In addition to replicating findings for rs1800796 explored in previous Asian studies [12
], this study for the first time identifies two IL-6
htSNPs (rs2069837 and rs1524107) representative for the Chinese population, and rs1524107 showed a significant association with LOAD. We found that a variant of SNP rs1800796 is significantly associated with decreased risk of LOAD, which is consistent with the findings from a Chinese study [12
]. In addition, we found that the intronic SNP rs1524107 and a haplotype CAT have a significant protective effect on LOAD risk, which has not been reported previously. Unlike rs1800796 and rs1524107, variant rs2068937 was not significantly associated with LOAD (Table ). Although they are located in one block [i.e., highly linkage disequilibrium (LD) with dark gray in Figure ], rs2068937 shows a low correlation with rs1800796 (r2
= 0.58) and rs1524107 (r2
= 0.62) which explains its lack of a significant association with LOAD.
rs1800796 is a promoter SNP, which may enhance transcription efficiency [28
] and affect plasma CRP levels [29
] and subsequent inflammatory responses. These results indicate that the promoter SNP rs1800796 might be involved in the course of inflammation, and the variant rs1800796 could alter IL-6 production in the development of AD. Sequence variants of rs1524107 may affect disease risk via their effect on alternative splicing, e.g., altering mRNA folding or the stability of mRNA structure, and subsequent protein production. Besides, the most common IL-6
haplotype CAT, composed of three major alleles, was associated with decreased risk of LOAD. Therefore, carrying 0 or 1 copies of CAT showed consistent protective effects on LOAD risk, as did the variant IL-6
SNPs. These sequence changes may either block or attenuate inflammation signaling which leads to reduced risk of AD. This supports the finding of a protective effect from IL-6
polymorphisms on LOAD. The postulated mechanism of IL-6 in LOAD is demonstrated in Figure .
Figure 2 Postulated pathway of IL-6 and factors involved in the pathogenesis of dementia. Solid lines indicate pathways that have been well documented; dotted lines indicated speculative pathways. Abbreviations: Aβ, beta amyloid; IL-6R, interleukin 6 receptor; (more ...)
Although ApoE e4
status is a well-known predictor for AD risk, over half of AD cases (61% in this study, Table ) do not carry the ApoE e4
allele. Therefore, prediction of LOAD risk among ApoE e4
non-carriers becomes an important task. This study found significant associations between rs1800796 or rs1524107 and LOAD in ApoE e4
non-carriers, which remained statistically significant after correction for type I error by using FDR. A Chinese study [13
] found that the variant rs1800796 was associated with AD risk in ApoE e4
carriers but not in the wider population. This may be a chance finding because a significant protective effect of rs1800796 variants on AD risk was observed only after stratification by ApoE e4
status. In contrast, both He et al. [12
] and our study found a significant association before stratification. A previous study showed that elevated serum IL-6 induces hypertriglyceridemia [30
], which manifests before the deposition of beta amyloid (Aβ) in AD [31
]. Therefore, IL-6
polymorphisms may be important in predicting LOAD in ApoE e4
Genotyping data from public domains (HapMap and dbSNP) show that IL-6 and ApoE SNPs show geographic variations (Table ). MAFs of three IL-6 SNPs (rs1800796, rs2069837, and rs1524107) are similar for controls of this Chinese population (0.19-0.27) and CHB of the HapMap project (0.17-0.29). In comparison with these two Chinese populations, for the same IL-6 SNPs, Japanese populations have lower MAFs (0.10-0.18), and the MAFs are even lower in Caucasians (0.04-0.08). For ApoE SNPs, the MAF of AopE112 (rs429358) is highest among Caucasians (dbSNP: 0.15), followed by controls in this Chinese population (0.08), and by Japanese (0.01) and CHB (0.00) from the HapMap Project. The inconsistency between the two Chinese populations for ApoE112 may be attributable to the small number of samples genotyped in HapMap study (n = 45 for CHB and n = 43 for JPN). For ApoE158 (rs7412), the MAFs were similar between Chinese (0.08-0.11) and Caucasians (0.08) across ethnic groups with a lower value observed in Japanese (0.05).
Hypertension significantly modified the association of IL-6
SNPs with LOAD risk. The protective effect of three IL-6
SNPs for LOAD was especially evident among participants with hypertension (Table ), which may be a result of medication for treating hypertension that can lower inflammatory responses (Figure ). For example, angiotensin receptor blockers or angiotensin-converting enzyme inhibitors have been used to lower blood pressure. Their accompanying neuroprotective effects can reduce neuronal damage and lead to slowed progression of AD [32
]. Sequence variants of IL-6
may lower blood pressure, and subsequent brain hypoperfusion and neural degeneration, which eventually decreases LOAD risk (Figure ). However, experimental studies are needed to clarify the underlying mechanism.
This study had some strengths. First, the htSNPs in IL-6
were identified to explore LOAD risk for the first time. Second, the selection of two representative htSNPs captured abundant genetic information regarding the IL-6
= 1.00) as compared to the genetic information captured by the single promoter SNP (rs1800796, r2
= 0.81) in previous candidate-gene studies [12
]. Third, the associations between IL-6
SNPs and LOAD risk remained significant after correction for type I error using FDR, which indicates that these findings are not chance findings. In addition, high false positive rate in genome-wide association studies prevent identifying SNPs associated with disease outcome but with moderate p
values in the exploratory stage [34
]. This study, which selected htSNPs that are representative for Chinese and captured abundant genetic information for IL-6
, may solve the above issue. Furthermore, brain imaging was used to exclude other diseases with similar presentation as LOAD.
Our study had some limitations. A self-report questionnaire was used to collect information on vascular risk factors (e.g., hypertension, hyperlipidemia, and type 2 DM). Because these diseases/conditions are major health issues, participants' recall of disease/condition diagnosis and their awareness of these diseases/conditions tend to be relatively accurate [35
]. Therefore, information bias should not be a concern.