The impact of the HLA DQB1 gene and amino acids on the development of narcolepsy.

INTRODUCTION: Narcolepsy is a chronic neurological and a genetic disorder of autoimmune origin, which is characterized by five main symptoms, including excessive day time sleepiness, sudden loss of muscle tone or cataplexy, sleep paralysis, hypnagogic hallucinations, and disturbed nocturnal sleep. While there are several diagnostic tests for Narcolepsy such as MSLT (mean sleep latency test), polysomnography and low range of hypocretin in cerebrospinal fluid (CSF), sensitivity and specificity in these methodologies are not sufficient enough. Therefore, methods with higher sensitivity for the accurate diagnosis and confirmation of the disease are necessary. METHODS: According to the infrequent prevalence of narcolepsy disease, we scheduled a case-control association study with 20 narcoleptic patients and 150 healthy individuals in a high-resolution HLA typing procedure employing SSP-PCR. RESULTS: Our study demonstrates that the DQB1*06:02 allele provides the highest susceptibility with absolute risk of 0.13%, for Narcolepsy (P = 1x10-14, RR = 60.5, PcPPV = 0.13%), while, HLA-DQB1* 03:05 allele presents protection to Narcolepsy (P = 1x10-4, PcPPV = 3.19x10-4%). Furthermore, for the first time, the AA analysis displayed that AA serine182 and threonine185 located on epitope of DQß1 chain receptor (DQB1Ser182,Thr185) present significant susceptibility for Narcolepsy (Pc= 87.03 × 10-13, PcPPV = 0.024%) while, asparagine182 located on epitope of DQß1 protein receptor (DQB1Asn182) confers the highest protection against development of Narcolepsy (Pc= 2.16 × 10-5, PcPPV = 0.0012%). CONCLUSION: Thus, this can be proposed that the polymorphic differences in the epitope of the HLA receptor could contribute to their differential association with the Narcolepsy in Iranian population.

Pharmacogenetic and Association Studies on the Influence of HLA Alleles and Rivastigmine on the Iranian Patients with Late-Onset Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting cognitive function. A number of allelic genes from HLA complex have shown variable associations with AD in different populations. In this study, we investigated the association of DQB1*06:00/x, DRB1*04:00/x, DRB1*15:00/x, and B*07:00/x genotypes with AD and their relevance to the efficacy of rivastigmine treatment in the Iranian population. Our findings suggest that DQB1*06:00/x genotype offers strong protection against AD (P = 0.0074), while B*07:00/x genotype imposes a significant susceptibility for sporadic Alzheimer's disease (SAD) (P = 0.009). Interestingly, B*07:00/x genotype does not show any apparent associations with familial Alzheimer's disease (FAD). Our studies also suggest a pharmacogenetic relationship between drug treatment and presence of a particular genotype in the Iranian LOAD patient population. The Clinical Dementia Rating analysis showed that LOAD patients carrying DRB1*04:00/x genotype tend to display a downward trend in the disease severity and symptoms after 2-year follow-up with rivastigmine treatment. Moreover, in our total patient population, the carriers of DQB1*06:00/x and B*07:00/x alleles have better and worse responses to rivastigmine respectively. We also measured the clinical relevance of the testing for these genotypes employing prevalence-corrected positive predictive value (PcPPV) formula. The PcPPV of testing for DQB1*06:00/x in the Iranian LOAD patients was 1.17% which means that people carrying this genotype have half of the probability of the absolute risk for developing LOAD, whereas the PcPPV of testing for B*07:00/x was 4.45% for SAD, which can be interpreted as a doubling chance for developing LOAD among the Iranian population carrying this genotype. These results also suggest that DQß1 peptide containing positively charged AAs histidine30 and arginine55 and HLA class I ß chain containing negatively charges aspartic acid114 and glutamic acid45,152 in their binding groove plays important roles in protection against and susceptibility for LOAD respectively.