Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes

Abstract

Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 × 10−5], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.

Multiple genetic variants explain measurable variance in type 2 diabetes-related traits in Pakistanis

“…This principle of Mendelian randomisation has been used to assess the causal relationship between several related metabolic phenotypes, e.g. C-reactive protein and heart disease [3], and sex hormone-binding globulin levels and diabetes [4]. Most recently, studies have combined multiple risk variants in a 'genetic risk score' to provide more power compared with individual variants.…”

Impact of Genetic Polymorphisms on Insulin Resistance

“…In addition, rs6259, rs6257 and rs1799941 polymorphisms in the SHBG gene were strongly associated with SHBG levels and type 2 diabetes (Zeggini et al, 2008;Perry et al, 2010). However, there was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance (Perry et al, 2010).…”

“…Moreover, polycystic ovarian syndrome was associated with higher risk of type 2 diabetes and insulin resistance in women (Dunaif, 1995). Recent studies have demonstrated that higher levels of circulating sex hormone binding protein (SHBG) were associated with reduce risk of type 2 diabetes (Ding et al, 2009;Perry et al, 2010). In addition, rs6259, rs6257 and rs1799941 polymorphisms in the SHBG gene were strongly associated with SHBG levels and type 2 diabetes (Zeggini et al, 2008;Perry et al, 2010).…”

“…Recent studies have demonstrated that higher levels of circulating sex hormone binding protein (SHBG) were associated with reduce risk of type 2 diabetes (Ding et al, 2009;Perry et al, 2010). In addition, rs6259, rs6257 and rs1799941 polymorphisms in the SHBG gene were strongly associated with SHBG levels and type 2 diabetes (Zeggini et al, 2008;Perry et al, 2010). However, there was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance (Perry et al, 2010).…”

Genetic factors of hyperandrogenism development among women

“…Глобулін, що зв'язує статеві стероїди (ГЗСС), являє собою глікопротеїд, який регулює біодоступність андрогенів шляхом зв'язування статевих стероїдів [9,33,34]. Дослідження показали, що зниження рівня сироваткового ГЗСС асоційоване з ризиком розвитку СПКЯ у жінок, а також цукрового діабету (ЦД) 2 типу у чоловіків і жінок [22,17,35,36].…”