فارماکوژنومیک در بیماری آلزایمر: یک مطالعه ارتباط ژنوم گسترده در واکنش به مهار کننده های کولین استراز
|کد مقاله||سال انتشار||مقاله انگلیسی||ترجمه فارسی||تعداد کلمات|
|30808||2013||6 صفحه PDF||سفارش دهید||5862 کلمه|
Publisher : Elsevier - Science Direct (الزویر - ساینس دایرکت)
Journal : Neurobiology of Aging, Volume 34, Issue 6, June 2013, Pages 1711.e7–1711.e13
We conducted a genome-wide association study in a cohort of 176 Italian Alzheimer's disease (AD) patients with extreme phenotype of response to cholinesterase inhibitors. Patients were classified into responders in case of positive, stable, or ≤1 worsening of mini-mental state examination score and into nonresponders if >3 points worsening during a median follow-up of 0.85 years of treatment. Forty-eight single-nucleotide polymorphisms were selected for replication in 198 additional AD-treated patients. By using the dichotomous response trait and a quantitative trait approach (change of mini-mental state examination), a nominal replication and evidence of association when combining data were achieved for 2 single-nucleotide polymorphisms associated with response to treatment: rs6720975A (pcombined = 2.9 × 10−5, beta regression coefficient: 1.61) and rs17798800A (pcombined = 6.8 × 10−6, odds ratio = 0.38, 95% confidence interval = 0.25–0.58). Rs6720975 maps in the intronic region of PRKCE, a protein kinase involved in several cellular functions, whereas rs17798800 is intergenic and, according to expression quantitative trait locus (eQTL) analysis, it acts as a cis-regulator of NBEA, an A kinase–anchoring protein playing a substantial role in the maturation of the nervous system. Despite its limitations, this project paves the way for the application of personalized medicine in AD patients and for collaborative efforts in this field.
Alzheimer's disease (AD) is the most frequent neurodegenerative disorder and one of the most common diseases in the industrialized world, affecting more than 33.9 million people worldwide, a figure predicted to triple over the next 40 years (Barnes and Yaffe, 2011). AD causes progressive loss of cognitive functions leading to dementia and death. Novel therapeutic approaches have emerged over the last years, but confirmation in clinical trials (Katsuno et al., 2012) has been very poor, and cholinesterase inhibitors (ChEI) are still the mainstay in the treatment of AD. These drugs act mainly by increasing cholinergic neurotransmission and raising the level of cerebral acetylcholine, but recent studies also suggest alternative modes of action including neuroprotective and immunomodulatory effects (Akaike et al., 2010; Noh et al., 2009; Reale et al., 2004). Evidence from therapeutic trials and clinical practice shows not only that AD patients with mild, moderate, or severe dementia treated with ChEIs improved in cognitive function after 6 months with an average of 1.4 points (Birks, 2006) on mini-mental state examination (MMSE), but also that the clinical response is variable and unpredictable (Birks, 2006). Therefore, clinical and genetic predictors of response to treatment are needed to help individualize therapy. So far, a fair amount of knowledge has been accumulated for clinical predictors, such as less cognitive impairment at drug start and the MMSE gain after 3 months of therapy (Calabria et al., 2009; Wallin et al., 2011; Wattmo et al., 2011). But less is known about AD-related genetic loci. Previous studies have applied a candidate-gene approach focusing on the apolipoprotein-E (APOE) epsilon 4 (e4) allele ( Blesa et al., 2006; Choi et al., 2008), BCHE ( Chianella et al., 2011; Scacchi et al., 2009), ACHE ( Scacchi et al., 2009), CHAT ( Harold et al., 2006; Scacchi et al., 2009), PON1 ( Klimkowicz-Mrowiec et al., 2011; Pola et al., 2005), and CYP2D6, the key regulator of acetyl ChEI metabolism ( Cacabelos, 2008; Chianella et al., 2011; Varsaldi et al., 2006). To our knowledge, this is the first genome-wide association study (GWAS) aimed at identifying common genetic variants predictive of response to ChEI in an Italian sample of AD patients.