In:
Alcoholism: Clinical and Experimental Research, Wiley, Vol. 42, No. 6 ( 2018-06), p. 1034-1043
Abstract:
The gene encoding phosphatidylinositol‐4‐phosphate 5‐kinase ( PIP 5K1C ) has been recently implicated in pain regulation. Interestingly, a recent cross‐tissue and cross‐phenotypic epigenetic analysis identified the same gene in alcohol use disorder ( AUD ). Given the high comorbidity between AUD and chronic pain, we hypothesized that genetic variation in PIP 5K1C might contribute to susceptibility to AUD . Methods We conducted a case–control association study of genetic variants in PIP 5K1C . Association analyses of 16 common PIP 5K1C single nucleotide polymorphisms ( SNP s) were conducted in cases and controls of African (427 cases and 137 controls) and European ancestry (488 cases and 324 controls) using standard methods. In addition, given the prominent role of the opioid system in pain signaling, we investigated the effects of acute alcohol exposure on PIP 5K1C expression in humanized transgenic mice for the μ ‐opioid receptor that included the OPRM 1 A118G polymorphism, a widely used mouse model to study analgesic response to opioids in pain. PIP 5K1C expression was measured in the thalamus and basolateral amygdala ( BLA ) in mice after short‐term administration (single 2 g/kg dose) of alcohol or saline using immunohistochemistry and analyzed by 2‐way analysis of variance. Results In the case–control association study using an NIAAA discovery sample , 8 SNP s in PIP 5K1C were significantly associated with AUD in the African ancestry (AA) group ( p 〈 0.05 after correction; rs4807493, rs10405681, rs2074957, rs10432303, rs8109485, rs1476592, rs10419980, and rs4432372). However, a replication analysis using an independent sample ( N = 3,801) found no significant associations after correction for multiple testing. In the humanized transgenic mouse model with the OPRM 1 polymorphism, PIP 5K1C expression was significantly different between alcohol and saline‐treated mice, regardless of genotype, in both the thalamus ( p 〈 0.05) and BLA ( p 〈 0.01). Conclusions Our discovery sample shows that genetic variants in PIP 5K1C are associated with AUD in the AA group, and acute alcohol exposure leads to up‐regulation of PIP 5K1C, potentially explaining a mechanism underlying the increased risk for chronic pain conditions in individuals with AUD .
Type of Medium:
Online Resource
ISSN:
0145-6008
,
1530-0277
DOI:
10.1111/acer.2018.42.issue-6
Language:
English
Publisher:
Wiley
Publication Date:
2018
detail.hit.zdb_id:
2046886-6
detail.hit.zdb_id:
3167872-5
SSG:
15,3
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