GENERAL DISCUSSION 211 10 Migraine in perspective, focussing on lipids and amines In Chapters 2 - 5 different metabolites in different body fluids obtained inside or outside migraine attacks were investigated. Because migraine is a multifactorial complex brain disorder there are a multitude of aspects that can be and have to be investigated in order to fully understand the mechanism of disease. An important question in the context of migraine is whether outside of attacks, migraine patients differ biochemically from controls or whether this is only during attacks. What we know from Part II of the thesis is that migraine patients differ genetically from controls. This makes it conceivable that there are also differences in metabolite concentrations interictally between migraine patients and controls. In this respect it is of interest to note that twin studies have shown that the heritability of blood metabolites is up to 80%.1 Given that genetics are static, this means that when looking at metabolites in body fluids interictally a difference may be expected. This is also follows from the research in Chapters 2 and 3, were migraine patients differed in their metabolite profile from controls. Although we have investigated a variety of aspects in migraine patients (i.e. different biochemical and genetic aspects), we have not specifically investigated the interplay between the biochemical and the genetic system in this thesis. The correlation of metabolites and genetic data was combined with previous knowledge on the increased cardiovascular disease risk in migraine patients, by an Australian group.2-5 The Australian researchers hypothesized that routine chemistry tests and serum markers for cardiovascular disease might be associated with migraine risk, directly as well as on a genetic basis. They showed that there was an association between clinical chemistry tests traditionally used to monitor cardiovascular disease and migraine risk.6 More importantly, in cross-trait genetic analyses it was shown that migraine and the associated chemistry tests have an underlying shared genetic basis.6 Notably, the association and genetic overlap between a lower level of HDL-C and an increased migraine risk are in part due to shared biology.6 This observed link where genetic factors influence blood metabolite levels and risk for migraine indicates a change of metabolite concentrations in migraine patients. This example from literature illustrates the relevant interplay between the genetic and biochemical underpinnings of migraine and in addition confirms that a difference in metabolite concentration interictally is very probable and thus in line with the results from Chapter 2 and 3. In a subsequent study by the same Australian group, the genetic underpinning and causality of even more blood metabolites (n = 316) and migraine risk were investigated.7 Their study showed a significant correlation between migraine and 44 metabolites that were mostly associated with lipid metabolism.7 In addition, they found a causal effect of some lipoproteins on migraine risk.7 These findings in lipids were perhaps not that unexpected as epidemiological studies had already shown that obesity is a risk factor for migraine, as well as the comorbidity of cardiovascular and cerebrovascular disease in migraine.2-5 Regardless, studies directly into lipid levels of migraine have not shown consistent results; in some studies differences in lipid levels were found in migraine patients,8, 9 whereas in other studies this was not the case.8, 10 A previous very thorough meta-
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