Desrivières Sylvane, Krause Kristina, Dyer Anne, Frank Josef, Blomeyer Dorothea, Lathrop Mark, Mann Karl, Banaschewski Tobias, Laucht Manfred, Schumann Gunter
Section of Addiction Biology, Interdisciplinary Research Group Addiction and NIHR-Biomedical Research Centre, Institute of Psychiatry, King's College, London, United Kingdom.
PLoS One. 2008 Mar 12;3(3):e1769. doi: 10.1371/journal.pone.0001769.
While the phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway is typically known to regulate cell growth and survival, emerging evidence suggest a role for this pathway in regulating the behavioural responses to addictive drugs.
METHODOLOGY/PRINCIPAL FINDINGS: To investigate whether PI3K contributes to patterns of risky alcohol drinking in human, we investigated genetic variations in PIK3R1, encoding the 85 kD regulatory subunit of PIK, in 145 family trios consisting of 15-16 year old adolescents and their parents. Screening for mutations in exons, exon-intron boundaries and regulatory sequences, we identified 14 single nucleotide polymorphisms (SNPs) in the PIK3R1 gene region from exon 1 to the beginning of the 3' untranslated region (UTR). These SNPs defined haplotypes for the respective PIK3R1 region. Four haplotype tagging (ht)SNPs (rs706713, rs2302975, rs171649 and rs1043526), discriminating all haplotypes with a frequency >or=4.5% were identified. These htSNPs were used to genotype adolescents from the "Mannheim Study of Risk Children" (MARC). Transmission disequilibrium tests in these adolescents and their parents demonstrated sex-specific association of two SNPs, rs2302975 and rs1043526, with patterns of risky alcohol consumption in male adolescents, including lifetime prevalence of drunkenness (p = 0.0019 and 0.0379, respectively) and elevated maximum amount of drinking (p = 0.0020 and 0.0494, respectively), as a measure for binge drinking pattern.
CONCLUSIONS/SIGNIFICANCE: Our findings highlight a previously unknown relevance of PIK3R1 genotypes for alcohol use disorders and might help discriminate individuals at risk for alcoholism.
虽然磷脂酰肌醇3激酶（PI3K）依赖性信号通路通常被认为可调节细胞生长和存活，但新出现的证据表明该通路在调节对成瘾性药物的行为反应中发挥作用。
方法/主要发现：为了研究PI3K是否在人类危险饮酒模式中起作用，我们在由15 - 16岁青少年及其父母组成的145个家庭三联体中，研究了编码PI3 85 kD调节亚基的PIK3R1基因的遗传变异。通过筛选外显子、外显子 - 内含子边界和调控序列中的突变，我们在PIK3R1基因区域从外显子1到3'非翻译区（UTR）起始处鉴定出14个单核苷酸多态性（SNP）。这些SNP定义了各自PIK3R1区域的单倍型。确定了四个能够区分所有频率≥4.5%单倍型的单倍型标签（ht）SNP（rs706713、rs2302975、rs171649和rs1043526）。这些htSNP用于对来自“曼海姆风险儿童研究”（MARC）的青少年进行基因分型。对这些青少年及其父母进行的传递不平衡检验表明，两个SNP，rs2302975和rs1043526，与男性青少年的危险饮酒模式存在性别特异性关联，包括终身醉酒患病率（分别为p = 0.0019和0.0379）以及饮酒最大量升高（分别为p = 0.0020和0.0494），以此作为暴饮模式的衡量指标。
结论/意义：我们的研究结果突出了PIK3R1基因型与酒精使用障碍之前未知的相关性，并可能有助于鉴别酗酒风险个体。
