Gene to AD via its role in innate immunity. Two TLR

Gene to AD via its role in innate immunity. Two TLR4 missense polymorphisms (Asp299Gly, equivalent to rs4986790; Thr399Ile, equivalent to rs4986791) have been related to a blunted inflammatory response to LPS [12]. Asp299Gly may affect the production of pro-inflammatory cytokines [13] and has been associated with an increased risk of AD in two Italian studiesSequence Variants of TLR4 and Alzheimer’s DiseaseTable 1. Characteristics of the study population.[21,22,23]. This study further 1655472 explored how these factors and ApoE e4 status modify the association above.Variables Age (mean6SD) Female ( ) Education ( ) , 6 years = 6?2years .12 years BMI at age 40 s, kg/ m2(mean6SD) Cigarette smoking ( ) Alcohol consumption ( ) Type 2 DM ( ) Hypertension ( ) Hypercholesteremia ( ) ApoE e4 carriers ( )LOAD N = 269 79.866.3 172 (64)Control N = 449 p 73.265.8 234 (52) ,0.001* 0.002* ,0.001*Materials and Methods Study PopulationThis was a case-control study. A total of 294 LOAD cases were recruited from the neurology clinics of three teaching hospitals in northern 76932-56-4 web Taiwan from 2007 to 2010. Healthy controls (n = 503) were recruited from elderly health checkup and volunteers of the hospital during the same period of time. All participants were Taiwanese aged 65 years or older. Participants with the history of the following diseases were excluded: depression, Parkinson’s disease, hemorrhagic or ischemic stroke, cerebral infarction, or organic brain TA 02 web tumors. A questionnaire was administered to collect information on demography, vascular risk factors (hypertension, hypercholesteremia, and type 2 DM), and life style (cigarette smoking and alcohol consumption, etc.). For each participant, a blood sample was collected in a tube containing sodium EDTA. After centrifugation, genomic DNA was extracted from buffy coat by QuickGeneMini80 system (Fujifilm, Tokyo, Japan) and then stored in a 280uC freezer. After further exclusion of participants without blood samples, a total of 269 cases and 449 controls were included for data analyses.136 (51) 91 (34) 39 (15) 22.663.1 62 (23) 32 (12) 50 (17) 104 (39) 49 (18) 105 (39)51 (11) 179 (40) 217 (48) 22.462.8 76 (17) 49 (11) 63 (13) 241 (54) 133 (30) 66 (15) 0.43 0.05 0.69 0.11 ,0.001* 0.001* ,0.001**p value,0.05 was obtained by comparing LOAD cases and controls. Abbreviations: LOAD, late-onset Alzheimer’s disease; SD, standard deviation; BMI, body mass index; DM, diabetes mellitus; ApoE e4, apolipoprotein E e4. doi:10.1371/journal.pone.0050771.t[14,15]. However, both Thr399Ile and Asp299Gly are very rare in Chinese [16] and other populations (Indonesian, Papuan, Trio Indians in Surinam) [17]. In addition, TLR4/11367, a SNP in the 39 untranslated region (UTR), has been associated with an increased risk of AD in a Chinese population [18]. In summary, few studies have assessed the association between TLR4 polymorphisms and the risk of AD, and only 1 or 2 TLR4 SNPs were explored previously. TLR4 plays an important role in inflammation and age-related diseases [19]. Past studies relating TLR4 polymorphisms to AD risk have been limited to few coding SNPs in TLR4 (Table S1). In addition, apolipoprotein E (ApoE) e4 is an important risk factor of AD but has low sensitivity (about 0.4) in screening late-onset (aged 65 or older) AD (LOAD) patients [20]. Therefore, this study was aimed to identify genetic marker(s) supplementary to ApoE e4 for identifying LOAD. We used a systematic approach to select TLR4 haplotype-tagging single nucleo.Gene to AD via its role in innate immunity. Two TLR4 missense polymorphisms (Asp299Gly, equivalent to rs4986790; Thr399Ile, equivalent to rs4986791) have been related to a blunted inflammatory response to LPS [12]. Asp299Gly may affect the production of pro-inflammatory cytokines [13] and has been associated with an increased risk of AD in two Italian studiesSequence Variants of TLR4 and Alzheimer’s DiseaseTable 1. Characteristics of the study population.[21,22,23]. This study further 1655472 explored how these factors and ApoE e4 status modify the association above.Variables Age (mean6SD) Female ( ) Education ( ) , 6 years = 6?2years .12 years BMI at age 40 s, kg/ m2(mean6SD) Cigarette smoking ( ) Alcohol consumption ( ) Type 2 DM ( ) Hypertension ( ) Hypercholesteremia ( ) ApoE e4 carriers ( )LOAD N = 269 79.866.3 172 (64)Control N = 449 p 73.265.8 234 (52) ,0.001* 0.002* ,0.001*Materials and Methods Study PopulationThis was a case-control study. A total of 294 LOAD cases were recruited from the neurology clinics of three teaching hospitals in northern Taiwan from 2007 to 2010. Healthy controls (n = 503) were recruited from elderly health checkup and volunteers of the hospital during the same period of time. All participants were Taiwanese aged 65 years or older. Participants with the history of the following diseases were excluded: depression, Parkinson’s disease, hemorrhagic or ischemic stroke, cerebral infarction, or organic brain tumors. A questionnaire was administered to collect information on demography, vascular risk factors (hypertension, hypercholesteremia, and type 2 DM), and life style (cigarette smoking and alcohol consumption, etc.). For each participant, a blood sample was collected in a tube containing sodium EDTA. After centrifugation, genomic DNA was extracted from buffy coat by QuickGeneMini80 system (Fujifilm, Tokyo, Japan) and then stored in a 280uC freezer. After further exclusion of participants without blood samples, a total of 269 cases and 449 controls were included for data analyses.136 (51) 91 (34) 39 (15) 22.663.1 62 (23) 32 (12) 50 (17) 104 (39) 49 (18) 105 (39)51 (11) 179 (40) 217 (48) 22.462.8 76 (17) 49 (11) 63 (13) 241 (54) 133 (30) 66 (15) 0.43 0.05 0.69 0.11 ,0.001* 0.001* ,0.001**p value,0.05 was obtained by comparing LOAD cases and controls. Abbreviations: LOAD, late-onset Alzheimer’s disease; SD, standard deviation; BMI, body mass index; DM, diabetes mellitus; ApoE e4, apolipoprotein E e4. doi:10.1371/journal.pone.0050771.t[14,15]. However, both Thr399Ile and Asp299Gly are very rare in Chinese [16] and other populations (Indonesian, Papuan, Trio Indians in Surinam) [17]. In addition, TLR4/11367, a SNP in the 39 untranslated region (UTR), has been associated with an increased risk of AD in a Chinese population [18]. In summary, few studies have assessed the association between TLR4 polymorphisms and the risk of AD, and only 1 or 2 TLR4 SNPs were explored previously. TLR4 plays an important role in inflammation and age-related diseases [19]. Past studies relating TLR4 polymorphisms to AD risk have been limited to few coding SNPs in TLR4 (Table S1). In addition, apolipoprotein E (ApoE) e4 is an important risk factor of AD but has low sensitivity (about 0.4) in screening late-onset (aged 65 or older) AD (LOAD) patients [20]. Therefore, this study was aimed to identify genetic marker(s) supplementary to ApoE e4 for identifying LOAD. We used a systematic approach to select TLR4 haplotype-tagging single nucleo.