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

Cluster 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.

To 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.

A 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.

For 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.

The 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.