||~1.5x? increased risk for cluster headaches
||2-6x increased risk for cluster headaches
rs2653349, also known as G1246A, is a SNP in the HCRTR2 hypocretin-orexin gene. It has been linked primarily to cluster headaches. The more common allele (G) has been linked to increased risk; alternatively, this could be seen as implying that the less common (A) allele reduces cluster headache risk.
In the (first) study, 100+ Italian patients were analyzed to reveal that rs2653349(G;G) genotypes were at 5x increased risk for the disorder, compared with (A;G) and (A;A) genotypes.[PMID 15477554]
A study of 200+ German patients indicated that (G;G) homozygotes were at 2x increased risk (CI: 1.32-2.92, p = 0.0007) for cluster headaches.[PMID 16554494]
A meta-analysis of 3 pooled studies concluded that the rs2653349(G;G) genotype showed a higher disease risk compared to the remaining genotypes (odds ratio 1.69, CI:1.11-2.58).[PMID 17563843]
Not all studies have found this association; a study of Northern Europeans did not find an association.[PMID 16801656]
Also, a study has been performed to find out if treatment success for cluster headaches is correlated with rs2653349 genotype. Among 184 Caucasian patients, while the rs2653349(G) allele was significantly associated with cluster headaches, treatment outcomes with triptans, oxygen, verapamil and corticosteroids were not.[PMID 17376114]
Independently, a study has been performed to see if rs2653349 might be associated with migraine; in this study at least, the answer was no.[PMID 17883525]
[PMID 25398231] The LUCA study, the largest performed meta-analysis couldn't find evidence for an association between rs2653349 and cluster headaches.
[PMID 25398231] Cluster headache and the hypocretin receptor 2 reconsidered: A genetic association study and meta-analysis
[PMID 29318394] Genetic association of HCRTR2, ADH4 and CLOCK genes with cluster headache: a Chinese population-based case-control study.