Interleukin-10(IL-10)1082-A and Tumor Necrosis Factor(TNF)-Alpha 238/308A Genotypes Are Associated with Earlier (Younger Than 55) Onset of Multiple Myeloma.
Authors: Beksac Meral , Kizil Merih , Soydan Ender A. , Serbest Esin , Dalva Klara 
Published: April 2020

Abstract
The individual differences among the polymorphic regions of the cytokine genes involved in the pathogenesis of myeloma have been investigated by various groups: Neben et al have found the TNF238 A allel to be associated with a higher serum level of TNF-alpha and with better response to Thalidomide. The IL 10-1082 G promoter gene genotype have been found to be associated with high secretory pattern and in increased frequency among myeloma patients compared to normal controls by Zheng et al. Van Ness et al have reported the IL-10-G genotype to be associated with shorter survival compared to IL-10-A allele carriers None of these groups have analyzed the impact of these genotypes on age of onset. With an aim to analyze the association between the frequencies of the cytokines known to be important in the pathogenesis of Myeloma, TNF-alpha, IL-6, IL-10 and the age of diagnosis, we have isolated DNA from peripheral blood of 59 patients. Patients with a median age of 56(28–83)M/F:35/24 diagnosed and treated in our center between 2002–2004 were analyzed. To determine the TNF 238 and 308(G/A), IL-6 174(G/C), IL-10 1082(G/A),819(T/C) and 592(A/C) bp polymorphic allele frequencies Cytokine Genotyping Kit (Pel-Freeze) and/or Cytgen (OneLambda) Genotyping Trays have been used. Evaluation of results were done as described in the worksheets. Interpretation and definition of phenotypes(low and high secretory patterns) were based on the previously published reports. 30 patients(50,8%) were younger than 56 (median=the cutoff:56). TNF-A homozygous alelle couldnot be observed among all patients. The frequencies of all alleles were: TNF-alfa308A, TNF-alfa238A, IL-10 1082 G 20%, 20%, 12% respectively. IL-6 -GG/GC alleles which have been linked with high secretory pattern constituted the majority of the patients(58/59). When TNFalfa-A were detected based on the 238 bp reactivity the association of low phenotype with elder age was remarkable(p=0.019). This finding wasnot valid for the 308 bp location. IL-10 phenotypes were more complicated with an accumulation in the intermediate level of secretion. The impact of TNF was varified with the separate evaluation of this group, based on their TNF-238/308 genotype, p=0.031). Conclusion: There is a trend towards younger age of onset in Myeloma. Genetic factors for susceptibility have not been defined yet. The new tools for detection of single nucleotide polymorphisms have a promising role in this field. In our prospective study we have found a predominance of low IL-10 secretory A genotype and the high secretory TNF-A genotype among patients younger than 56. To our knowledge this is the first report on such an association. Investigation of other genes in linkeage with TNF on the neighboring MHC region may be necessary for understanding myeloma pathogenesis.
Age TNF 238 H/L TNF 308 H/L TNF 238,308 H/L IL-10 H/I/L IL-10 I,TNF H(238 or 308)/ IL-10 I,TNF L(238 or308) L:Low, H: High,I:Intermediate secretory, TNF238A:H, TNF238G:L, TNF308A:H, TNF308G:L, IL-10G: H ≤55 5 / 7 6 / 24 7 / 5 1 /16 / 13 5 / 2 &gt;55 1 / 16 6 / 23 4 / 13 6 /13 / 8 1 / 6 N=29, p=0.019 N=59, p=0.948 N=29, p=0.057 N=57, p=0.085 N=14, p=0.031