Similarly, our evidence suggested that allele A of TOMM40 rs2075650 polymorphism was a risk factor for AD (OR=2.87, 95% CI: 2.46-3.34, P value <0.001).
Both methods' results showed two identical significant SNPs associated with the A β-42 levels in CSF (rs2075650 at intron region TOMM40 with p-value ≥ 1 × 10-16 and rs439401 in the intergenic region of LOC100129500 and APOC1 with p-value ≥ 1 × 10-9) and highlighted APOC1 and TOMM40, which are well-known genes previously associated with AD.
Our prevalent case study comparing prevalent AD cases (n = 428) with participants with no cognitive impairment (n = 524) revealed a significant association of rs6656401 and rs3818361 (CR1), rs2075650 (TOMM40), rs7561528 (BIN1), and rs3865444 (CD33) with late-onset AD that were robust to adjustment with age and apolipoprotein E ε4 genotype.
However, Kaplan-Meier survival analyses suggest that AD patients with TOMM40 allele rs2075650-G have an average age of disease onset of 6 years earlier compared with carriers of the A allele.
The SNPs rs2075650 and rs4420638 were linked to the most replications within a single reclassified phenotype or very similar reclassified phenotypes; both were associated with Alzheimer's disease (AD).
In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058).
Recently, the rs2075650 single nucleotide polymorphism in the translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene was identified as a risk factor for AMD and Alzheimer disease.
Three SNPs [rs429358 in APOE: odds ratio (OR)=4.24, 95% confidence interval (CI)=3.01-5.96, P=1.23×10; rs2075650 in APOE: OR=3.57, 95% CI=2.51-5.06, P=1.23×10; and rs677909 in PICALM: OR=0.63, 95% CI=0.49-0.81, P=0.00036, log additive model] were significantly associated with AD susceptibility after correction for multiple testing.
There were four significant associations between genotypes and phenotypes of AD patients: CR1 SNP rs11803956 correlated with Mini-Mental State Examination (MMSE) score (β=1.718, Pcorrected=0.002); ABCA7 SNP rs3752232 correlated with Rey Complex Figure Test (RCFT) copy score (β=-6.861, Pcorrected=0.013); APOE SNP rs2075650 correlated with the percentile of RCFT copy score (β=14.005, Pcorrected=0.021) and the percentile of total score in phonemic fluency (β=11.052, Pcorrected=0.035).
The AA genotype of the aging-related single-nucleotide polymorphism (SNP) rs2075650 in TOMM40 has been associated with longevity, while the AG and GG genotypes are associated with an increased risk of Alzheimer's disease.
Our data provide no evidence to support an association of rs2075650 in TOMM40 with nAMD or PCV, suggesting that this gene is unlikely to be a major AMD and PCV susceptibility gene locus in the Chinese population.
In conclusion, our study did not confirm the impact of rs2075650 on advanced AMD risk, indicating that rs2075650 is unlikely a superior marker for APOE/TOMM40 susceptible region with advanced AMD in Han Chinese population.
GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD.
Alleles A of CD33 rs3865444 and A of TOMM40 rs157580 were both protective factors for AD onset (OR=0.94, 95% CI: 0.90-0.98, P value=0.003; OR=0.62, 95% CI: 0.57-0.66, P value <0.001).
We found 2 independent associations among European-Americans in the 19q13.32 region: rs769449 (APOE intron; p = 3.1 × 10(-20)) and rs115881343 (TOMM40 intron; p = 6.6 × 10(-11)). rs769449 was also associated with cognitive decline among African-Americans (p = 0.005), but rs115881343 was not.
The minor allele (G) (CAD risk allele) of rs2075650 (TOMM40/APOE) was associated with lower levels of high-sensitivity C-reactive protein (effect per risk allele: -0.37 mg/l [95%CI -0.56 to -0.18 mg/l]).
We previously discovered that a polymorphic, deoxythymidine-homopolymer (poly-T, rs10524523) in intron 6 of the TOMM40 gene is associated with age-of-onset of Alzheimer's disease and with cognitive performance in elderly.
Thirty-two presenilin 1 (PSEN1) mutation carriers with AD, 27 presenilin 2 (PSEN2) mutation carriers with AD, 59 participants with late-onset AD (LOAD), and 168 autopsied subjects from a community-based cohort were genotyped for TOMM40 intron 6 poly-T (rs10524523) length using short tandem repeat assays.
A number of recent studies have not replicated the association of the translocase of the outer mitochondrial membrane pore subunit (TOMM40) rs10524523 polymorphism, which is in linkage disequilibrium with apolipoprotein E (APOE), with age of onset of Alzheimer's disease (AD).