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1.  Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes 
Human Molecular Genetics  2009;19(3):535-544.
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.
doi:10.1093/hmg/ddp522
PMCID: PMC2798726  PMID: 19933169
2.  Epidemiological Study Designs to Investigate Gene–Behavior Interactions in the Context of Human Obesity 
Obesity (Silver Spring, Md.)  2008;16(Suppl 3):S66-S71.
The epidemiology of obesity suggests that, for the majority of individuals, the disorder arises from an interaction between genetic predisposition and lifestyle behaviors such as dietary intake and physical activity. Unravelling the molecular basis of such interactions is complex but is becoming a realistic proposition as evidence emerges from whole genome association studies of genetic variants that are definitively associated with obesity. A range of possible study designs is available for investigating gene–lifestyle interaction, and the strengths and weaknesses of each approach are discussed in this article. Given the likely small main effect of common genetic variants and the difficulties in demonstrating associations of lifestyle factors with future risk of obesity, we would favor an analytical approach based on the clear specification of prior probabilities to reduce the likelihood of false discovery. Mixed approaches combining data from large-scale observational studies with smaller intervention trials may be ideal. In designing new studies to investigate these issues, a key choice is how precisely to quantify the important, but difficult to measure lifestyle behaviors. It is clear from power calculations that an approach based on enhancing precision of measurement of diet and physical activity is critical.
The high heritability of obesity coupled with the rapid increase in prevalence suggests that a combination of genetic and behavioral factors is critical to the etiology of obesity (1). It is easy to propose such a model for the development of obesity, but it is altogether much harder to identify the molecular mechanisms that underlie such a model. In this article, we review overall strategies and possible epidemiological study designs for investigating how genetic and behavioral risk factors combine to lead to excess weight gain.
doi:10.1038/oby.2008.521
PMCID: PMC2703295  PMID: 19037217

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