IL-6 levels and genotype are associated with risk of young adult Hodgkin lymphoma

Abstract

Identical twins of young adult Hodgkin lymphoma case subjects are much more likely to develop the disease compared with fraternal twins of case subjects, suggesting a genetic determinant. Interleukin 6 (IL-6) levels are increased in patients with Hodgkin lymphoma and are correlated with a poor prognosis. We hypothesized that a heritable abnormality in IL-6 regulation may predispose to young adult Hodgkin lymphoma. We obtained blood specimens from 88 young adult Hodgkin lymphoma case subjects and their twins as well as from 87 matched control subjects. IL-6 was measured from unstimulated peripheral blood mononuclear cell (PBMC) supernatant with enzyme-linked immunosorbent assays (ELISAs) and compared by using analysis of covariance. Unaffected identical twins of case subjects (surrogate case subjects) had a 87.8% higher IL-6 level compared with matched control subjects (mean difference, ؉483.7 pg/mL, P ‫؍‬ .04). Analysis of the IL-6 174G>C promoter polymorphism genotypes showed that risk decreased with an increasing number of C alleles (P ‫؍‬ .01). The CC (low secreting) genotype was associated with a decreased risk of young adult Hodgkin lymphoma relative to the GG (high secreting) genotype (odds ratio [ IntroductionHodgkin lymphoma is characterized clinically by symptoms resembling those of a chronic infectious disease and pathologically by a rare neoplastic giant cell (Hodgkin or Reed-Sternberg cell) surrounded by a mixed inflammatory and benign small lymphocytic infiltrate that varies by histologic type. 1 In developed countries, the age-specific incidence curve is bimodal, 2 with a peak among young adults aged 15 to 34 years (young adult Hodgkin lymphoma), consisting mostly of the nodular sclerosis type, and a second peak among older adults (older than 50 years), consisting mainly of the mixed cellularity type. 3 Risk factors (small sibship size, high socioeconomic status, and growing up in a single-family dwelling) strongly suggest that it results from delayed exposure to a common childhood virus. 4,5 Epstein-Barr virus has been suggested as an etiologic agent on the basis of a higher frequency of past infectious mononucleosis in patients, 6,7 higher Epstein-Barr virus (EBV) titers in prospective serologic studies 8,9 and demonstration of the Epstein-Barr viral genome in some Hodgkin lymphoma tumors, (demonstrated more commonly in mixed cellularity tumors occurring in young children and the elderly than in nodular sclerosis tumors in young adults 10 ).Genetic factors also contribute to susceptibility. A 3-to 7-fold higher risk of childhood and young adult Hodgkin lymphoma is reported in siblings of case subjects. 11,12 We also reported that identical (monozygotic) twins of case subjects have a 100-fold higher risk of developing this lymphoma than that expected on the basis of population incidence, whereas no increased risk was observed among fraternal (dizygotic) twins of case subjects. 13 We hypothesized that an inherited immune phenotype was responsible for the development of young adult Hodgkin lymphoma,...

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“…Genotyping of the SNP -174G/C (rs1800795) in the IL-6 gene was performed by the TaqMan Custom SNP assay using primer sequences 5 -CGACCTAA GCTGCACTTTTCC-3 (forward) and 5 -GGGCTGATTGG AAACCTTATTAAGATTG-3 (reverse) and probe sequences CCTTTAGCATgGCAAGAC (for allele C) and CCTTTAG CATcGCAAGAC (for allele G). 29,30 The fluorescence signals were detected on a StepOne Plus Real-Time PCR System (Applied Biosystems, Foster City, CA). All polymerase chain reaction (PCR) reactions were carried out with a final volume of 10 μL containing 3.5 μL molecular grade water, 0.5 μL 20 + SNP assay mix, and 5 μL TaqMan Gene Expression Master Mix (Applied Biosystems, Foster City, CA) with 1.0 μL sample DNA.…”

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