Young adult Hodgkin lymphoma (YAHL)is associated clinically with altered immunity, including a systemic defect in cellmediated responses. There is strong evidence of a genetic contribution to risk, so we hypothesized that heritable alterations in cytokine production associated with Th1 function may contribute to susceptibility. We identified twin pairs in whom at least one member had YAHL and measured interleukin-2 (IL-2), interleukin-12 (IL-12), and interferon-␥ (IFN-␥) levels in PHA-stimulated peripheral blood mononuclear cell supernatant in 90 case-twins, 84 of their disease-free twins (unaffected cotwins), and 90 matched controls. Mean difference and mean percentage difference in cytokine levels between casetwins and controls, and unaffected cotwins and controls were determined using analysis of covariance. YAHL casetwins and their unaffected cotwins had IL-12 levels that were 60.6% (P ؍ .002) and 49% (P ؍ .04) lower than those of their matched controls, respectively. IL-2 levels were significantly higher in casetwins (P ؍ .049), but not unaffected cotwins (P ؍ .57), compared with controls. Differences in IFN-␥ levels were not statistically significant in either comparison. An IL-12 polymorphism known to regulate expression was associated with a 2.8-fold (P ؍ .03) increase in YAHL risk. Thus, both case-twins and their unaffected cotwins had a decreased ability to produce IL-12, which may contribute to YAHL susceptibility.
IntroductionHodgkin lymphoma is characterized by 3 distinctive age-specific incidence peaks associated with different demographic factors, probably representing distinct etiologies. 1 Young adult Hodgkin lymphoma (YAHL), diagnosed approximately from ages 13 to 45 years, consists mainly of an Epstein-Barr virus (EBV)-negative, nodular sclerosis subtype, and has been historically strongly (positively) correlated with higher socioeconomic status and low sibship size. 2 These factors suggest an association between early childhood isolation from infection and risk, consistent with delayed exposure to a common childhood infection ("polio model"). 3 Although Epstein-Barr virus infection would be consistent with this set of factors, the best study to date found no increased risk of EBV-negative Hodgkin lymphoma, the most common type of YAHL, among 40 000 persons with laboratory-documented infectious mononucleosis. 4 (The same study did demonstrate a 20-fold risk of EBV-positive Hodgkin lymphoma within 5 years of the infectious mononucleosis diagnosis, but EBV-positive Hodgkin lymphoma accounts for only 10% to 25% of the disease in young adults.)Genetic factors also contribute to YAHL susceptibility. Excess risk has been reported in siblings 5 and family members 6 of cases, and we found a greater excess risk in identical (monozygotic, MZ) cotwins compared with fraternal (dizygotic, DZ) cotwins of cases. 7 An immune response phenotype associated with altered cytokine levels constitutes a likely candidate for a heritable risk factor since the pathological and clinical hallmark of Hodgkin ly...