Clinical Laboratory Strategies: November 24, 2009

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Analyzing the Role of Sex Hormone-Binding Globulin in Type 2 Diabetes Risk Prediction
Plasma Levels and Genotype Variants Associated with Increased Risk
By Genna Rollins

Previous research has demonstrated an inverse relationship between sex hormone-binding globulin (SHBG) levels and impaired glucose control, but SHBG’s role in predicting the risk of type 2 diabetes has not been examined extensively. Now, new research explores the link between SHBG levels and SHBG polymorphisms and the risk of developing type 2 diabetes. The findings are the subject of this issue of Strategies.

Although risk factors for developing type 2 diabetes are well recognized, the hunt has been on for additional predictors that can identify individuals at risk earlier and with higher sensitivity so that preventive measures can be implemented. One such possible predictor is sex hormone-binding globulin (SHBG), a protein that binds to sex hormones and controls their levels circulating throughout the body. Studies since the mid-1990s have implied that SHBG may have a role beyond its primary function in regulating amounts of free sex hormones, and accumulating evidence has linked low circulating levels of SHBG to impaired glucose control. Previous research also has indicated that genetic variations may influence circulating levels of SHBG. The authors of a recent study explored both plasma SHBG levels and SHBG polymorphisms as risk factors for developing type 2 diabetes (N Engl J Med 2009;361:1152-63).

"There are no studies available directly examining the role of the genes coding for sex steroids or SHBG in relation to diabetes risk," explained senior author, Simin Liu, MD, ScD, professor of medicine at the David Geffen School of Medicine and director of the Center for Metabolic Disease Prevention at UCLA. "There were no long-term prospective studies that had comprehensively evaluated the role of circulating sex steroids and SHBG in the development of diabetes, although there have been quite a number of clinical observations available showing that sex hormones are associated with insulin resistance."

The researchers also were intrigued by well-described sex-specific differences in the development of type 2 diabetes and its various complications. "This is sort of a paradox: adiposity is a stronger risk factor for type 2 diabetes risk in women than in men. Women are at much lower risk of developing cardiovascular disease than men, but once they develop type 2 diabetes their risk doubles or quadruples. This caught our attention," said Liu.

To explore these issues, the researchers conducted a nested-case control study on data from the Women’s Health Study (WHS), a landmark investigation of the effects of low-dose aspirin and vitamin E in preventing cardiovascular disease (CVD) and cancer among nearly 40,000 female health professionals. For the present study, the researchers randomly selected 359 controls from WHS participants who did not develop type 2 diabetes and matched them based on age, duration of study follow-up, race, and fasting status at the time of initial blood draw to 359 case patients newly diagnosed with type 2 diabetes. A replication study subsequently was performed using data from the all-male Physicians’ Health Study II, with 170 cases and controls, respectively.

The investigators used a chemiluminescent immunoassay to measure plasma levels of SHBG. Genotyping of five SHBG polymorphisms –rs6257, rs6259, rs6260, rs6258, and rs9282845– also was performed. In addition, the researchers employed a complex mendelian randomization analysis to use genetic variants as randomization instruments to estimate the potential causal link between SHBG plasma levels and the risk of type 2 diabetes.

One of the principal findings of the analysis was that higher levels of SHBG were "strongly and consistently" associated with a lower risk of type 2 diabetes in both female and male participants. Among female subjects, the multivariable odds ratios of type 2 diabetes ranged from 1.00 for the lowest quartile to 0.09 in the highest quartile, a 10-fold difference. Among male subjects the odds ratio for the highest versus lowest quartile was 0.10. The findings remained "highly robust" in multiple sensitivity analyses and were consistent across subgroups, according to the authors.

A second key finding was that carriers of the rs6257 variant allele had a 10% lower plasma level of SHBG than wild-type homozygotes. Carrying of the variant allele appeared to increase the risk of type 2 diabetes in both women and men. Conversely, carriers of the rs6259 variant allele had a 10% higher plasma level of SHBG and a lower risk of type 2 diabetes. Using the rs6257 and rs6259 alleles as randomization instruments in the mendelian randomization analysis, the researchers found that the predicted odds ratio of type 2 diabetes based on increased plasma levels of SHBG was 0.28 in women and 0.29 in men. "By using this analysis, we explained almost all the potential sex-specific differences in the risk of developing type 2 diabetes," observed Liu.

The investigators also evaluated whether plasma levels of SHBG improved the relative prediction of type 2 diabetes in all models, including the base model with traditional risk factors, and separate expanded models that used C-reactive protein (CRP) and HbA1c, respectively, in addition to traditional risk factors, as well as a comprehensive model that included both CRP and HbA1c with traditional risk factors. In this series of analyses, the investigators found that SHBG plasma levels added predictive value beyond traditional risk factors, CRP and HbA1c.

According to the authors, these results suggest a new understanding of the role of SHBG. "Classical thinking and teaching in medicine has never focused on SHBG in the development of any disease, let alone type 2 diabetes. It has always been seen as a bystander, as a carrier protein," explained Liu. But this study found that both circulating SHBG protein levels and SHBG plasma levels predict type 2 diabetes, reflecting both the genetic risk that stays with an individual throughout his or her lifetime, as well as potentially modifiable environmental risk factors.

Although the findings are "very important from a biomarker development standpoint," further investigation is needed to fully understand their implications, according to Scott M. Kahn, PhD, director of basic urologic research at St. Luke's-Roosevelt Health Science Center and assistant professor of clinical urology at Columbia University. "Are lower SHBG plasma concentrations themselves causative for the disease state? Might they instead only mirror th degree of local expression of SHBG within specific tissues, and could this be where functionality arises? Or, might plasma SHBG concentrations simply serve as a downstream marker of the disease? I don’t know whether those questions are clear from these results." Kahn’s research has focused on examining SHBG expression in hormonally responsive tissue like the breast and prostate. "The factors that regulate SHBG expression within individual tissues requires further investigation, and the functionality of intracellular SHBG, for example, on hormonal responsiveness, needs to be addressed. That information will give us insight into why one sees these types of relationships between SHBG and, in this case, diabetes," he added.

Liu agrees that more work is needed in understanding the potential regulators of gene expression for SHBG. The researchers also hope to have their findings verified in larger studies with more diverse populations, since both the WHS and Physicians Health Study II had primarily Caucasian subjects. Should these steps take place, Liu envisions a day when both plasma and genotyping analysis of SHBG will be part of routine screening for type 2 diabetes. "This marker, SHBG, would not only become a marker for genetic susceptibility, but also one of how genes and environmental exposure interact, thus presenting opportunity for developing preventive and therapeutic measures," he said.

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