Winham Stacey J, Preuss Ulrich W, Geske Jennifer R, Zill Peter, Heit John A, Bakalkin Georgy, Biernacka Joanna M, Karpyak Victor M
Health Sciences Research, Mayo Clinic, Rochester, MN.
Department of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University of Halle-Wittenberg, Halle/Saale, Germany.
Sci Rep. 2015 Oct 27;5:15670. doi: 10.1038/srep15670.
We previously demonstrated that prodynorphin (PDYN) haplotypes and single nucleotide polymorphism (SNP) rs2281285 are associated with alcohol dependence and the propensity to drink in negative emotional states, and recent studies suggest that PDYN gene effects on substance dependence risk may be sex-related. We examined sex-dependent associations of PDYN variation with alcohol dependence and related phenotypes, including negative craving, time until relapse after treatment and the length of sobriety episodes before seeking treatment, in discovery and validation cohorts of European ancestry. We found a significant haplotype-by-sex interaction (p = 0.03), suggesting association with alcohol dependence in males (p = 1E-4) but not females. The rs2281285 G allele increased risk for alcohol dependence in males in the discovery cohort (OR = 1.49, p = 0.002), with a similar trend in the validation cohort (OR = 1.35, p = 0.086). However, rs2281285 showed a trend towards association with increased negative craving in females in both the discovery (beta = 10.16, p = 0.045) and validation samples (OR = 7.11, p = 0.066). In the discovery cohort, rs2281285 was associated with time until relapse after treatment in females (HR = 1.72, p = 0.037); in the validation cohort, it was associated with increased length of sobriety episodes before treatment in males (beta = 13.49, p = 0.001). Our findings suggest that sex-dependent effects of PDYN variants in alcohol dependence are phenotype-specific.
我们之前证明，强啡肽原（PDYN）单倍型和单核苷酸多态性（SNP）rs2281285与酒精依赖以及在负性情绪状态下饮酒的倾向相关，并且最近的研究表明，PDYN基因对物质依赖风险的影响可能与性别有关。我们在欧洲血统的发现队列和验证队列中，研究了PDYN变异与酒精依赖及相关表型（包括负性渴求、治疗后复发时间以及寻求治疗前戒酒期的长度）之间的性别依赖性关联。我们发现了一个显著的单倍型与性别的交互作用（p = 0.03），表明其与男性的酒精依赖相关（p = 1×10⁻⁴），而与女性无关。在发现队列中，rs2281285的G等位基因增加了男性酒精依赖的风险（OR = 1.49，p = 0.002），在验证队列中有类似趋势（OR = 1.35，p = 0.086）。然而，rs2281285在发现样本（β = 10.16，p = 0.045）和验证样本（OR = 7.11，p = 0.066）中均显示出与女性负性渴求增加相关的趋势。在发现队列中，rs2281285与女性治疗后复发时间相关（HR = 1.72，p = 0.037）；在验证队列中，它与男性治疗前戒酒期长度增加相关（β = 13.49，p = 0.001）。我们的研究结果表明，PDYN变异在酒精依赖中的性别依赖性影响是表型特异性的。
