APOE-TOMM40 haplotypes and Alzheimer’s disease

phenotypes Dmitry Goldgaber 1, Alexander Vostrov*1, Lon White2

1Psichiatry and Behavioral Sciences, Stony Brook university, Stony Brook, United States, 2Pacific Health Research and Education Institute, Honolulu,

United States

• AD could be subdivided in familiar and sporadic type.

• Most sporadic cases represent Late Onset Alzheimer’s Disease (LOAD) which is the subject of this study. LOAD accounts for more than 80% of all AD cases.

• While mutations in several genes were found to cause familiar AD, only the APOE gene was identified as a risk factor for LOAD.

LOAD and APOE

• APOE gene is located on Chr.19 and is flanked by TOMM40 and APOC genes

• A small number of studies showed that genetic variations in the TOMM40 and APOC could be associated with LOAD in addition to APOE.

TOMM40 APOE APOC

Roses AD, et al. 2010. “A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease.”

• The length of the variable poly-T affected the age of onset in LOAD patients with APOE3/4 genotype.

• The lengths of the variable poly-T were associated with specific APOE genotypes.

rs10524523

rs10524523 is a variable poly-T region located in the Intron 6 of the TOMM40 gene

Chr19 …ATTGCATCTGGCTTTTT………TTTTTTGAGATGGG…

from 12 to 50 bp

Populations studied

1. 332 participants of Honolulu-Asia Aging Study (HAAS), a community based study involving male Hawaiian residents of Japanese origin.

2. 192 Caucasian residents of Great Britain, healthy controls, both males and females.

Population ApoE2/2 ApoE2/3 ApoE2/4 ApoE3/3 ApoE3/4 ApoE4/4 total

Japanese 2 (0.6%) 26 (7.8%) 4 (1.2%) 223 (67.2%) 73 (22.0%) 4 (1.2%) 332

European 0 (0%) 21 (10.9%) 4 (2.1%) 119 (62.0%) 47 (24.5%) 1 (0.5%) 192

TOMM40 poly-T lengths associated with ApoE2

TOMM40 poly-T lengths associated with ApoE3

TOMM40 poly-T lengths associated with ApoE4

APOE promoter SNPs.

• Several reports described associations of cpecific Single Nucleotide Polymorphisms (SNPs) in the promoter region of the APOE gene with LOAD.

• In this study we sequenced promoter region in two populations.

• We found that TOMM40 poly-T region, 5 APOE promoter SNPs and APOE genotypes formed haplotypes.

APOE promoter SNPs observed in our study

• Only 5 SNPs were observed in the sequenced area with allelic frequencies of more than 1%. We designated them from rs1 through rs5. The database Id’s and the reference alleles are shown below:

APOE2 related haplotypes

APOE3 related haplotypes

APOE4 related haplotypes

n Age Cog AD LB MVL HS Hap Group poly-T rs1 rs2 rs3 rs4 rs5 ApoE (%) Dth Imp Index Index Index Index LoBrWt Diabetes MS-3

E23pT1616 16 A A C G G 2 8 4.9 ns 0.16 ns ns ns ns ns ns16 A A T G G 3 (2.5) (1.16-20.9) (0.02-1.28)

E23pT16L 16 A A C G G 2 15 ns ns ns ns 0.23 ns 3.5 ns 3.1VL A A T T C 3 (4.7) (0.05-1.05) (1.23-10.25 (1.12-8.75)

E23other 16 or 29 various combinations 2 3 ns ns ns ns ns ns ns ns ns16 or VL various combinations 3 (1.0)

E33pT16L 16 A A T G G 3 86 ns ns ns ns ns ns ns ns nsVL A A T T C 3 (26.7)

E33pTLL VL A A T T C 3 83 1 1 1 1 1 1 1 1 1VL A A T T C 3 (25.8) ref ref ref ref ref ref ref ref ref

E33pT1616 16 A A T G G 3 15 ns ns ns ns ns ns ns ns ns16 A A T G G 3 (4.7)

E33pT1629 16 A A T G G 3 13 ns ns ns ns ns ns ns ns ns29 A A T T C 3 (4.0)

E33other 16 or VL various combinations 3 26 ns ns ns ns ns ns ns ns ns16 or VL various combinations 3 (8.1)

E34pTL29 VL A A T T C 3 33 ns 2.5 2.5 ns ns ns ns ns 2.729 A A T T G 4 (10.3) (0.89-6.98) (1.28-5.68) (1.30-5.79)

E34pT1629 16 A A T G G 3 16 ns 2 2.7 14.1 2.8 6.6 ns ns ns29 A A T T G 4 (5.0) (0.93-4.36) (0.94-6.61) (3.46-57.8) (1.02-7.43) (1.64-26.7)

E34pTL15 VL A A T T C 3 10 ns 3.3 ns 5.4 ns ns ns ns ns15 G T T T G 4 (3.1) (0.91-11.7) (0.84-34.6)

E34 other 16 or VL various combinations 3 14 ns ns ns ns ns ns ns ns ns15 or 29 various combinations 4 (4.5)

Observed haplotypes in 322 Hawaiian Japanese participants; frequencies associated with phenotypes

Conclusions

1. A strong haplotypical relationship between (rs10524523 poly-T) – (APOE promoter SNPs)-(APOE genotype SNPs) was observed in both population groups.

2. While the most frequent haplotypes were the same, ethnicity-specific haplotypes were also observed.

3. Cognitive impairment and Alzheimer brain lesion index were associated with APOE4 related haplotypes in the Japanese group

4. There was a statistically significant association of specific haplotypes with certain pathological features in the brains of APOE3/4 participants.

Acknowledgements