-specific context of the loci in genetic risk assessment.
Subject(s)
Genetic Predisposition to Disease , Haplotypes , Lymphoma, Non-Hodgkin/genetics , Tumor Necrosis Factor-alpha/genetics , Adult , Aged , Case-Control Studies , Female , Genotype , Heteroduplex Analysis/methods , Humans , Linkage Disequilibrium , Lymphotoxin-alpha/genetics , Male , Microsatellite Repeats , Middle Aged , Polymorphism, Single NucleotideABSTRACT
This study described the haplotypic structure across a region of chromosome 6 including the tumour necrosis factor (TNF) gene, and investigated its influence on the aetiology of myeloma. A total of 181 myeloma cases from the Medical Research Council Myeloma VII trial and 233 controls from the Leukaemia Research Fund Case Control Study of Adult Acute Leukaemia were included in the analysis. Genotyping by induced heteroduplex generator analysis was carried out for single nucleotide polymorphisms (SNP) located at positions -1031, -863, -857, -308 and -238 of the 5' promoter region of TNF-alpha gene, and 252 in the LT-alpha gene; and five microsatellites, TNFa, b, c, d and e. Haplotypes were inferred statistically using the phase algorithm. A limited diversity of haplotypes was observed, with the majority of variation described by 12 frequent haplotypes. Detailed characterization of the haplotype did not provide greater determination of disease risk beyond that described by the TNF-alpha-308 SNP. Some evidence was provided for a decreased risk of myeloma associated with the TNF-alpha-308 variant allele A, odds ratio, 0.57; 95% confidence interval, 0.38-0.86. The results of this study did not support our starting hypothesis; that high producer haplotypes at the TNF locus are associated with an increased risk of developing myeloma.
