Cholinergic receptor, neuronal nicotinic, alpha polypeptide 7 (CHRNA7) polymorphism, a well-known genetic marker in many neurological and psychological disorders, is found to interact with apolipoprotein E (APOE) ε4 status and smoking on risk of late-onset Alzheimer’s disease (LOAD), which has not be explored previously. This work was published as an original article in Scientific Reports, June 2, 6: 27231 (2016).
This four-year research was a collaborative project among associate professor Dr. Yen-Ching Karen Chen (principal investigator) and Dr. Pei-Hsuan Weng from Institute of Epidemiology and Preventive Medicine of National Taiwan University, as well as neurologists and geriatricians from National Taiwan University Hospital, Cardinal Tien’s Hospital, and En Chu Kong Hospital in northern Taiwan.
α7 nicotinic acetylcholine receptor (α7nAChR, encoded by CHRNA7) plays a pivotal role in dementia pathogenesis through cholinergic neurotransmission, inducing long-term potentiation and neuroprotective effect. As dementia progresses, elevated amyloid β (Aβ) binds to α7nAChR, inactivating α7nAChR and inhibiting its neuroprotective effect. Smoking promotes atherosclerosis and increases dementia risk, but nicotine exerts neuroprotective effect via α7nAChR in preclinical studies. Previous studies revealed inconsistent associations between CHRNA7 polymorphisms and dementia risk, which may be attributable to differences in ethnicity and lack of information on gene–gene or gene–environment interactions. This study aims at exploring the interactions between CHRNA7 polymorphism, APOE ε4 status and smoking on dementia risk, which are currently unknown.
This case-control study recruited 254 LOAD, 115 vascular dementia (VaD) cases, and 435 controls (age ≥ 65) during 2007–2010. Nine CHRNA7 haplotype-tagging single nucleotide polymorphisms representative for Taiwanese were genotyped. Among APOE ε4 non-carriers, rs7179008 variant and GT haplotype in CHRNA7 block4 was significantly associated with decreased LOAD risk after correction for multiple tests. A significant interaction was found between rs7179008, GT haplotype in block4 and APOE ε4 on LOAD risk. rs7179008 variant also reduced the detrimental effect of smoking on LOAD risk. No significant association was found between CHRNA7 and VaD. The interaction between CHRNA7 polymorphisms and two important risk factors of dementia, APOE ε4 and smoking, helps to understand the complicated etiology of dementia.
Article link: http://www.nature.com/articles/srep27231