Protective association of the ε2/ε3 heterozygote with Alzheimer's disease is strengthened by <i>TOMM40–APOE</i> variants in men

Kulminski, Alexander M.; Philipp, Ian; Loika, Yury; He, Liyun; Culminskaya, Irina

doi:10.1002/alz.12413

Cited by 8 publications

(7 citation statements)

References 68 publications

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“…None of these group-specific SNP-metabolite associations were significant in the pooled sample of the E2, E3, and E4 groups. The group-specific associations indicate genetic heterogeneity of plasma metabolites in the APOE 19q13.3 locus, which is in line with our previous studies that demonstrated complex LD structure differentially affects AD risk in this locus (Kulminski et al, 2018(Kulminski et al, , 2020aNazarian et al, 2022a,b). Therefore, we suggest APOE-stratified analyses are essential for dissecting the genetic architecture of complex diseases and traits sensitive to APOE ε2/ε3/ε4 polymorphism.…”

Section: Discussionsupporting

confidence: 90%

“…The APOE 19q13.3 locus is a genetically heterogenous region within which complex haplotype structures, interactions, and compound genotypes have been identified (Templeton et al, 2005;Yu et al, 2007;Lescai et al, 2011;Lutz et al, 2016;Babenko et al, 2018;Kulminski et al, 2018Kulminski et al, , 2020aKulminski et al, ,b, 2021Zhou et al, 2019;Nazarian et al, 2022a,b). For instance, linkage disequilibrium (LD) and association studies have highlighted complex genetic structure in this locus that are statistically different between AD-affected and unaffected subjects (Kulminski et al, 2018(Kulminski et al, , 2020a. In addition, stratified 10.3389/fnagi.2022.1023493 analyses have identified sets of interactions and compound genotypes in the APOE locus of the ε2and ε4-carriers, which may modify the effects of these alleles on AD risk and, to some extent, justify their incomplete penetrance (Nazarian et al, 2022a,b).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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APOE alleles modulate associations of plasma metabolites with variants from multiple genes on chromosome 19q13.3

Nazarian

Loiko²,

Yassine³

et al. 2022

Front. Aging Neurosci.

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The APOE ε2, ε3, and ε4 alleles differentially impact various complex diseases and traits. We examined whether these alleles modulated associations of 94 single-nucleotide polymorphisms (SNPs) harbored by 26 genes in 19q13.3 region with 217 plasma metabolites using Framingham Heart Study data. The analyses were performed in the E2 (ε2ε2 or ε2ε3 genotype), E3 (ε3ε3 genotype), and E4 (ε3ε4 or ε4ε4 genotype) groups separately. We identified 31, 17, and 22 polymorphism-metabolite associations in the E2, E3, and E4 groups, respectively, at a false discovery rate PFDR < 0.05. These entailed 51 and 19 associations with 20 lipid and 12 polar analytes. Contrasting the effect sizes between the analyzed groups showed 20 associations with group-specific effects at Bonferroni-adjusted P < 7.14E−04. Three associations with glutamic acid or dimethylglycine had significantly larger effects in the E2 than E3 group and 12 associations with triacylglycerol 56:5, lysophosphatidylethanolamines 16:0, 18:0, 20:4, or phosphatidylcholine 38:6 had significantly larger effects in the E2 than E4 group. Two associations with isocitrate or propionate and three associations with phosphatidylcholines 32:0, 32:1, or 34:0 had significantly larger effects in the E4 than E3 group. Nine of 70 SNP-metabolite associations identified in either E2, E3, or E4 groups attained PFDR < 0.05 in the pooled sample of these groups. However, none of them were among the 20 group-specific associations. Consistent with the evolutionary history of the APOE alleles, plasma metabolites showed higher APOE-cluster-related variations in the E4 than E2 and E3 groups. Pathway enrichment mainly highlighted lipids and amino acids metabolism and citrate cycle, which can be differentially impacted by the APOE alleles. These novel findings expand insights into the genetic heterogeneity of plasma metabolites and highlight the importance of the APOE-allele-stratified genetic analyses of the APOE-related diseases and traits.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

APOE alleles modulate associations of plasma metabolites with variants from multiple genes on chromosome 19q13.3

Nazarian

Loiko²,

Yassine³

et al. 2022

Front. Aging Neurosci.

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“…Despite strong associations between APOE and AD, neither the ε2 nor ε4 allele is considered as a causal factor for AD development [5,[8][9][10]. Addressing the mechanisms of actions of the ε2 and ε4 alleles is essential for understanding AD pathogenesis and AD risk assessment.…”

Section: Introductionmentioning

confidence: 99%

Inter- and intra-chromosomal modulators of the APOE ɛ2 and ɛ4 effects on the Alzheimer’s disease risk

et al. 2022

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The mechanisms of incomplete penetrance of risk-modifying impacts of apolipoprotein E (APOE) ε2 and ε4 alleles on Alzheimer’s disease (AD) have not been fully understood. We performed genome-wide analysis of differences in linkage disequilibrium (LD) patterns between 6,136 AD-affected and 10,555 AD-unaffected subjects from five independent studies to explore whether the association of the APOE ε2 allele (encoded by rs7412 polymorphism) and ε4 allele (encoded by rs429358 polymorphism) with AD was modulated by autosomal polymorphisms. The LD analysis identified 24 (mostly inter-chromosomal) and 57 (primarily intra-chromosomal) autosomal polymorphisms with significant differences in LD with either rs7412 or rs429358, respectively, between AD-affected and AD-unaffected subjects, indicating their potential modulatory roles. Our Cox regression analysis showed that minor alleles of four inter-chromosomal and ten intra-chromosomal polymorphisms exerted significant modulating effects on the ε2- and ε4-associated AD risks, respectively, and identified ε2-independent (rs2884183 polymorphism, 11q22.3) and ε4-independent (rs483082 polymorphism, 19q13.32) associations with AD. Our functional analysis highlighted ε2- and/or ε4-linked processes affecting the lipid and lipoprotein metabolism and cell junction organization which may contribute to AD pathogenesis. These findings provide insights into the ε2- and ε4-associated mechanisms of AD pathogenesis, underlying their incomplete penetrance.

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“…The second is at best the indirect role of evolution in mechanisms of age‐related traits (Nesse et al, 2012 ). Accordingly, the genetic contributions to age‐related traits could manifest in various forms including, for example, the impacts of causal variants, structural diversity of the genome, intricate genetic architectures of complex traits, combinations of risk alleles, haplotypes, and combinations of genotypes (called compound genotypes) (Eichler et al, 2010 ; Franceschi et al, 2018 ; Gibson, 2012 ; Kulminski et al, 2021 ; Rogaev et al, 1995 ; Wainberg et al, 2020 ; Zhou et al, 2019 ). Dissecting the genetic complexity is a challenging task as exemplified by the well‐studied apolipoprotein E ( APOE ) ε2/ε3/ε4 polymorphism; despite decades of APOE research, its role in age‐related traits is still unclear (Belloy et al, 2019 ; Genin et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

APOE ɛ4 allele and TOMM40‐APOC1 variants jointly contribute to survival to older ages

et al. 2022

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Age‐related diseases characteristic of post‐reproductive life, aging, and life span are the examples of polygenic non‐Mendelian traits with intricate genetic architectures. Polygenicity of these traits implies that multiple variants can impact their risks independently or jointly as combinations of specific variants. Here, we examined chances to live to older ages, 85 years and older, for carriers of compound genotypes comprised of combinations of genotypes of rs429358 (APOE ɛ4 encoding polymorphism), rs2075650 (TOMM40), and rs12721046 (APOC1) polymorphisms using data from four human studies. The choice of these polymorphisms was motivated by our prior results showing that the ɛ4 carriers having minor alleles of the other two polymorphisms were at exceptionally high risk of Alzheimer's disease (AD), compared with non‐carriers of the minor alleles. Consistent with our prior findings for AD, we show here that the adverse effect of the ɛ4 allele on survival to older ages is significantly higher in carriers of minor alleles of rs2075650 and/or rs12721046 polymorphisms compared with their non‐carriers. The exclusion of AD cases made this effect stronger. Our results provide compelling evidence that AD does not mediate the associations of the same compound genotypes with chances to survive until older ages, indicating the existence of genetically heterogeneous mechanisms. The survival chances can be mainly associated with lipid‐ and immunity‐related mechanisms, whereas the AD risk, can be driven by the AD‐biomarker‐related mechanism, among others. Targeting heterogeneous polygenic profiles of individuals at high risks of complex traits is promising for the translation of genetic discoveries to health care.

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Protective association of the ε2/ε3 heterozygote with Alzheimer's disease is strengthened by TOMM40–APOE variants in men

Cited by 8 publications

References 68 publications

APOE alleles modulate associations of plasma metabolites with variants from multiple genes on chromosome 19q13.3

APOE alleles modulate associations of plasma metabolites with variants from multiple genes on chromosome 19q13.3

Inter- and intra-chromosomal modulators of the APOE ɛ2 and ɛ4 effects on the Alzheimer’s disease risk

APOE ɛ4 allele and TOMM40‐APOC1 variants jointly contribute to survival to older ages

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