Associations of plasma sex-related hormone and protein levels and alcohol dependence.

BACKGROUND AND AIMS: Sex-related hormones and proteins may underlie sex differences in alcohol use disorder characteristics and consequences. Previous reports suggest steroid sex hormones may influence alcohol consumption behaviors while proteins that regulate their circulation levels are rarely investigated. Following up on our earlier study of individual sex-related hormones' associations with alcohol dependence (AD), this study measured the associations between the combinations of sex-related hormones and proteins and AD in a larger sample.

DESIGN

Sex-stratified case-control comparison and clustering of plasma sex-related hormone and protein levels, plus a genome-wide association study on the AD-associated hormone and protein combinations.

SETTING

Addiction treatment programs in the United States.

PARTICIPANTS

Four hundred treatment-seeking recently abstained AD patients (median = 24.5 days) and 388 age-and-sex-matched controls from a community biobank (male:female ≈ 2:1).

MEASUREMENTS: Plasma levels of total testosterone, estrone (E1), estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin (SHBG) and albumin.

FINDINGS: In males, we found higher E2 [β = 0.13, Punadjusted < 0.001, false discovery rate (FDR) = 0.005], progesterone (β = 0.01, Punadjusted = 0.025, FDR = 0.054), LH (β = 0.12, Punadjusted = 0.017, FDR = 0.044) and albumin (β = 0.09, Punadjusted < 0.001, FDR = 0.005) in AD patients than controls; in females, we observed lower E1 (β = -0.24, Punadjusted = 0.024, FDR = 0.113) and progesterone (β = -1.86, Punadjusted = 0.026, FDR = 0.113) and higher albumin (β = 0.18, Punadjusted < 0.001, FDR = 0.001) in AD patients than controls. Three principal components (PCs), reflecting hormone signatures, were statistically significantly associated with AD in each sex: PC1 (TT, E2 and SHBG; β = -0.15, P = 0.016), PC3 (E1, progesterone and albumin; β = 0.28, P = 0.007) and PC4 (SHBG and albumin; β = 0.34, P = 0.001) in males; PC3 (progesterone and albumin; β = -0.38, P = 0.009), PC4 (TT and albumin; β = -0.49, P = 0.001) and PC5 (TT and progesterone; β = 0.54, P = 0.004) in females. Statistically significant SNP × group associations were found in females between PC4 and polymorphisms in RP51004I9.1 (top SNP: rs6082693; P = 5.41E-12) and in males between PC3 and a genomic locus that contained SLC35E4, DUSP18 and OSBP2 (top SNP: rs13053277; P = 1.77E-07).

CONCLUSIONS

Three sex-related hormone and protein signatures appear to be associated with alcohol dependence in each sex. Peripheral levels of sex-related hormones and proteins, as well as their combinations, could be altered in people with alcohol dependence who have abstained for a few weeks compared with controls, and such differences may be sex-specific.