Genotypes and haplotypes in the IL-1 gene cluster: analysis of two genetically and diagnostically distinct groups of Alzheimer patients.
Increased risk of Alzheimer's disease (AD) has been associated with polymorphisms in the IL-1 gene cluster, and in particular with the IL-1alpha-889 T/T genotype. However, this association is still unclear, and needs further investigation. In order to clarify the role of these polymorphisms in the complex pathogenesis of AD we examined genotype and haplotype frequencies of the two C-to-T SNPs at position -889 and -551 in the IL-1alpha and IL-1beta genes, respectively, and of the 86 bp VNTR intron-2 polymorphisms in the IL-1Ra gene. The analysis was performed in two genetically and diagnostically distinct groups of sporadic AD from Italy and the USA. In the Italian group a significant association between the IL-1alpha-889 T/T genotype and AD (OR=3.022, 95% CI: 1.001-9.119) was found, whereas no difference was found in the group from the USA. Results were also compared with previously published studies that analyzed the same IL-1 polymorphisms in AD. In both groups, the analysis of the estimated haplotypes shows that AD patients and controls who carry the IL-1beta-511 C allele, were also more frequently carriers of the IL-1Ra 1 allele (haplotypes -C-1). The total frequency of the two -C-1 haplotypes (C-C-1 plus T-C-1) was about one half of the total frequency of the eight estimated haplotypes. This was confirmed by significant linkage disequilibrium between these two loci in both the Italian and USA groups. In the Italian group a weak association of the T-C-2 haplotype with the disease (OR=1.648, 95% CI: 1.519-1.788) was also found, whereas in the USA group no difference was found. Although ours and other published data on different samples of Caucasian and non-Caucasian AD show a great heterogeneity in the frequencies of the IL-1alpha-889, the IL-1beta-511 and the IL-1Ra VNTR gene polymorphisms, we confirm the role of the IL-1alpha-889 T/T genotype as a risk factor for sporadic AD, and show the presence of an allelic association between IL-1beta C and IL-1Ra 1 alleles in both the Italian and the USA groups, confirmed by the presence of significant levels of linkage disequilibrium between these two loci.
Seripa
Davide
D
Laboratory of Gene Therapy, I.R.C.C.S. Casa Sollievo della Sofferenza, Padre Pio da Pietrelcina Foundation, San Giovanni Rotondo, FG, Italy. dseripa@operapadrepio.it
Matera
Maria G
MG
Dal Forno
Gloria
G
Gravina
Carolina
C
Masullo
Carlo
C
Daniele
Antonio
A
Binetti
Giuliano
G
Bonvicini
Cristian
C
Squitti
Rosanna
R
Palermo
Mark T
MT
Davis
Daron G
DG
Antuono
P
P
Wekstein
David R
DR
Dobrina
Aldo
A
Gennarelli
Massimo
M
Fazio
Vito M
VM
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics*; D000704:Analysis of Variance; D016009:Chi-Square Distribution; D016000:Cluster Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007375:Interleukin-1 / Q000145:classification / Q000235:genetics*; D007558:Italy / Q000453:epidemiology; D015810:Linkage Disequilibrium; D008875:Middle Aged; D018598:Minisatellite Repeats / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012307:Risk Factors; D018709:Statistics, Nonparametric; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics
D007375:Interleukin-1; D012333:RNA, Messenger