Screening of Two ADH4 Variations in a Swedish Cluster Headache Case–Control Material

Abstract

BackgroundCluster headache (CH) is a severe neurovascular disorder and an increasing amount of evidence points to a genetic contribution to this disease. When CH was first described, it was observed that alcohol may precipitate an attack during the active phase of the disease. The alcohol dehydrogenase 4 (ADH4) gene encodes an enzyme which contributes to the metabolization of alcohol and is, therefore, an interesting candidate gene for CH. Two Italian groups have reported association of the single nucleotide polymorphism (SNP) rs1126671 located in the ADH4 gene with an increased risk of CH in Italy. In addition, one of the groups found an association between the ADH4 SNP rs1800759 and CH.ObjectiveTo perform a replication study on the ADH4 SNPs rs1126671 and rs1800759 in a large homogeneous Swedish case–control cohort in order to further investigate the possible contribution of ADH4 to CH.MethodsA total of 390 unrelated patients diagnosed with CH and 389 controls representing a general Swedish population were recruited to the study. DNA samples from patients and controls were genotyped for the two ADH4 SNPs rs1126671 and rs1800759 using quantitative real‐time polymerase chain reaction. Statistical analyses of genotype, allele and haplotype frequencies for the two SNPs were performed and compared between patients and controls.ResultsFor rs1126671, the minor allele frequency (A allele) was 32.8% (n = 254) in controls compared with 31.9% (n = 249) in CH patients. The minor allele frequency (A allele) of rs1800759 was 42.3% (n = 324) in controls and 41.9% (n = 327) in CH patients. Statistical analysis showed no significant differences in allele as well as in genotype or haplotype frequencies between the patient and control group for either SNP. This was also seen after stratifying the patient group for experiencing alcohol as a trigger factor.ConclusionsThe data did not support an association of the ADH4 SNPs rs1126671 and rs1800759 with CH. A comparison with previous studies revealed variance in genotype, allele, and haplotype frequencies among the different populations which might contribute to the contradictory results. Although a significant association with CH in Swedish case–control group was not found, ADH4 as a candidate gene for CH could not be excluded.

Genetic association of HCRTR2, ADH4 and CLOCK genes with cluster headache: a Chinese population-based case-control study

“…In addition, Zarrilli et al (2015) also found an association between the ADH4 SNP rs1800759 and CH [ 24 ]. However, the association was not supported by the case control study of Fourier et al (2016), who reported no association of the ADH4 SNPs rs1126671 and rs1800759 with CH using a largest Sweden population [ 25 ]. Similarly, the data of our study did not support an association of the ADH4 SNPs rs1126671 and rs1800759 with CH.…”

“…Alcohol is a well-known trigger factor for CH attacks during the active phases of the disease. Three studies have been made,two Italian groups revealed significant association of the rs1126671 locus in the ADH4 gene with CH incidence,one of the experiments have also found the association between the ADH4 SNP rs1800759 and CH,but those results were not confirmed in a large Swedish case–control cohort study [ 23 – 25 ].…”

Distinct Prognostic Values of Alcohol Dehydrogenase Family Members for Non-Small Cell Lung Cancer

“…ADH1 and ADH2 are mainly expressed in the liver and gastric mucosa, where both are involved in the metabolism of oral alcohol, that is, the conversion of ethanol into the carcinogenic metabolite acetaldehyde, especially in the elimination stage [ 41 – 43 ]. In the esophageal muscle tissue, 2 single-nucleotide polymorphisms (rs1126671 and rs1800759) were associated with lower ADH4 expression levels in fibroblasts [ 44 ]. The ADH4 gene encodes the π subunit in humans and can metabolize many substances, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products [ 45 ].…”

Anoctamin 3: A Possible Link between Cluster Headache and Ca2+ Signaling

“…Genetic associations with CH have today been reported for several candidate genes [11,12,13,14,15,16]. The two most extensively studied genes in relation to CH are clock circadian regulator ( CLOCK ) and hypocretin receptor 2 ( HCRTR2 ) which are both linked to diurnal rhythm and sleep; however, results are not consistent between studies [17,18,19,20,21]. As yet, there has only been one small study reported using a genome wide association approach.…”