2. 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.
3. 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.
4. Methods
Study Population
The Women's 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
5. 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
6. 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
7. 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
14. 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.
15. 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
16. 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.
