Dikkat eksikliği hiperaktivite bozukluğunda (DEHB), yavaş bilişsel tempo (YBT) semptomlarının dopaminerjik yolak ile ilişkisinin genetik açıdan incelenmesi
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Tarih
2018
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Yayıncı
Ege Üniversitesi, Tıp Fakültesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Amaç: Dikkat Eksikliği ve Hiperaktivite Bozukluğu (DEHB), yüksek kalıtsallık gösteren, multifaktöriyel, poligenik bir hastalıktır. Şimdiye kadar DEHB tanısıyla ilişkilendirilmiş varyantlar patogenezin çok küçük bir kısmını açıklayabilmektedir. Buna da en büyük sebep olarak DEHB olgularındaki fenotipik heterojenite gösterilmektedir. DEHB heterojenitesini azaltmaya yönelik çalışmalar yavaş bilişsel tempo (YBT) kavramını araştırmaya dair ilgiyi arttırmıştır. Bu çalışmadaki amacımız DEHB hastalarında saptanan genetik varyantların biyobelirteç olarak temsil gücünü arttırmak için, DEHB klinik heterojenitesini azaltmak ve bu varyantların YBT tanısı ile olan ilişkisini incelemektir. Gereç ve Yöntem: Çalışmamızda 26 YBT tanılı olgu, 69 YBT-DEHB tanılı olgunun verileri 147 DEHB tanılı olgu ve 92 sağlıklı kontrolün verileriyle karşılaştırıldı. YBT tanısı alan olgularda, DEHB tanısı alan olgularda ve sağlıklı kontrollerde DAT1 (3'UTR bölgesinde 40 bç tekrar bölgesi), DRD4 geni (ekzon 3' te meydana gelen 48 bç tekrar bölgesi) VNTR bölgeleri incelendi. Bunun yanı sıra, BDNF (rs6265), SNAP-25 (rs3746544-rs1051312) ve SYN3 (rs133945-rs133946) polimorfizmleri ise RFLP yöntemi ile değerlendirildi. Bulgular: DAT1, DRD4 ve BDNF genlerinde gruplar arasında istatiksel olarak anlamlı farklılık saptanırken (p<0,05), SNAP-25 ve SYN3 genlerinde anlamlı düzeyde farklılık bulunmamıştır (p>0,05). DAT1 geni için 10R/10R genotipi, DRD4 geni için 7R alleli ve BDNF geni için A alleli en yüksek oranda YBT olgularında saptanmıştır. Sonuç: YBT semptomları olan olguların DEHB tedavisinde kullanılan metilfenidat tedavisine yanıtsız olduğu önceki çalışmalarda belirtilmiştir. DEHB ile ilişkili farmokogenetik çalışmalarda azalmış metilfenidat yanıtıyla ilişkili genetik belirteçler DAT1 geni için 10R/10R genotipi, DRD4 geni için 7R alleli ve BDNF geni için A allelidir. Çalışmamızda metilfenidata yanıtsızlıkla ilişkili bulunan allellerin tümü YBT olgularında hem sağlıklı kontrollerden hem de DEHB olgularından yüksek saptanmıştır. Çalışmamızın sonuçları sonraki yapılacak DEHB aday gen çalışmaları ve farmakogenetik çalışmalarında, DEHB ile birlikte YBT semptomlarının da araştırılması gerekliliğini göstermektedir. YBT tanı grubuna yönelik yapılmış ilk aday gen çalışması olup bulguların farmakogenetik çalışmalarla desteklenmesine ihtiyaç duyulmaktadır.
Objective: Attention Deficit and Hyperactivity Disorder (ADHD) is a multifactorial and polygenic disease with high inheritance. Up to now, variants associated with the diagnosis of ADHD can explain a very small proportion of pathogenesis. The most important reason for this is the phenotypic heterogeneity in ADHD cases. Studies to reduce ADHD heterogeneity have increased interest in researching the concept of Sluggish Cognitive Tempo (SCT). The aim of this study was to decrease the clinical heterogeneity of ADHD and to investigate the relationship of these variants with the diagnosis of SCT in order to increase the representation of the genetic variants identified in ADHD patients as biomarkers. Materials and Methods: In our study, 26 cases with SCT, 69 cases with SCT-ADHD were compared with 147 cases with ADHD and 92 healthy controls. DAT1 (40 bp repeat region in the 3’ UTR region) and DRD4 gene (48 bp repeat region in the exon 3) were examined in cases diagnosed with SCT or ADHD and healthy controls. In addition, BDNF (rs6265), SNAP-25 (rs3746544-rs1051312) and SYN3 (rs133945-rs133946) polymorphisms were evaluated by RFLP method. Results: There was a statistically significant difference between the groups in the DAT1, DRD4 and BDNF genes (p <0.05) and there was no significant difference in SNAP-25 and SYN3 genes (p> 0.05). The 10R / 10R genotype for the DAT1 gene, the 7R allele for the DRD4 gene and the A allele for the BDNF gene were found in the highest rate of SCT cases. Conclusion: It has been reported in previous studies that patients with symptoms of SCT are unresponsive to methylphenidate treatment that is main pharmacological treatment of ADHD. Genetic markers associated with decreased methylphenidate response in pharmacological studies associated with ADHD are the 10R / 10R genotype for the DAT1 gene, the 7R allele for the DRD4 gene, and the A allele for the BDNF gene. In our study, alleles associated with unresponsiveness to methylphenidate were found to be higher in SCT cases than in both healthy controls and ADHD cases. The results of our study indicate the necessity of investigating the symptoms of ADHD as well as the symptoms of SCT in ADHD candidate gene studies and pharmacogenetic studies. It is the first candidate gene study to be used for the diagnosis of SCT, and the findings need to be supported by pharmacogenetic studies.
Objective: Attention Deficit and Hyperactivity Disorder (ADHD) is a multifactorial and polygenic disease with high inheritance. Up to now, variants associated with the diagnosis of ADHD can explain a very small proportion of pathogenesis. The most important reason for this is the phenotypic heterogeneity in ADHD cases. Studies to reduce ADHD heterogeneity have increased interest in researching the concept of Sluggish Cognitive Tempo (SCT). The aim of this study was to decrease the clinical heterogeneity of ADHD and to investigate the relationship of these variants with the diagnosis of SCT in order to increase the representation of the genetic variants identified in ADHD patients as biomarkers. Materials and Methods: In our study, 26 cases with SCT, 69 cases with SCT-ADHD were compared with 147 cases with ADHD and 92 healthy controls. DAT1 (40 bp repeat region in the 3’ UTR region) and DRD4 gene (48 bp repeat region in the exon 3) were examined in cases diagnosed with SCT or ADHD and healthy controls. In addition, BDNF (rs6265), SNAP-25 (rs3746544-rs1051312) and SYN3 (rs133945-rs133946) polymorphisms were evaluated by RFLP method. Results: There was a statistically significant difference between the groups in the DAT1, DRD4 and BDNF genes (p <0.05) and there was no significant difference in SNAP-25 and SYN3 genes (p> 0.05). The 10R / 10R genotype for the DAT1 gene, the 7R allele for the DRD4 gene and the A allele for the BDNF gene were found in the highest rate of SCT cases. Conclusion: It has been reported in previous studies that patients with symptoms of SCT are unresponsive to methylphenidate treatment that is main pharmacological treatment of ADHD. Genetic markers associated with decreased methylphenidate response in pharmacological studies associated with ADHD are the 10R / 10R genotype for the DAT1 gene, the 7R allele for the DRD4 gene, and the A allele for the BDNF gene. In our study, alleles associated with unresponsiveness to methylphenidate were found to be higher in SCT cases than in both healthy controls and ADHD cases. The results of our study indicate the necessity of investigating the symptoms of ADHD as well as the symptoms of SCT in ADHD candidate gene studies and pharmacogenetic studies. It is the first candidate gene study to be used for the diagnosis of SCT, and the findings need to be supported by pharmacogenetic studies.
Açıklama
Anahtar Kelimeler
Psikiyatri, Genetik, Dopamin, Dikkat Eksikliği Hiperaktivite Bozukluğu, Yavaş Bilişsel Tempo, Psychiatry, Genetics, Dopamine, Attention Deficit Hyperactivity Disorders, Sluggish Cognitive Tempo