Red with ApoE e4 non-carriers. After stratified by ApoE e4 status, SNP3 was significantly associated with an increased LOAD risk [TT vs. CC: AOR = 3.07, 95 CI = 1.49?.33, p = 0.004, Table 5] among ApoE e4 non-carriers, which remained statistically significant after Bonferroni correction (a = 0.05/5). However, no significant association was observed for SNP3 in ApoE e4 carriers. Similar findings were observed for SNP4 among ApoE e4 non-carriers (GC vs. GG: AOR = 1.82, 95 CI = 1.11?.96, Table 5). For TLR4 haplotypes, ApoE e4 status significantly modified the association Title Loaded From File between TLR4 HAP1 and the risk of LOAD (pinteraction = 0.01, Table 4). After stratified by ApoE e4 status, ApoE e4 non-carriers carrying 1 or 2 Title Loaded From File copies of HAP1 had a decreased risk of LOAD [1 vs. 0 copies: AOR = 0.59, 95 CI = 0.36?.96; 2 vs. 0 copies: AOR = 0.31, 95 CI = 0.14?.67, p = 0.003]. These associations 23727046 remained statistically significant after Bonferroni correction (a = 0.05/4).DiscussionThis study is the first to assess the association between five TLR4 htSNPs and LOAD risk. These htSNPs captured abundant genetic information in TLR4 gene and were representative of Chinese ethnic group. We found that homozygosity rs1927907 (SNP3) was significantly associated with an increased risk of LOAD, which has not been explored previously. rs1927907 is an intronic SNP and may affect LOAD risk via regulating the alternative splicing andSequence Variants of TLR4 and Alzheimer’s DiseaseTable 6. Association between TLR4 SNPs and LOAD risk by hypertension status.Co-dominant modela 0 copies Case/Control SNP1 No Yes SNP2 No Yes SNP3 No Yes SNP4 No Yes SNP5 No Yes 123/159 83/182 1.00 1.00 33/40 15/45 1.17 (0.59?.32) 0.73 (0.34?.55) 3/1 2/4 0.51 (0.01?2.48) 0.74 (0.07?.70) 0.59 103/128 61/145 1.00 1.00 53/61 37/84 1.51 (0.84?.72) 1.22 (0.66?.26) 7/15 6/9 1.07 (0.31?.73) 1.07 (0.24?.85) 0.86 80/109 53/133 1.00 1.00 57/74 27/80 1.04 (0.58?.86) 0.78 (0.40?.54) 24/15 19/17 1.75 (0.67?.57) 3.60 (1.47?.84)* 0.57 117/157 79/178 1.00 1.00 40/45 21/54 1.30 (0.69?.47) 0.95 (0.47?.91) 4/4 1/5 0.31 (0.03?.45) 0.47 (0.05?.59) 0.76 50/78 42/83 1.00 1.00 68/87 37/121 1.37 (0.74?.53) 0.64 (0.34?.22) 44/42 25/37 1.15 (0.55?.38) 1.39 (0.65?.98) 0.18 AOR 1 copy Case/Control AOR (95 CI) 2 copies Case/Control AOR (95 CI)pinteractionAll models were adjusted for age, gender, education, and ApoE e4 status. Abbreviations: LOAD, late-onset Alzheimer’s disease; AOR, adjusted odds ratio; CI, confidence interval; SNP, single nucleotide polymorphism. Numbers in bold indicates statistically significant findings(p,a = 0.05). a 0 copies, wild type; 1 copy, heterozygotes; 2 copies, homozygous variants. *The result remained significant (2 copies of variant SNP3 in hypertensive persons, p = 0.002) after controlling for type I error by using Bonferroni correction (a = 0.05/5). Before stratification, hypertensive patients showed a decreased the risk of LOAD (AOR = 0.41, 95 CI = 0.28?.61). doi:10.1371/journal.pone.0050771.tthe subsequent protein production [32]. Sequence variants of TLR4 may enhance the production of pro-inflammatory molecules and cytokine that leads to an increased risk of LOAD (Figure 2). Although five htSNPs are located in one linkage disequilibrium (LD) block (Figure 1), the pairwise correlations between TLR4 htSNPs were not strong (most of pairwise r2,0.40). This may explain the sole significant association for rs1927907 (SNP3) but not for other TLR4 htSNPs in the same block. Only two TLR4 SNPs.Red with ApoE e4 non-carriers. After stratified by ApoE e4 status, SNP3 was significantly associated with an increased LOAD risk [TT vs. CC: AOR = 3.07, 95 CI = 1.49?.33, p = 0.004, Table 5] among ApoE e4 non-carriers, which remained statistically significant after Bonferroni correction (a = 0.05/5). However, no significant association was observed for SNP3 in ApoE e4 carriers. Similar findings were observed for SNP4 among ApoE e4 non-carriers (GC vs. GG: AOR = 1.82, 95 CI = 1.11?.96, Table 5). For TLR4 haplotypes, ApoE e4 status significantly modified the association between TLR4 HAP1 and the risk of LOAD (pinteraction = 0.01, Table 4). After stratified by ApoE e4 status, ApoE e4 non-carriers carrying 1 or 2 copies of HAP1 had a decreased risk of LOAD [1 vs. 0 copies: AOR = 0.59, 95 CI = 0.36?.96; 2 vs. 0 copies: AOR = 0.31, 95 CI = 0.14?.67, p = 0.003]. These associations 23727046 remained statistically significant after Bonferroni correction (a = 0.05/4).DiscussionThis study is the first to assess the association between five TLR4 htSNPs and LOAD risk. These htSNPs captured abundant genetic information in TLR4 gene and were representative of Chinese ethnic group. We found that homozygosity rs1927907 (SNP3) was significantly associated with an increased risk of LOAD, which has not been explored previously. rs1927907 is an intronic SNP and may affect LOAD risk via regulating the alternative splicing andSequence Variants of TLR4 and Alzheimer’s DiseaseTable 6. Association between TLR4 SNPs and LOAD risk by hypertension status.Co-dominant modela 0 copies Case/Control SNP1 No Yes SNP2 No Yes SNP3 No Yes SNP4 No Yes SNP5 No Yes 123/159 83/182 1.00 1.00 33/40 15/45 1.17 (0.59?.32) 0.73 (0.34?.55) 3/1 2/4 0.51 (0.01?2.48) 0.74 (0.07?.70) 0.59 103/128 61/145 1.00 1.00 53/61 37/84 1.51 (0.84?.72) 1.22 (0.66?.26) 7/15 6/9 1.07 (0.31?.73) 1.07 (0.24?.85) 0.86 80/109 53/133 1.00 1.00 57/74 27/80 1.04 (0.58?.86) 0.78 (0.40?.54) 24/15 19/17 1.75 (0.67?.57) 3.60 (1.47?.84)* 0.57 117/157 79/178 1.00 1.00 40/45 21/54 1.30 (0.69?.47) 0.95 (0.47?.91) 4/4 1/5 0.31 (0.03?.45) 0.47 (0.05?.59) 0.76 50/78 42/83 1.00 1.00 68/87 37/121 1.37 (0.74?.53) 0.64 (0.34?.22) 44/42 25/37 1.15 (0.55?.38) 1.39 (0.65?.98) 0.18 AOR 1 copy Case/Control AOR (95 CI) 2 copies Case/Control AOR (95 CI)pinteractionAll models were adjusted for age, gender, education, and ApoE e4 status. Abbreviations: LOAD, late-onset Alzheimer’s disease; AOR, adjusted odds ratio; CI, confidence interval; SNP, single nucleotide polymorphism. Numbers in bold indicates statistically significant findings(p,a = 0.05). a 0 copies, wild type; 1 copy, heterozygotes; 2 copies, homozygous variants. *The result remained significant (2 copies of variant SNP3 in hypertensive persons, p = 0.002) after controlling for type I error by using Bonferroni correction (a = 0.05/5). Before stratification, hypertensive patients showed a decreased the risk of LOAD (AOR = 0.41, 95 CI = 0.28?.61). doi:10.1371/journal.pone.0050771.tthe subsequent protein production [32]. Sequence variants of TLR4 may enhance the production of pro-inflammatory molecules and cytokine that leads to an increased risk of LOAD (Figure 2). Although five htSNPs are located in one linkage disequilibrium (LD) block (Figure 1), the pairwise correlations between TLR4 htSNPs were not strong (most of pairwise r2,0.40). This may explain the sole significant association for rs1927907 (SNP3) but not for other TLR4 htSNPs in the same block. Only two TLR4 SNPs.
