Interactions of Interleukin-6 Promoter Polymorphisms With Dietary and Lifestyle Factors and Their Association With Bone Mass in Men and Women From the Framingham Osteoporosis Study

Authors

  • Serge L Ferrari,

    Corresponding author
    1. Division of Bone Diseases and WHO Collaborating Center for Osteoporosis, Departments of Geriatrics and Internal Medicine, Geneva University Hospital, Geneva, Switzerland
    • Division of Bone Diseases, University Hospital, 21, rue Micheli-du-Crest, Geneva 1211, Switzerland
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  • David Karasik,

    1. Division of Aging, Harvard Medical School, Hebrew Rehabilitation Center for Aged Research and Training Institute, Boston, Massachusetts, USA
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  • Jun Liu,

    1. Department of Neurology, Framingham Heart Study Genetics Laboratory, Boston University School of Medicine, Boston, Massachusetts, USA
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  • Samev Karamohamed,

    1. Department of Neurology, Framingham Heart Study Genetics Laboratory, Boston University School of Medicine, Boston, Massachusetts, USA
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  • Alan G Herbert,

    1. Department of Neurology, Framingham Heart Study Genetics Laboratory, Boston University School of Medicine, Boston, Massachusetts, USA
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  • L Adrienne Cupples,

    1. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA
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  • Douglas P Kiel

    1. Division of Aging, Harvard Medical School, Hebrew Rehabilitation Center for Aged Research and Training Institute, Boston, Massachusetts, USA
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  • The authors have no conflict of interest.

Abstract

Lifestyle and dietary factors may influence the association of IL-6 polymorphisms with bone mass. In 1574 unrelated men and women from the Framingham Offspring Cohort, we observed significant hip BMD differences between IL-6 −174 genotypes only in older women, those without estrogens, and those with a poor calcium intake. Hence, association of IL-6 polymorphisms with BMD may be limited to discrete population subgroups.

Introduction: Interleukin (IL)-6 plays a central role in the pathogenesis of osteoporosis. Two functional variants in the IL-6 promoter have previously been associated with IL-6 expression, bone resorption levels, and BMD in late postmenopausal women, but results were conflicting in different populations. We hypothesized that the association between IL-6 promoter alleles and BMD may be affected by interactions with lifestyle and dietary factors known to influence bone turnover.

Materials and Methods: Among the Offspring Cohort of the Framingham Heart Study, 1574 unrelated men and women were genotyped for IL-6 −572 and −174 alleles. Interaction analyses with years since menopause, estrogen status, physical activity, smoking, dietary calcium, vitamin D, and alcohol intake were based on BMD measurements at the hip.

Results and Conclusions: In models that considered only the main effects of IL-6 polymorphisms, no significant association with BMD was observed in either gender. In contrast, p values (0.003–0.096 by ANOVA) suggestive of an interaction between IL-6 −174 genotypes and years since menopause, estrogen status, dietary calcium, and vitamin D intake were observed in women (n = 819). In turn, BMD was significantly lower with genotype −174 GG compared with CC, and intermediate with GC, in women who were more than 15 years past menopause and in those without estrogens or with calcium intake <940 mg/day. In estrogen-deficient women with poor calcium intake, BMD differences between genotypes CC and GG were 10.2% at femoral neck (p = 0.012), 12.0% at trochanter (p = 0.012), and 16.8% at Ward's area (p = 0.0014). In contrast, no such interactions were observed in men (n = 755). In conclusion, IL-6 genetic variation was prominently associated with hip BMD in late postmenopausal women, those without estrogen replacement therapy, and those with inadequate calcium intake. In contrast, IL-6 polymorphisms are unlikely to be significant determinants of bone mass in other women or men.

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