Original Article (NEJM-8/5/09)Presented by Zainab Basheer (Research volunteer)
Sex Hormone–Binding Globulin and Risk of Type 2 Diabetes in Women and Men Eric L. Ding, Sc.D., Yiqing Song, M.D., Sc.D., JoAnn E. Manson, M.D., Dr.P.H., David J. Hunter, M.B., B.S., Sc.D., Cathy C. Lee, M.D., Nader Rifai, Ph.D., Julie E. Buring, Sc.D., J. Michael Gaziano, M.D., M.P.H., and Simin Liu, M.D., Sc.D.
Background Circulating SHBG levels are inversely associated with insulin resistance, but whether these levels can predict the risk of developing type 2 diabetes is uncertain.
Methods Study Population The Womens Health Study begun in 1993 39,876 female >28,345 >12,304 were postmenopausal and were not using hormone-replacement therapy at the time of blood collection . 10 yr f/u period, 366 cases new DM 2 Using risk set sampling , 359 case patients and 359 matched controls were selected .■ Physicians Health Study II of men begun in 1997 14,641 US male physicians> 11,130 8 yr f/u period, 170 new DM 2 Using risk set sampling ,170 cases and 170 matched controls were selected
Methods (con)Laboratory Procedures Plasma levels of sex hormone–binding globulin were measured with the use of a chemiluminescent immunoassay validated for plasma sex hormone–binding globulin Genotyping of SHBG polymorphisms of women and replication genotyping of men were conducted in two separate labs using PCR amplification. Five SNPs were genotyped in women namely rs6257 , rs6258 , rs6259 , rs6260 , rs9282845 Two informative SNPs, rs6257 and rs6259, were included in the study
Methods(con)■ Statistical analysis The distributions of plasma SHBG levels among controls into quartiles and compared baseline characteristics across the quartiles Simple and multivariable models in women, Simple and multivariable models in men Sensitivity models
Methods (con) In mendelian randomisation analyses SHBG variants seem to satisfy 3 main criteria :- 1) Genotypes should be robustly associated with the intermediate phenotype 2) No confounding factors b/w the intermediate phenotype and disease outcome 3) It’s effect on the clinical outcome only thru the specific intermediate phenotype■ The mendelian randomization estimate reflects the potential causal effect of SHBG levels on the risk of type 2 diabetes
Discussion The risk for type 2 DM in participants with highest SHBG quartile is 1/10 compared to the ones with lowest SHBG quartile Variants of SHBG SNP’ rs6257 & rs6259 were associated with a risk of type 2 DM depending on their respective effects on SHBG levels. The strong relation b/w plasma SHBG levels and type 2 DM confirmed both in multivariable analyses and in mendelian randomization analyses.
Discussion SHBG plasma levels appeared to have a predictive ability for the risk of type 2 DM beyond that of traditional risk factors, including HbA1c & CRP£ Limitation Statistical power < 600 newly diagnosed type 2 DM in the 2 cohorts Biomarkers, plasma SHBG levels were modestly correlated with adiposity
Conclusions Low circulating levels of sex hormone–binding globulin are a strong predictor of the risk of type 2 diabetes in women and men. The clinical usefulness of both SHBG genotypes and plasma levels in stratification and intervention for the risk of type 2 diabetes warrants further examination.