Cluster headache is associated with the alcohol dehydrogenase 4 (ADH4) gene

Alcohol is a well-known trigger factor for cluster headache attacks during the active phases of the disease. The alcohol dehydrogenase (ADH) pathway, which converts alcohol to the toxic substance acetaldehyde, is responsible for most of the alcohol breakdown in the liver. Humans have 7 ADH genes, tightly clustered on chromosome 4q21-q25, that encode different ADH isoforms. The ADH4 gene encodes the class II ADH4 pi subunit, which contributes, in addition to alcohol, to the metabolization of a wide variety of substrates, including retinol, other aliphatic alcohols, hydroxysteroids, and biogenic amines. The purpose of this study was to investigate the association of genetic variants within the ADH4 gene with cluster headache susceptibility and phenotype.

A total of 110 consecutive unrelated cluster headache patients and 203 age- and sex-matched healthy controls of Caucasian origin were involved in the study. Patients and controls were genotyped for 2 bi-allelic single nucleotide polymorphisms (SNPs) of the ADH4 gene: SNP1 - rs1800759 and SNP2 - rs1126671. Allele, genotype, and haplotype frequencies of the examined polymorphisms were compared between cases and controls.

Genotype frequencies of the rs1126671 polymorphism resulted significantly different between cluster headache patients and controls (chi(2) = 10.269, P = .006). The carriage of the AA genotype, in comparison with remaining genotypes, was associated with a significantly increased disease risk (OR = 2.33, 95% CI: 1.25-4.37). Haplotype analysis confirmed the association between the ADH4 gene and the disease. No association between different clinical characteristics of cluster headache and the examined polymorphisms was found.

Our data suggest that cluster headache is associated with the ADH4 gene or a linked locus. Additional studies are warranted to elucidate the role of this gene in the etiopathogenesis of the disease.