Sex hormone-binding globulin associations with circulating lipids and metabolites and the risk for type 2 diabetes: observational and causal effect estimates

Qin Wang, Antti J Kangas, Pasi Soininen, Mika Tiainen, Tuulia Tynkkynen, Katri Puukka, Aimo Ruokonen, Jorma Viikari, Mika Kähönen, Terho Lehtimäki, Veikko Salomaa, Markus Perola, George Davey Smith, Olli T Raitakari, Marjo-Riitta Järvelin, Peter Würtz, Johannes Kettunen, Mika Ala-Korpela

Research output: Contribution to journalArticle (Academic Journal)peer-review

56 Citations (Scopus)

Abstract

BACKGROUND: The causal role of circulating sex hormone-binding globulin (SHBG) for type 2 diabetes is controversial. Information on the relations between SHBG and new biomarkers of cardiometabolic risk is scarce.

METHODS: We applied quantitative nuclear magnetic resonance metabolomics in three Finnish population-based cohorts to comprehensively profile circulating lipids and metabolites and study their associations with SHBG. Mendelian randomization was used to examine potential causality of SHBG on the metabolic measures and insulin resistance. Prospective associations and causal effect estimates of SHBG on type 2 diabetes were assessed via meta-analysis including summary statistics from the DIAGRAM consortium.

RESULTS: In cross-sectional analysis in 6475 young adults (mean age 31, 57% men), higher SHBG was linked with a more favourable cardiometabolic risk profile, including associations with lipoprotein subclasses, fatty acid composition, amino acids, ketone bodies and inflammation-linked glycoproteins. Prospective analysis of 1377 young adults with 6-year follow-up indicated that SHBG is also associated with future insulin resistance. Mendelian randomization suggested only minor, if any, causal effects of SHBG on lipid and metabolite measures and insulin resistance(n = 10,895).Causal effect estimates on type 2 diabetes for 41,439 cases and 103,870 controls indicated a causative protective role of SHBG (OR = 0.83 per 1-SD, 95% CI: 0.76, 0.91); however, effects were considerably weaker than observed in meta-analysis of prospective studies [hazard ratio (HR) = 0.47 per 1-SD, 95% CI: 0.41, 0.53].

CONCLUSION: Circulating SHBG is strongly associated with systemic metabolism and predictive for insulin resistance and diabetes. The weaker causal estimates suggest that the observational associations are partly confounded rather than conferred directly via circulating SHBG.

Original languageEnglish
Pages (from-to)623-37
Number of pages15
JournalInternational Journal of Epidemiology
Volume44
Issue number2
DOIs
Publication statusPublished - Apr 2015

Keywords

  • Adaptor Proteins, Signal Transducing
  • Adolescent
  • Adult
  • Cross-Sectional Studies
  • Diabetes Mellitus, Type 2
  • Female
  • Finland
  • Humans
  • Insulin Resistance
  • Lipid Metabolism
  • Magnetic Resonance Imaging
  • Male
  • Mendelian Randomization Analysis
  • Metabolomics
  • Risk Factors
  • Sex Hormone-Binding Globulin
  • Young Adult

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