Association of complement factor H Y402H gene polymorphism with Alzheimer's disease

Abstract

Alzheimer's disease (AD) and age-related macular degeneration (AMD) share several epidemiological and biochemical features. The present study aimed to assess the possible influence of the AMD-associated complement factor H (CFH) Y402H (1277T > C) polymorphism on the risk of AD. Caucasian subjects (n = 800) meeting the criteria for probable (n = 717) or definite (n = 83) AD and Caucasian non-demented controls (n = 1265) were included in this multi-center case-control study, in which genotype and allele frequencies of the CFH 1277T > C polymorphism were determined and related to diagnosis, APOE genotype, Mini-Mental State Examination score (MMSE) and the cerebrospinal fluid (CSF) biomarkers total-tau (T-tau), phospho-tau(181) (P-tau(181)), and beta-amyloid(1-42) (Abeta(1-42)). The AMD-associated CFH genotypes (1277CC and 1277TC) were overrepresented in subjects with AD as compared to control individuals (P = 0.029). Positive C carrier status was associated with an odds ratio (OR) for AD of 1.24 (95% confidence interval [CI] 1.02-1.50). When APOE epsilon4 carrier status was included in the regression model, this association was even stronger (OR 1.34, 95% CI: 1.08-1.65, P = 0.007). Subgroup analysis showed that the association between CFH C allele positivity and AD was only evident for individuals carrying the APOE epsilon4 allele. Positive C carrier status was also associated with lower levels of CSF Abeta(1-42) selectively in the control group in an APOE epsilon4-independent manner (P = 0.003). In conclusion, the CFH 1277T > C polymorphism seems to influence the risk of AD and there appears to be an interaction between CFH 1277C and APOE epsilon4 alleles. The CFH 1277C allele may predispose patients for co-morbidity in AD and AMD.

Complement Factor H Binds to Human Serum Apolipoprotein E and Mediates Complement Regulation on High Density Lipoprotein Particles

“…As a result, apoE2 is associated with type III hyperlipoproteinemia (33), and apoE4 is associated with, for example, Alzheimer disease (34). But apoE polymorphism is also associated with AMD, characterized by strong association with FH polymorphism Y402H within the domain 7, and these two polymorphisms could have an additive effect (35,36). It remains, however, to be studied whether the various apoE isoforms affect binding to FH.…”

Genetics of primary progressive multiple sclerosis

“…Complement factor H regulates the formation of C3 and C5 convertase enzymes and the functional Tyr402His allele has been associated with Alzheimer's dementia in individuals carrying the APOE4 allele (Zetterberg et al, 2008). A case (PPMS n ¼ 53, RRMS n ¼ 212, SPMS n ¼ 85)-control (n ¼ 86) study of the Tyr402His allele of complement factor H found no difference in the allele frequency (Ingram et al, 2010).…”

A novel ARC gene polymorphism is associated with reduced risk of Alzheimer’s disease

“…The study material was in part the same as the one used in a number of previous publications (Zetterberg et al 2008;Landgren et al 2010;von Otter et al 2010avon Otter et al , 2010b and consisted of 713 AD cases and 841 individuals without dementia, all of Swedish nationality. Clinical diagnoses were set according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria (McKhann et al 1984) after completion of a detailed clinical examination including medical history, physical, neurological and psychiatric examination, screening laboratory tests, ECG, EEG, chest X-ray and computed tomography of the brain.…”