Oxytocin receptor polymorphism rs53576 is linked to habitual alcohol and sucrose intake, as well as liver steatosis, in a general Japanese population cohort.

BACKGROUND Oxytocin (OXT) signaling through the oxytocin receptor (OXTR) produces stress-relieving effects and modulates alcohol reward and sucrose preference in animal models. These findings suggest the therapeutic potential of OXT for alcohol use disorder (AUD) and liver steatosis. However, human genetic evidence linking OXT signaling to these cravings remains scarce.

OBJECTIVE This study examined the association between the OXTR rs53576 polymorphism and habitual intake of alcohol and sucrose in a general population, with a further focus on related liver pathology.

METHODS A cross-sectional analysis was conducted using data from the Shika study, comprising 696 participants with complete information on both single-nucleotide polymorphisms (SNPs) and dietary intake, assessed using the Brief Dietary History Questionnaire (BDHQ). We examined the association of the rs53576 SNP with alcohol and sucrose consumption, as well as with clinical outcomes related to these dietary factors, including liver enzyme levels and liver steatosis.

RESULTS Among individuals with regular alcohol consumption, those with the rs53576 G/G genotype (under a recessive model) exhibited significantly lower alcohol intake (p = 0.002) and higher sucrose intake (p = 0.004) compared to A allele carriers. An association between rs53576 and aspartate aminotransferase (AST) levels, an indicator of alcoholic liver disease (ALD), further supported the relationship between this genotype and alcohol intake. Sex-stratified analysis revealed that the G/G genotype was linked to a greater prevalence of liver steatosis in women, but not in men. Mediation analysis indicated that this association in women was driven by a direct effect independent of sucrose intake volume.

CONCLUSIONS These findings indicate that the OXTR rs53576 polymorphism is associated with distinct alcohol and sucrose intake patterns and susceptibility to liver steatosis, supporting the potential for genotype-informed nutritional interventions aimed at reducing the risk of AUD, ALD, and metabolic dysfunction-associated steatotic liver disease (MASLD). CLINICAL TRIALS REGISTRATION NUMBER AND WEBSITE WHERE IT WAS OBTAINED: This study was approved by the Ethics Committee for Human Studies at Kanazawa University Hospital (1491, 2016-376) and performed following the principles outlined in the Declaration of Helsinki. Network Clinical Trials Registry (UMIN-CTR) under the registration number UMIN000024915. The detailed trial information is available at the following URL: https://center6.umin.ac.jp/cgi-open-bin/icdr/ctr_his_list.cgi?recptno=R000028662.