Genetically elevated sex hormone-binding globulin (SHBG) has been found to have a protective effect on asthma, according to a study recently published in Thorax. This may explain the tendency for asthma to affect men more during childhood and women more during adolescence and adulthood.
This observational study included individuals from 3 different data sets: 14,541 from the Avon Longitudinal Study of Parents and Children, around 500,000 from the UK Biobank, and 23,948 asthma cases from the Trans-National Asthma Genetics Consortium genome-wide association study. Longitudinal data about SHBG, asthma, and testosterone from a subset of male patients (n=512) of the first study were combined with genetic evidence and asthma through the use of Mendelian randomization. Mendelian randomization outcomes were replicated separately on samples from men (n=154,564) and women (n=180,018). A meta-analysis of the 2-sample Mendelian randomization outcomes was used to examine the causal association between SHBG and asthma.
Despite detecting a slight protective effect of elevated testosterone on asthma in participants who were adolescent men, the study researchers found no significant observational correlation between asthma and SHBG. However, 2-sample Mendelian randomization yielded evidence of a protective effect of elevated SHBG on asthma, with an inverse-variance weighted odds ratio of 0.86 (95% CI, 0.74-1.00) and a weighted median estimator odds ratio of 0.83 (95% CI, 0.72-0.96) per additional unit in natural log SHBG. A sensitivity analysis stratified by sex suggested the protective effect was predominantly present among women participants.
Limitations to this study include non-normal testosterone levels among a subsample in the Avon Longitudinal Study of Parents and Children aged at 13.8 years, the use of immunoassays, a lack of temporal discrimination in 2-sample Mendelian randomization, measurement error in the UK Biobank, and a genetic relationship between SHBG and testosterone.
The study researchers conclude that “increased circulating SHBG is causally associated with a decreased risk of asthma, with effects stronger in females. Although findings from the observational epidemiological analysis indicated little evidence of an effect of SHBG on asthma and only weak evidence for a protective effect of increased testosterone on asthma in the subsample of males, genetic epidemiological approach indicated some evidence of a protective effect of increased SHBG on asthma. These findings from multiple independent data sets align with previous hypotheses suggesting that fluctuating sex hormones, particularly during puberty, may promote asthma development in females.”
Arathimos R, Granell R, Haycock P, et al. Genetic and observational evidence supports a causal role of sex hormones on the development of asthma [published online April 1, 2019]. Thorax. doi: 10.1136/thoraxjnl-2018-212207