Interleukin-6 Promoter and Receptor Polymorphisms, Body Mass Index and Risk of Multiple Myeloma.

Interleukin-6 (IL-6) is a cytokine necessary for successful differentiation of plasma cells from B lymphocytes and high levels have been linked to prognosis of multiple myeloma. Several studies have examined a common functional single nucleotide polymorphism in the promoter region of the IL-6 gene (−174G→C) with null results. Terry et. al. reported that at least three promoter polymorphisms contribute to regulation of IL-6 levels (Terry, 2000). We evaluated the four promoter polymorphisms described by Terry et. al. plus an IL-6 receptor polymorphism in a case-control study to determine if any were associated with multiple myeloma risk. Blood samples and questionnaires were obtained from incident cases (n=150) ascertained from the population-based cancer registry in Los Angeles County. Similar samples were collected from two control groups consisting of siblings or cousins of cases (n=114) and population-controls obtained by random digit dialing (n=131). DNA was extracted and amplified by PCR and the −174 G→C, −572 G→C, −597 G→A promoter polymorphisms determined using Taqman. The −373 A_nT_n VNTR was determined by direct sequencing and IL-6 receptor A→D polymorphism was determined using RFLP. When cases were compared to relative and population controls, risk of multiple myeloma increased by 71% and 67% in persons carrying the −572 GC genotype compared to those with the GG genotype, respectively (odds ratio [OR] for cases v. relatives = 1.71, 95% Confidence Interval [CI ]= 1.10–2.78; OR for cases v. population-based controls =1.67, 95% CI=1.10–2.70). The effect was stronger among African-Americans, but not statistically significant (OR for cases v. relatives = 3.07; OR for cases v. population controls = 2.52). The other IL-6 promoter polymorphisms and receptor polymorphism had no effect on multiple myeloma risk. Increased body mass index was a statistically significant predictor of multiple myeloma risk when cases were compared to population controls but not when compared to relatives, and the effect was stronger in whites than African-Americans. We conclude that the −572 IL-6 promoter polymorphism is associated with multiple myeloma risk in both African-Americans and whites. Increased body mass index may be a risk factor for multiple myeloma in some groups. Finally, since the estimates of risk were very similar for the two comparison groups, relative controls offer a good alternative for genetic studies when population controls are difficult to recruit or are not available.