Interaction between prion protein and interleukin-1A genes increases early-onset Alzheimer’s disease risk

Abstract

Sirs: Individuals homozygous for a common polymorphism (methionine [M]/valine [V]) at codon 129 in the gene (PRNP) encoding the prion protein (PrP) are at increased risk of developing Creutzfeldt-Jakob disease [1] and other neurodegenerative processes including Alzheimer’s disease (AD) [6, 8, 15]. Given the extensive heterogeneity of PRNP 129 polymorphism frequencies across ethnic groups [11], homozygosity at PRNP 129 seems to be a risk factor for AD in some European populations (Dutch [6], German [15] and Polish [8]) but this association was not confirmed by studies in Spanish [3], Italian [2]and Japanese [12] populations. The postulated common pathway of PrP and interleukin-1A (IL-1A) in the cytokine-mediated inflammation occurring in the experimentally-induced prion disease [13, 17], prompted us to investigate the interaction between PRNP 129 and IL-1A ()889) polymorphisms in determining the risk of early-onset and late-onset AD. The study included 258 AD patients (68% women; mean age at the time of study 75.4 years; SD 9.3; range 50–98 ; mean age at onset 71.6 years; SD 9.2; range 48–95 ) who met NINCDS/ADRDA criteria for probable AD. As assessed by Mini Mental State Examination (MMSE), 24% of AD cases had scores between 24 and 18, 38% had scores between 18 and 12, and 38% of patients had scores lower than 12. All AD cases were defined as sporadic because their family history did not mention any first-degree relative with dementia; this information was obtained by direct interviews with relatives. Control subjects consisted of 249 unrelated individuals (70% women; mean age 80.0 years; SD 7.9; range 63–98 years) who had complete neurological and medical examinations establishing that they were free of significant illness and all had MMSE scores of 28 or more. Control subjects were randomly selected from a nursing home, and they arose from the same base population as the cases. Cases and controls were stratified into two age groups: according to the median age at onset of AD patients and age of controls at sampling together (76 years) as a cut-off point, early age at onset was defined as £ 76 years and late age at onset as > 76 years. The AD and control samples were Caucasians originating from a homogeneous population in a limited geographical area in Northern Spain. All patients and control subjects were ascertained to have parents and grandparents born in Northern Spain to ensure ethnicity; consequently, possible confounding effects of the inclusion in the study of members of different ethnic groups have been minimized. Blood samples were taken after written informed consent had been obtained from the subjects or their representatives. The study was approved by the ethical committee of the University Hospital ‘‘Marques de Valdecilla’’. The PRNP 129 and IL-1A ()889) polymorphisms were determined as described previously [3, 4]. Association between dichotomous variables was analyzed with odds ratio, and 95% confidence intervals were estimated by the Cornfield method or the exact method. P-values were estimated by chi-square or Fisher exact tests. Interrelations were analyzed by multiple logistic regression. All statistical analysis were performed with the package Stata Intercooled, version 8/SE (Stata Corporation, College Station, Texas, USA). The distributions of the PRNP 129 (p = 0.090) and IL-1A ()889) (p = 0.060) genotypes were in Hardy-Weinberg equilibrium. Stratification of the data by age groups (Table 1), indicated that in the early-onset (£ 76 years) group the adjusted OR in the subjects who only carried the PRNP 129 M/ M genotype was 0.80 (95% CI 0.322.00, p = 0.632) and in those with only the IL-1A ()889) allele 2 (1/2 and 2/2 genotypes) it was 1.71 (95% CI 0.68-4.31, p = 0.254); however, the subjects carrying both the PRNP 129 M/M genotype and the IL-1A ()889) allele 2 (1/2 and 2/2 genotypes) had about a O. Combarros (&) AE P. Sanchez-Juan I. Mateo AE J. Infante AE E. Rodriguez C. Sanchez-Quintana AE J. Berciano Neurology Service ‘‘Marques de Valdecilla’’ University Hospital University of Cantabria 39008 Santander, Spain Fax: +34-942/202655 E-Mail: combarro@unican.es