Association studies of transforming growth factor-β1 and Alzheimer's disease

Substantial laboratory evidence suggests Transforming Growth Factor-beta 1 (TGFB1) is linked to Alzheimer's Disease (AD) pathology. The purpose of the study was to estimate the genetic association of TGFB1 with AD while controlling for apolipoprotein E4 allele (APOE4) status, the only well-established genetic risk factor for AD. Two study populations were genotyped for the TGFB1-509 and +869 single nucleotide polymorphisms (SNPs) that have been associated with TGFB1 levels. Constituting these populations were 203 families from the NIMH AD Genetic Initiative with at least two affected siblings and a normal sibling, and a population of 126 African-American (AA) AD cases versus 93 age matched controls. Results from family-based analyses showed a significant association between the TGFB1 -509 SNP and AD for the entire set of 203 families (P = 0.007), and a subset of these families without a homozygous APOE4 family member (P = 0.026). Results from family-based analyses on the TGFB1 +869 SNP were not significant in the 203 families. While associations for the main effects of the TGFB1 +869 and -509 SNP with AD in the AA case-control study were also not significant, results did indicate that TGFB1 may function as an effect modifier of APOE4 risk. Specifically, the odds of AD associated with having at least one APOE4 allele increased in an additive fashion with one or two copies of the higher producer allele when stratified by TGFB1 -509 genotype and by TGFB1 +869 genotype. Results support a role for TGFB1 in AD pathogenesis. (c) 2005 Wiley-Liss, Inc.