Obesity is associated with an increased risk of monoclonal gammopathy of undetermined significance among black and white women

Multiple myeloma (MM) is a neoplasm of plasma cells characterized by an overproduction of monoclonal immunoglobulins.¹  Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the presence of a monoclonal immunoglobulin (M-protein) without evidence of MM or other lymphoproliferative malignancies.²  MM is consistently preceded by MGUS.³ 

Prior studies show racial disparity patterns in the epidemiology of both MGUS and MM.⁴  Compared with whites, MGUS and MM are 2- to 3-fold more common in blacks and in Africans.⁴  In addition, MGUS and MM are associated with familial clustering.^5,6 

Obesity is associated with a 1.5- to 2-fold elevated risk of developing MM.^7-9  This is of particular interest given that elevated levels of the proinflammatory cytokine interleukin-6 have been found in obese persons,¹⁰  and interleukin-6 has well-known proliferative and antiapoptotic effects on monoclonal plasma cells.¹¹  In addition, insulin-like growth factors play a role in obesity,¹⁰  and insulin-like growth factor-I has growth/survival effects on monoclonal plasma cells.¹² 

We speculated that obesity might increase the risk of MGUS, or, alternatively, that obesity may increase the risk for transformation from MGUS to MM. In this large screening study, we assessed the role of obesity and race in relation to MGUS risk.

This study was based on the population-based Southern Community Cohort Study (SCCS) cohort (Table 1).¹³  The 1996 SCCS subjects made available for inclusion in this study had already been randomly selected within the SCCS strata for another project of obesity biomarkers (Table 1). All participants provided informed consent in accordance with the Declaration of Helsinki, and the protocol was approved by appropriate institutional review boards of all participating institutions.

All serum samples were analyzed in an identical fashion and in the same laboratory as the population-based study of MGUS in Olmsted County, MN (Table 2).^2,14,15 

Characteristics for different racial groups were compared using χ² test statistics. Unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between MGUS and subject characteristics were estimated using logistic regression.

The median age was 48 years (range, 40-79 years; Table 1). Per sampling strategy, 50% were obese based on self-reported height and weight (medical record–abstracted weight and height available for approximately 25% of the cohort was very highly concordant with the self-reported values; Pearson correlation greater than 0.95 for body mass index). Socioeconomic status (SES) tended to be low, with 73% of the women not attending any college and 60% having annual household incomes less than $15 000. Nineteen percent of the women reported a history of diabetes mellitus.

MGUS was detected in the serum of 60 (3.0%) of the 1996 participants. More specifically, 39 (3.9%) blacks and 21 (2.1%) whites were found to have MGUS, yielding a crude 1.9-fold (95% CI, 1.1-3.2; P = .02) higher risk of MGUS among blacks (vs whites; Table 2). Although it is well known that MM is 2- to 3-fold more common among blacks than whites,⁴  the literature indicating an excess of the precursor MGUS among blacks is restricted to a small number of studies.^4,16-18  On multivariate analysis, we found obesity (OR = 1.8; 95% CI, 1.03-3.1; P = .04), black race (OR = 1.8; 95% CI, 1.04-3.1; P = .04), and increasing age (OR = 2.5; 95% CI, 1.1-5.7; P = .03 for age > 55 years compared with age < 43 years) to be associated with an increased risk of MGUS (Table 2). Using educational status and household income as proxy markers for SES, we found no significant association between these variables and MGUS (Table 2). Neither was a medical history of diabetes mellitus associated with an increased risk of MGUS in the multivariate analysis. Our novel finding that MGUS was twice as common among obese versus nonobese women, and independent of race, supports the hypothesis that obesity is etiologically linked to myelomagenesis. Furthermore, it suggests that the previously observed 2-fold increased risk of MM among obese persons^7-9  may be because they are more likely to develop MGUS, which in turn puts them at risk for developing MM.

In contrast to prior studies, we had access to extensive questionnaire data with which to evaluate the effect of several potential confounders of the race-MGUS association. We were specifically interested in assessing confounding by SES, following up on inconsistent findings from prior studies, with some showing elevated risks of MM associated with lower SES (based on education and income status) among both blacks and whites,^19,20  some showing elevated risk of MM mortality with higher social class,^21,22  and other studies finding no association between SES and MM.²³  In the present study, the doubling of risk for blacks was virtually unchanged when we included obesity, education status, and income status in the same multivariate model. Our findings therefore suggest that the racial difference is not an artifact of differences in SES, and strengthen the hypothesis that other factors are involved, including perhaps a role for susceptibility genes in myelomagenesis.^4,6,24,25 

Among black women with MGUS (n = 39), the isotype of the monoclonal immunoglobulin was immunoglobulin G (IgG) in 79%, IgA in 8%, IgM in 8%, and biclonal in 5% (Table 3). In the 21 white women with MGUS, the isotype of the monoclonal immunoglobulin was IgG in 71%, IgM in 19%, IgA in 0%, biclonal in one patient, and triclonal in one patient. This is in accord with prior studies reporting a significantly lower prevalence of IgM MGUS and Waldenström macroglobulinemia among blacks compared with whites.^26,27 

More than 70% of the MGUS cases, independent of race, had a very small (unquantifiable) monoclonal Ig (Table 2). This fraction is very high compared with a prior MGUS screening study in Olmsted County, MN (12%).²  Interestingly, despite earlier thinking that MGUS is probably not present before the age of 50 years,²  we detected MGUS in 21 subjects in the 40- to 50-year age group, accounting for 35% of our MGUS cases (Table 2). The reported differences across studies may be the result of variations in environmental exposures and obesity status, which may result in differing immune responses.

Strengths of our study include its base in a well-described cohort with carefully obtained baseline data and blood specimens. The very similar SES of the black and white women included in the study also limited, by design, the potential for SES to confound the association between MGUS and race. Differential accuracy in the reporting of body size measurements or other important variables in our analysis was minimized as this risk factor information was collected before blood draw and serum protein analysis. Limitations of our study include the lack of access to clinical or pathologic details regarding the MGUS cases. The cross-sectional nature of the study also precludes assessment of temporality and the drawing of causal inferences.

In conclusion, we found a 2-fold increased risk of MGUS associated with both obesity and with black race, supporting the hypothesis that obesity is etiologically linked to myelomagenesis and further strengthening evidence of the racial difference in MGUS, possibly signifying a role for susceptibility genes in MGUS. Future research is needed to better understand underlying biologic mechanisms of our observations.

This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, the National Cancer Institute providing basic support for the Southern Community Cohort Study (grant R01 CA092447), Susan G. Komen for the Cure (grant OP05-0927-DR1) providing for additional information on the study participants, the National Cancer Institute (grants CA 62242 and CA 107-476-03) and the facilities and resources of the Divisions of Hematology, Biostatistics, Clinical Biochemistry and Immunology, and Epidemiology at the Mayo Clinic. All electrophoresis and immunofixation analyses were conducted by Ms Clark at the Mayo Clinic. Serum sample preparation was conducted at the Survey and Biospecimen Shared Resource, which is supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA68485).

National Institutes of Health

Contribution: O.L., W.J.B., and L.B.S. had full access to all the data in the study, had final responsibility for the decision to submit the article for publication, oversaw all aspects of the study, participated in the study conception and design, interpreted the data, drafted the manuscript, managed all revisions to the manuscript, and obtained funding for the study; R.A.K. and J.A.K. reviewed all serum protein electrophoretic patterns; and R.M.P. was primarily responsible for the statistical analysis and takes responsibility for the accuracy of the data analysis. All authors participated in the study design and interpretation of the data, made important intellectual contributions to the manuscript, and read, gave comments, and approved the final version of the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Ola Landgren, National Cancer Institute, National Institutes of Health, Center for Cancer Research, Medical Oncology Branch, 9000 Rockville Pike, Bldg 10, Rm 13N240, Bethesda, MD, 20892; e-mail: landgreo@mail.nih.gov.