@Valentijn, is it possible to find this gene in the 23andme data? Endocr Res. 2004 Aug;30(3):417-29. Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism. Torpy DJ1, Bachmann AW, Gartside M, Grice JE, Harris JM, Clifton P, Easteal S, Jackson RV, Whitworth JA. Author information Abstract Chronic fatigue syndrome (CFS) is characterized by idiopathic fatigue of greater than 6 months' duration with postexertional exacerbation and many other symptoms. A trend toward relative hypocortisolism is described in CFS. Twin and family studies indicate a substantial genetic etiologic component to CFS. Recently, severe corticosteroid-binding globulin (CBG) gene mutations have been associated with CFS in isolated kindreds. Human leukocyte elastase, an enzyme important in CBG catabolism at inflammatory sites, is reported to be elevated in CFS. We hypothesized thatCBG gene polymorphisms may act as a genetic risk factor for CFS. A total of 248 patients with CFS defined by Centers for Disease Control criteria, and 248 controls were recruited. Sequencing and restriction enzyme testing of the CBG gene coding region allowed detection of severe CBG gene mutations and a common exon 3 polymorphism (c.825G-->T, Ala-Ser224). Plasma CBG levels were measured in 125 CFS patients and 198 controls by radioimmunoassay. Total and free (calculated and measured) cortisol levels were ascertained in single samples between 8-10 a.m. The age of onset (mid 30s) and gender ratio (2.2:1, female:male) of the patients were similar to those reported in U.S. epidemiologic studies. A trend toward a preponderance of serine224 homozygosity among the CFS patients was noted, compared with controls (chi2 = 5.31, P = 0.07). Immunoreactive-CBG(IR-CBG) levels were higher in Serine/Alanine (Ser/Ala) than Ala/Ala subjects and higher again in Ser/Ser subjects, this effect was strongest in controls; Ser/Ser: 46.1+/-1.8 (n = 31, P = 0.03) vs. Ser/Ala: 42.4+/-1.0 (n = 56, P = 0.05) vs. Ala/Ala: 40.8+/-1.7 microg/mL (n = 21). Despite higherCBG levels, there was a nonsignificant trend toward lower total and free plasma cortisol in serine allele positive patients, total cortisol: Ser/Ser: 13.3+/-1.4 (n = 34) vs. Ser/Ala: 14.0+/-0.7 (n = 66) vs. Ala/Ala: 15.4+/-1.0 (n = 23). Homozygosity for the serine allele of the CBG gene may predispose to CFS, perhaps due to an effect on hypothalamic-pituitary-adrenal axis function related to altered CBG-cortisol transport function or immune-cortisol interactions. Mol Cell Endocrinol. 2010 Mar 5;316(1):24-34. doi: 10.1016/j.mce.2009.07.015. Epub 2009 Jul 28. Corticosteroid-binding globulin: the clinical significance of altered levels and heritable mutations. Gagliardi L1, Ho JT, Torpy DJ. Author information Abstract Corticosteroid-binding globulin (CBG) is the specific high-affinity plasma transport glycoprotein for cortisol. Stress-induced falls in CBG levels may heighten hypothalamic-pituitary-adrenal axis responses and CBG:tissue interactions may allow targeted cortisol delivery. Three genetic variants ofCBG have been identified that reduce cortisol binding affinity and/or CBG levels. These include the Leuven and Lyon mutations which reduceCBG:cortisol binding affinity 3- and 4-fold, respectively, and the null mutation resulting in a 50% (heterozygote) or 100% (homozygote) reduction inCBG levels. The three reported null homozygotes demonstrate that complete CBG deficiency is not lethal, although it may be associated with hypotension and fatigue. The phenotype of a CBG null murine model included fatigue and immune defects. One community-based study revealed that severe CBG mutations are rare in idiopathic fatigue disorders. The mechanisms by which CBG mutations may cause fatigue are unknown. There are preliminary data of altered CBG levels in hypertension and in the metabolic syndrome; however, the nature of these associations is uncertain. Further studies may clarify the functions of CBG, and clinical observations may validate and/or extend the phenotypic features of various CBGmutations. Crown Copyright 2009. Published by Elsevier Ireland Ltd. All rights reserved.