KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference.
Level 3 - non-randomized controlled study
Genome-wide association meta-analysis of observational cohort data combined with mechanistic animal models
PubMed 27911795 · doi:10.1073/pnas.1611243113
What was done
Researchers conducted a genome-wide association study (GWAS) meta-analysis and replication study of alcohol consumption among >105,000 individuals of European ancestry. They followed up the top genetic finding by examining alcohol preference in brain-specific beta-Klotho knockout mice and testing the effect of the liver-derived hormone FGF21 on mouse alcohol intake.
What was found
The meta-analysis identified a genome-wide significant association between alcohol consumption and a locus in the *KLB* (beta-Klotho) gene (rs11940694, P = 9.2 × 10^-12). In functional mouse experiments, brain-specific beta-Klotho knockout mice demonstrated increased alcohol preference, and FGF21 was shown to inhibit alcohol drinking via central actions requiring brain beta-Klotho.
Why it matters
These findings delineate a liver-brain endocrine axis regulating alcohol intake, identifying beta-Klotho and FGF21 signaling as potential pharmacological targets for mitigating excessive alcohol consumption.
Limits
The human genetic analysis was restricted to individuals of European ancestry, limiting generalizability to other populations. Specific effect sizes on human drinking volume were not reported in the abstract, and therapeutic efficacy of modulating this pathway in humans remains unproven.
Cited by
- supports Alcohol intoxication triggers FGF21 release, which acts as a negative feedback mechanism through a liver-brain signaling axis to decrease subsequent alcohol intake.
- supports Human studies show that single nucleotide polymorphisms in genes involved in FGF21 signaling lead to greater alcohol consumption.
- supports Mice genetically incapable of producing or releasing FGF21 consume significantly more alcohol than wild-type mice.