Interleukin‐6–174 G/C Promoter Gene Polymorphism C Allele Reduces Alzheimer's Disease Risk

To the Editor: Alzheimer's disease (AD) pathophysiology encompasses a variety of neurodegenerative, inflammatory, metabolic, and genetic aspects. The cytokine interleukin-6 (IL-6) is reported to play a role in AD pathogenesis1-3 and neurodegeneration.3-5 In the IL-6 gene, a G/C (genotype) polymorphism in the promoter at position –174 (prom) is associated with altered IL-6 transcription rates.6 A variable number of tandem repeats (vntr) polymorphism in the IL-6 gene has been reported to be protective2 in AD. Haplotyping vntr and prom polymorphism showed a strong linkage dysequilibrium and demonstrated an interaction that modifies AD risk in the presence of the prom C allele,1 but, for the prom polymorphism alone, no association was found.1 We examined whether the prom polymorphism has protective properties in carriers versus noncarriers of the C allele in our population. The apolipoprotein E (ApoE) ɛ4 allele is a known genetic risk factor in AD. Therefore, a possible interaction with the IL-6 prom polymorphism was examined as well. We studied the IL-6 prom polymorphism and the ApoE genotype in German Caucasian AD patients (n = 101, 40 male, 61 female; mean age ± standard deviation = 72.5 ± 9.6) diagnosed according to National Institute of Neurological and Communicative Diseases and Stroke—Alzheimer's Disease and Related Disorders Association criteria.7 Healthy individuals (without cognitive impairment (n = 133, 64 male, 67 female; mean age = 48.9 ± 12.6) were included in a population-based sample as controls. The local ethical committee approved the study protocol. Informed consent was obtained from all subjects. IL-6 prom and ApoE genotypes were determined as described previously.1 Genotype and allele frequencies were compared between cases and controls using chi-square and Fisher exact tests. The odds ratio (OR) for AD according to IL-6 prom polymorphism was calculated based on presence of the prom C allele and allele frequencies using a logistic regression model. Patients and controls were sex matched; groups differed significantly in age distribution (P < .01). IL-6 prom genotypes and allele frequencies are shown in Table 1. Under the hypothesis that the C allele is protective, C allele frequency (CC and GC vs GG) of AD patients and controls was compared. A higher frequency of the C allele was found in the control group (Fisher exact test, one-tailed significance P = .04). The OR was 0.6 (90% confidence interval = 0.38–0.94, P = .03). Unadjusted data (CC vs GC vs GG) failed to reveal an association between IL-6 prom genotype and AD. No interaction between ApoE and IL-6 prom genotypes could be detected (Chi squared = 1.8, p = 0.23). We report a statistically significant risk-reducing association of the C allele of the IL-6 prom polymorphism in AD. An interaction with the IL-6 vntr polymorphism has been described,1 but the association with the IL-6 prom polymorphism alone had not previously been detected.2, 8 Therefore, a risk-reducing role of the prom C allele in carriers versus noncarriers has not yet been considered. The fact that the C allele is associated with lower plasma levels of IL-6 in healthy individuals6 supports these retrospective data of a relative risk reduction (OR = 0.7) and the protective role of the prom C allele in AD. The control group was younger than the AD group, but a risk-modifying effect in an age-matched control group has been reported.1 Therefore, it can be assumed that the results found in our sample are not merely due to an age-related effect. These data suggest that the presence of the C allele of the prom polymorphism in the IL-6 gene, even in heterozygous carriers, reduces AD risk.