Relationship between T-cell receptor a gene polymorphisms and symptomatic differences in patients with narcolepsy type 1
Narcolepsy type 1 (NT1) is a chronic immune-mediated disorder characterized by excessive daytime sleepiness (EDS) and cataplexy, often accompanied by sleep paralysis, hypnagogic hallucinations, and disturbed nocturnal sleep. The underlying pathophysiology of NT1 involves the loss of hypocretin-producing neurons in the hypothalamus, which is believed to be driven by an autoimmune process. Recent genome-wide association studies (GWAS) have identified the T-cell receptor alpha (TRA) gene as a significant contributor to narcolepsy susceptibility. However, the role of TRA haplotype polymorphisms in the symptomatic diversity of narcolepsy remains unclear. This study aimed to investigate the association between TRA polymorphisms and the symptomatic differences in patients with NT1, focusing on a Chinese population.
The study included 903 patients with NT1, recruited from the Sleep Laboratory of Peking University People’s Hospital. All patients met the diagnostic criteria for NT1 according to the International Classification of Sleep Disorders-3. The cohort predominantly consisted of Chinese Han ethnicity (95.2%), with a median age of onset at 9 years and a diagnostic delay of 2 years. The majority of patients presented with EDS and cataplexy, while other symptoms such as sleep paralysis and hypnagogic hallucinations were less common. The study aimed to explore the genetic basis of the symptomatic diversity in narcolepsy, with a particular focus on TRA gene polymorphisms.
Thirteen single nucleotide polymorphisms (SNPs) within the TRA gene were genotyped using the Affymetrix Axiom CHB array. These SNPs were selected based on previous GWAS findings and included rs227000, rs1258667, rs227017, rs8016421, rs1154153, rs1154155, rs1154158, rs1263638, rs1263640, rs7153643, rs1263642, rs1263645, and rs1263647. Quality control measures ensured a genotype call rate of over 99%, and 903 patients were included in the final analysis. The association between these SNPs and narcolepsy symptoms was assessed using the Chi-square test, with a Bonferroni correction applied to account for multiple comparisons.
The study identified three haplotype blocks within the TRA gene, formed by rs227017, rs1154153, and rs1154158; rs1263638 and rs1263640; and rs1263645 and rs1263647, respectively. These haplotype blocks were analyzed for their association with narcolepsy symptoms using logistic regression. The results revealed that specific TRA haplotypes were significantly associated with auditory hallucinations in patients with NT1. Specifically, the haplotypes TG and CT were associated with an increased risk of auditory hallucinations, with odds ratios of 1.235 and 1.236, respectively. Conversely, the ATG and CA haplotypes were more frequently observed in patients without auditory hallucinations.
The findings suggest that TRA polymorphisms may play a role in the phenotypic diversity of narcolepsy, particularly in the manifestation of auditory hallucinations. This aligns with previous studies that have implicated the TRA gene in narcolepsy susceptibility and highlights the potential role of T-cell-mediated immune processes in the disease’s pathogenesis. The study also underscores the importance of considering genetic factors in understanding the symptomatic variability of narcolepsy, which could inform personalized treatment strategies.
Despite these significant findings, the study has several limitations. First, it focused solely on genetic factors and did not account for environmental or non-genetic influences on narcolepsy symptoms. Second, the number of SNPs analyzed was limited, and future studies with a more comprehensive SNP-based approach may provide additional insights. Furthermore, the study population was exclusively Chinese, and the findings may not be generalizable to other ethnic groups. Future research should explore the gene-gene and gene-environment interactions that contribute to narcolepsy’s onset and symptomatic diversity.
In conclusion, this study provides evidence that TRA haplotype polymorphisms are associated with the symptomatic differences in patients with NT1, particularly in the occurrence of auditory hallucinations. These findings contribute to the growing body of knowledge on the genetic basis of narcolepsy and highlight the potential for precision medicine approaches in the treatment of this complex disorder. Further research is needed to elucidate the underlying mechanisms and to explore the broader implications of these genetic associations in diverse populations.
doi.org/10.1097/CM9.0000000000000348
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