New Genetic Biomarkers of the Overlap Syndrome Tension-Type Headache and Arterial Hypertension

Abstract

Background: Nitric oxide (NO) is an important autocrine and paracrine signaling molecule that plays a crucial role in cardiovascular physiology and pathology regulation. NO is an important molecule involved in regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. Reduced bioavailability of NO in the endothelium is an important precursor for impaired vasodilation and arterial hypertension (AH). Furthermore, NO is involved in nociceptive processing. A NO-induced biphasic response with immediate and a delayed headache is typical for chronic tension-type headaches (TTH) in humans. The aim was to study the association of allelic variants and genotypes of the single nucleotide variant (SNV) rs3782218 of the NOS1 gene with the TTH and AH overlap syndrome development in middle age adults. Materials and Methods: We observed 91 Caucasian participants who resided in Krasnoyarsk city: group 1 (TTH and AH overlap syndrome)—30 patients; group 2 (AH without headache)—30 patients; group 3 (control)—31 healthy volunteers. The diagnosis of AH was based on criteria of the European Society of Cardiology and the European Society of Hypertension (2018) и criteria of the Russian Society of Cardiology (2020). Diagnosis of TTH was based on criteria of the International Classification of Headache Disorders (2018). Real-time polymerase chain reaction was used for the determination of allelic variants and genotypes of the SNV rs3782218 of the NOS1 gene in all groups of participants. Results: The frequency of the minor allele T of rs3782218 was statistically significantly higher by 16.7 times in group 1 (TTH and AH) compared to group 3 (control): 26.7% versus 1.6%, respectively (p-value = 0.000065) and 3.2 times higher in group 1 (TTH and AH) compared to group 2 (AH without headache): 26.7% versus 8.3%, respectively (p-value = 0.008). The frequency of the heterozygous (CT) genotype was statistically significantly higher in group 1 (TTH and AH) compared to group 3 (control): 40.0% versus 3.2% (p-value = 0.000454) and in group 1 (TTH and AH) compared to group 2 (AH without headache): 40.0% versus 16.7% (p-value = 0.045). The minor allele T was statistically significantly associated with a high risk of developing the TTH and AH overlap syndrome compared with the controls (odds ratio (OR) = 22.2 (95% confidential interval (CI): 2.8–173.5)) and compared with AH without headache (OR = 4.0 (95% CI: 1.4–11.8)). Although the frequency of the minor allele T was 5.2 times higher in group 2 (AH without headache) compared with group 3 (control), there were not statistically significantly differences (p-value = 0.086). Conclusion: Thus, the minor allele T of rs3782218 of the NOS1 gene is an important genetic biomarker for a high risk of developing the TTH and AH overlap syndrome in hypertensive patients.

Genetic Profiling of the Nitric Oxide Synthases’ System in a 55-Year-Old Woman with the Tension-Type Headache and Arterial Hypertension Phenotype: Case Report

“…The genetic profiling results are consistent with our previously published study [12] showing that the minor allele T rs3782218 (117771511 C>T) of the NOS1 gene was statistically significantly associated with a high risk of developing the TTH and AH phenotype compared with the controls -healthy volunteers (odds ratio (OR) = 22.2 (95% confidential interval (CI): 2.8-173.5)) and compared with the hypertensive patients without headache (OR = 4.0 (95% CI: 1.4-11.8)) in Caucasian Siberian population of Russian Federation [12].…”

“…Thus, the frequency of allelic variants of SNV rs3782218 of the NOS1 gene, differently presented in the population of the European and Asian regions [18], may differ both within different populations of Western and Eastern Europe, and within the population system of Russia. According to the available data, the gene pool of the studied population living in Eastern Siberia is less affected by the "gene influx" from the countries of Western Europe, and, on the contrary, more affected by the "gene influx" from the countries of the Asian region, according to the central and European parts of Russia [12]. This has been demonstrated in associated genetic studies of other neurological diseases [33].…”

“…Thus, our data supplement our previous studies of the role of the SNV-marker rs3782218 of the NOS1 gene in the Russian population of Eastern Siberia, but do not agree with the results of Levinson's (2014) [17] study performed in the Swedish population (Northern Europe). It should be noted that the sample size and the absence of other ethnic control groups (for example, Asians living in Eastern Siberia), which could supplement the existing picture of the allele distribution, do not allow for general conclusions to be drawn at this stage regarding the strength of the association of this marker with a genetic predisposition to TTH and AH overlap syndrome in Eastern Siberia [12]. Nevertheless, the obtained data, by way of dozens of samples, determine the feasibility of further studies, while it is necessary to take into account the difference in the distribution of genetic biomarkers in different populations (population stratification factor).…”

“…At the same time, the risk of this syndrome developing increases with the heterozygous (CT) genotype. It is possible that an increase in the sample size in further population studies may provide new information on the frequency of the rare homozygous (TT) genotype in Caucasians of Eastern Siberia [12]. This is important from a scientific and clinical point of view, because a new class of drugs that inhibit nNOS has been proposed in recent years, both for the treatment of TTH and AH.…”

“…This is important from a scientific and clinical point of view, because a new class of drugs that inhibit nNOS has been proposed in recent years, both for the treatment of TTH and AH. A new strategy for predicting and disease-modifying therapy of the common TTH and AH overlap syndrome can increase the effectiveness and safety of treatment, improve patient quality of life, and reduce the risk of life-threatening cardiovascular complications [12].…”