Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: the NIMH Alzheimer Disease Genetics Initiative.
Tumor necrosis factor (TNF), a proinflammatory cytokine, may be involved in the pathogenesis of Alzheimer disease (AD) based on observations that senile plaques have been found to upregulate proinflammatory cytokines. Additionally, nonsteroidal anti-inflammatory drugs have been found to delay and prevent the onset of AD. A collaborative genome-wide scan for AD genes in 266 late-onset families implicated a 20 centimorgan region at chromosome 6p21.3 that includes the TNF gene. Three TNF polymorphisms, a -308 TNF promoter polymorphism, whose TNF2 allele is associated with autoimmune inflammatory diseases and strong transcriptional activity, the -238 TNF promoter polymorphism, and the microsatellite TNFa, whose 2 allele is associated with a high TNF secretion, were typed in 145 families consisting of 562 affected and unaffected siblings. These polymorphisms formed a haplotype, 2-1-2, respectively, that was significantly associated with AD (P = 0.005) using the sibling disequilibrium test. Singly, the TNFa2 allele was also significantly associated (P = 0.04) with AD in these 145 families. This TNF association with AD lends further support for an inflammatory process in the pathogenesis of AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:823-830, 2000.
Collins
J S
JS
Department of Epidemiology and International Health, University of Alabama at Birmingham, Birmingham, Alabama 35294-0022, USA.
Perry
R T
RT
Watson
B
B
Harrell
L E
LE
Acton
R T
RT
Blacker
D
D
Albert
M S
MS
Tanzi
R E
RE
Bassett
S S
SS
McInnis
M G
MG
Campbell
R D
RD
Go
R C
RC
D017668:Age of Onset; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D004247:DNA / Q000235:genetics; D005192:Family Health; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008126:Lod Score; D018895:Microsatellite Repeats; D009315:National Institute of Mental Health (U.S.); D009679:Nuclear Family; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D012984:Software; D018709:Statistics, Nonparametric; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D014481:United States
D014409:Tumor Necrosis Factor-alpha; D004247:DNA