Investigation of Genetic Variants, Birthweight and Hypothalamic-Pituitary-Adrenal Axis Function Suggests a Genetic Variant in the SERPINA6 Gene Is Associated with Corticosteroid Binding Globulin in the Western Australia Pregnancy Cohort (Raine) Study

Abstract

BackgroundThe hypothalamic-pituitary-adrenal (HPA) axis regulates stress responses and HPA dysfunction has been associated with several chronic diseases. Low birthweight may be associated with HPA dysfunction in later life, yet human studies are inconclusive. The primary study aim was to identify genetic variants associated with HPA axis function. A secondary aim was to evaluate if these variants modify the association between birthweight and HPA axis function in adolescents.MethodsMorning fasted blood samples were collected from children of the Western Australia Pregnancy Cohort (Raine) at age 17 (n = 1077). Basal HPA axis function was assessed by total cortisol, corticosteroid binding globulin (CBG), and adrenocorticotropic hormone (ACTH). The associations between 124 tag single nucleotide polymorphisms (SNPs) within 16 HPA pathway candidate genes and each hormone were evaluated using multivariate linear regression and penalized linear regression analysis using the HyperLasso method.ResultsThe penalized regression analysis revealed one candidate gene SNP, rs11621961 in the CBG encoding gene (SERPINA6), significantly associated with total cortisol and CBG. No other candidate gene SNPs were significant after applying the penalty or adjusting for multiple comparisons; however, several SNPs approached significance. For example, rs907621 (p = 0.002) and rs3846326 (p = 0.003) in the mineralocorticoid receptor gene (NR3C2) were associated with ACTH and SERPINA6 SNPs rs941601 (p = 0.004) and rs11622665 (p = 0.008), were associated with CBG. To further investigate our findings for SERPINA6, rare and common SNPs in the gene were imputed from the 1,000 genomes data and 8 SNPs across the gene were significantly associated with CBG levels after adjustment for multiple comparisons. Birthweight was not associated with any HPA outcome, and none of the gene-birthweight interactions were significant after adjustment for multiple comparisons.ConclusionsOur study suggests that genetic variation in the SERPINA6 gene may be associated with altered CBG levels during adolescence. Replication of these findings is required.

Emerging Role of Corticosteroid-Binding Globulin in Glucocorticoid-Driven Metabolic Disorders

“…Further investigation using part of the cohort showed that common SNPs in this locus were associated with variation in plasma CBG concentrations. These data were replicated in a recent candidate gene study, where SNPs within the SERPINA6 gene were also found associated with morning cortisol and CBG concentrations in a cohort of 1,077 adolescents (20). …”

An ancestry‐based approach for detecting interactions

“…For the GALA II Puerto Ricans, rs17091085 showed an interaction associated with the methylation state of SERPINA6 (Table ). Of note, interaction between birth weight and SERPINA6 has been previously associated with hypothalamic‐pituitary‐adrenal axis function (Anderson et al., ). Further investigations of our interaction findings are thus warranted.…”

An Ancestry Based Approach for Detecting Interactions

“…For the GALA II Puerto Ricans, rsl7091085 showed an interaction associated with the methylation state of SERP1NA6. Of note, interaction between birth weight and SERP1NA6 has been previously associated with Hypothalamic-Pituitary-Adrenal axis function[30]. Further investigations of our interaction findings are thus warranted.…”