Association of tagging SNPs in genes related to IGF-1 or IL-6 signaling with risk of multiple myeloma : selected findings

Insulin-like growth factor (IGF)-1 and interleukin (IL)-6 promote the proliferation and survival of multiple myeloma cells. Variation in genes related to IGF-1 and IL-6 signaling may influence susceptibility to multiple myeloma. To assess their etiologic role, we examined the association of 70 tagging single nucleotide polymorphisms (SNP) in seven IGF-1 and three IL-6 pathway genes with multiple myeloma risk in two prospective cohorts, the Nurses’ Health Study and the Health Professionals Follow-up Study. Among the participants who provided DNA specimens, we identified 58 women and 24 men with multiple myeloma and matched two controls per case. We used multivariable logistic regression models to assess the association of the SNPs or tagged haplotypes with multiple myeloma risk. Several SNPs had suggestive associations with multiple myeloma based on large odds ratios (OR), although the corresponding omnibus P values were not more than nominally significant (i.e., at P < 0.05). These SNPs included rs1801278 in the gene encoding insulin receptor substrate-1 [IRS1; C/T versus C/C genotypes; OR, 4.3; 95% confidence interval (CI), 1.5-12.1] and three IL-6 receptor SNPs: rs6684439 (T/T versus C/C; OR, 2.9; 95% CI, 1.2-7.0), rs7529229 (C/C versus T/T; OR, 2.5; 95% CI, 1.1-6.0), and rs8192284 (C/C versus A/A; OR, 2.5, 95% CI, 1.16.0). Additional SNPs in genes encoding IGF-1, IGF binding protein-2, IRS2, and gp130 also showed suggestive associations with multiple myeloma risk. We conducted a large number of statistical tests, and the findings may be due to chance. Nonetheless, the data are consistent with the hypothesis that IGF-1and IL-6-related gene variation influences susceptibility to multiple myeloma and warrant confirmation in larger populations. (Cancer Epidemiol Biomarkers Prev 2009;18(1):282–8)

[1]  D. Hunter,et al.  A prospective study of genetic polymorphism in MPO, antioxidant status, and breast cancer risk , 2009, Breast Cancer Research and Treatment.

[2]  David Reich,et al.  Discerning the Ancestry of European Americans in Genetic Association Studies , 2007, PLoS genetics.

[3]  F. Hu,et al.  Interleukin-6 Receptor Gene Variations, Plasma Interleukin-6 Levels, and Type 2 Diabetes in U.S. Women , 2007, Diabetes.

[4]  G. Colditz,et al.  Body Mass Index, Physical Activity, and Risk of Multiple Myeloma , 2007, Cancer Epidemiology Biomarkers & Prevention.

[5]  N. Rothman,et al.  Common variants in genes that mediate immunity and risk of multiple myeloma , 2007, International journal of cancer.

[6]  W. Willett,et al.  A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer , 2007, Nature Genetics.

[7]  A. Reiner,et al.  Admixture mapping of an allele affecting interleukin 6 soluble receptor and interleukin 6 levels. , 2007, American journal of human genetics.

[8]  G. Colditz,et al.  Common genetic variation in IGF1, IGFBP-1, and IGFBP-3 in relation to mammographic density: a cross-sectional study , 2007, Breast Cancer Research.

[9]  Christopher A. Haiman,et al.  Haplotype-Based Association Studies of IGFBP1 and IGFBP3 with Prostate and Breast Cancer Risk: The Multiethnic Cohort , 2006, Cancer Epidemiology Biomarkers & Prevention.

[10]  Simon G. Coetzee,et al.  Interleukin-6-Related Genotypes, Body Mass Index, and Risk of Multiple Myeloma and Plasmacytoma , 2006, Cancer Epidemiology Biomarkers & Prevention.

[11]  J. Manson,et al.  Genetic variation in IL6 gene and type 2 diabetes: tagging-SNP haplotype analysis in large-scale case-control study and meta-analysis. , 2006, Human molecular genetics.

[12]  D. Altshuler,et al.  Common genetic variation in IGF1 and prostate cancer risk in the Multiethnic Cohort. , 2006, Journal of the National Cancer Institute.

[13]  D. Hunter,et al.  Sequence variants of Toll-like receptor 4 and susceptibility to prostate cancer. , 2005, Cancer research.

[14]  S. Gabriel,et al.  Efficiency and power in genetic association studies , 2005, Nature Genetics.

[15]  J. Cerhan,et al.  Anthropometric Characteristics and Risk of Multiple Myeloma , 2005, Epidemiology.

[16]  Graham A. Colditz,et al.  The Nurses' Health Study: lifestyle and health among women , 2005, Nature Reviews Cancer.

[17]  Peter Kraft,et al.  Accounting for haplotype uncertainty in matched association studies: A comparison of simple and flexible techniques , 2005, Genetic epidemiology.

[18]  The Polish Breast Cancer Consortium.  A candidate gene approach to searching for low-penetrance breast and prostate cancer genes , 2005 .

[19]  R. Bataille,et al.  CD221 (IGF-1R) is aberrantly expressed in multiple myeloma, in relation to disease severity. , 2005, Haematologica.

[20]  K. Akazawa,et al.  Polymorphisms in the IL-6 receptor (IL-6R) gene: strong evidence that serum levels of soluble IL-6R are genetically influenced , 2004, Genes and Immunity.

[21]  S. Neuhausen,et al.  Associations among IRS1, IRS2, IGF1, and IGFBP3 genetic polymorphisms and colorectal cancer. , 2004, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[22]  S. Hankinson,et al.  Insulin-like growth factors and neoplasia , 2004, Nature Reviews Cancer.

[23]  P. Donnelly,et al.  The effects of human population structure on large genetic association studies , 2004, Nature Genetics.

[24]  T. Libermann,et al.  Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. , 2004, Cancer cell.

[25]  R. Hayes,et al.  Diet and nutrition as risk factors for multiple myeloma among blacks and whites in the United States , 2001, Cancer Causes & Control.

[26]  S. Rudikoff,et al.  Insulin-like growth factor I induces migration and invasion of human multiple myeloma cells. , 2004, Blood.

[27]  J. Manson,et al.  Relationship of total and abdominal adiposity with CRP and IL-6 in women. , 2003, Annals of epidemiology.

[28]  Daniel O. Stram,et al.  Modeling and E-M Estimation of Haplotype-Specific Relative Risks from Genotype Data for a Case-Control Study of Unrelated Individuals , 2003, Human Heredity.

[29]  C. Franceschi,et al.  Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of life span control. , 2003, The Journal of clinical endocrinology and metabolism.

[30]  Kenneth C. Anderson,et al.  Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group , 2003, British journal of haematology.

[31]  Michael J Thun,et al.  Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. , 2003, The New England journal of medicine.

[32]  A. Waage,et al.  Serum insulinlike growth factor is not elevated in patients with multiple myeloma but is still a prognostic factor. , 2002, Blood.

[33]  J. Potter,et al.  Buccal cell DNA yield, quality, and collection costs: comparison of methods for large-scale studies. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[34]  S. Rudikoff,et al.  Insulinlike growth factor-I signaling in multiple myeloma: downstream elements, functional correlates, and pathway cross-talk. , 2002, Blood.

[35]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[36]  G. Morgan,et al.  Interleukin 6, tumour necrosis factor α and lymphotoxin α polymorphisms in monoclonal gammopathy of uncertain significance and multiple myeloma , 2001, British journal of haematology.

[37]  R. Baserga.  The contradictions of the insulin-like growth factor 1 receptor , 2000, Oncogene.

[38]  S. Rudikoff,et al.  Insulin-like growth factor I is a dual effector of multiple myeloma cell growth. , 2000, Blood.

[39]  M. Björkholm,et al.  Interleukin 6, tumour necrosis factor α, interleukin 1β and interleukin 1 receptor antagonist promoter or coding gene polymorphisms in multiple myeloma , 2000 .

[40]  R. Baserga.  Insulin-like growth factor I receptor signalling in prostate cancer cells. , 2000, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[41]  J S Yudkin,et al.  The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. , 1998, The Journal of clinical investigation.

[42]  J S Yudkin,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1997 by The Endocrine Society Subcutaneous Adipose Tissue Releases Interleukin-6, But Not Tumor Necrosis Factor-�, in Vivo* , 2022 .

[43]  G A Colditz,et al.  Alcohol, height, and adiposity in relation to estrogen and prolactin levels in postmenopausal women. , 1995, Journal of the National Cancer Institute.

[44]  M. Stampfer,et al.  Test of the National Death Index and Equifax Nationwide Death Search. , 1994, American journal of epidemiology.

[45]  T. Hirano.  Interleukin 6 (IL-6) and its receptor: their role in plasma cell neoplasias. , 1991, International journal of cell cloning.

[46]  R. Marquet,et al.  Interleukin-6: historical background, genetics and biological significance. , 1990, Immunology letters.

[47]  T. Hirano,et al.  Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130 , 1989, Cell.

[48]  H. Asaoku,et al.  Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas , 1988, Nature.

[49]  W. Willett,et al.  Test of the National Death Index. , 1984, American journal of epidemiology.