APOC1
Apolipoprotein C-I precursor (Apo-CI) (ApoC-I) (Apolipoprotein C1) [Contains: Truncated apolipoprotein C-I]
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The special design of the Long Life Family Study provides a unique opportunity to investigate the genetics of human longevity by analyzing data on exceptional lifespans in families. In this article, we performed two series of genome wide association studies of human longevity which differed with respect to whether missing lifespan data were predicted or not predicted. We showed that the use of predicted lifespan is most beneficial when the follow-up period is relatively short. In addition to detection of strong associations of SNPs in APOE, TOMM40, NECTIN2, and APOC1 genes with longevity, we also detected a strong new association with longevity of rs1927465, located between the CYP26A1 and MYOF genes on chromosome 10. The association was confirmed using data from the Health and Retirement Study. We discuss the biological relevance of the detected SNPs to human longevity.
MeSH Terms
- Aged
- Aged, 80 and over
- Apolipoprotein C-I
- Apolipoproteins E
- Calcium-Binding Proteins
- Chromosomes, Human, Pair 10
- Chromosomes, Human, Pair 19
- Denmark
- Female
- Gene Frequency
- Genome-Wide Association Study
- Humans
- Logistic Models
- Longevity
- Longitudinal Studies
- Male
- Membrane Proteins
- Membrane Transport Proteins
- Muscle Proteins
- Nectins
- Pedigree
- Polymorphism, Single Nucleotide
- Retinoic Acid 4-Hydroxylase
- United States
We conducted a case-control genome-wide association study (GWAS) of human longevity, comparing 664,472 autosomal SNPs in 763 long-lived individuals (LLI; mean age: 99.7 years) and 1085 controls (mean age: 60.2 years) from Germany. Only one association, namely that of SNP rs4420638 near the APOC1 gene, achieved genome-wide significance (allele-based P=1.8×10(-10)). However, logistic regression analysis revealed that this association, which was replicated in an independent German sample, is fully explicable by linkage disequilibrium with the APOE allele ɛ4, the only variant hitherto established as a major genetic determinant of survival into old age. Our GWAS failed to identify any additional autosomal susceptibility genes. One explanation for this lack of success in our study would be that GWAS provide only limited statistical power for a polygenic phenotype with loci of small effect such as human longevity. A recent GWAS in Dutch LLI independently confirmed the APOE-longevity association, thus strengthening the conclusion that this locus is a very, if not the most, important genetic factor influencing longevity.
MeSH Terms
- Aged, 80 and over
- Alleles
- Apolipoproteins E
- Case-Control Studies
- Female
- Genetic Loci
- Genome-Wide Association Study
- Germany
- Humans
- Linkage Disequilibrium
- Longevity
- Male
- Polymorphism, Single Nucleotide
Alzheimer disease (AD) is the most common cause of dementia in elderly patients. Identification of risk factors for AD would contribute to the understanding of AD pathogenesis and thus, help in the development of preventive methods. Early-onset familial AD is associated with mutations of the genes encoding amyloid precursor protein (APP), presenilin 1 (PS-1), or PS-2, resulting in the overproduction of amyloid beta-protein. Epidemiological and case-control studies have led to the identification of several risk factors for sporadic AD. The most concrete genetic risk factor for AD is the epsilon4 allele of apolipoprotein E gene (APOE). In addition, several genes such as CTNNA3, GAB2, PVRL2, TOMM40, and APOC1 are known to be the risk factors that contribute to AD pathogenesis. On the other hand, nongenetic risk factors, such as age, sex, alcohol consumption, smoking, depression, head injury, and nutrition have also been reported. Although aging is the strongest risk factor for AD, the mechanisms underlying the development of AD as a result of ageing remain to be elucidated.
MeSH Terms
- Aging
- Alcohol Drinking
- Alzheimer Disease
- Amyloid beta-Peptides
- Amyloid beta-Protein Precursor
- Apolipoproteins E
- Cell Adhesion Molecules
- Craniocerebral Trauma
- Depression
- Humans
- Membrane Transport Proteins
- Mutation
- Nectins
- Presenilins
- Risk Factors
- Smoking
- alpha Catenin
Previous research has shown that polymorphisms of the apolipoproteins E ( APOE) and APOC1 represent genetic risk factors for dementia and for cognitive impairment in the elderly. The brain mechanisms by which these genetic variations affect behavior or clinical severity are poorly understood. We studied the effect of APOE and APOC1 genes on magnetic resonance imaging measures in a sample of 50 subjects with age-associated memory impairment. The APOE E4 allele was associated with reduced left hippocampal volumes and APOE*E3 status was associated with greater frontal lobe white matter volumes. However, no APOE effects were observed when analyses accounted for other potential confounding variables. The effects of APOC1 on hippocampal volumes appeared to be more robust than those of the APOE polymorphism. However, no modulatory effects on brain morphology outside the medial temporal lobe region were observed when demographic variables, clinical status, and other anatomical brain measurements were taken into consideration. Our results suggest that the role of the APOC1 polymorphism in brain morphology of the cognitively impaired elderly should be examined in further studies.
MeSH Terms
- Aged
- Aging
- Alleles
- Apolipoprotein C-I
- Apolipoprotein E2
- Apolipoprotein E3
- Apolipoprotein E4
- Apolipoproteins C
- Apolipoproteins E
- Brain
- Cephalometry
- Cerebral Ventricles
- Confounding Factors, Epidemiologic
- Female
- Frontal Lobe
- Genetic Predisposition to Disease
- Genotype
- Hippocampus
- Humans
- Magnetic Resonance Imaging
- Male
- Memory Disorders
- Neuropsychological Tests
- Polymorphism, Genetic
- Temporal Lobe
- Verbal Learning
We investigated the relationship among neuroanatomical, neurochemical and genetic variables in 44 subjects with age-related memory impairment. Hydrogen magnetic resonance spectroscopy was used to determine N-acetyl/creatine (NAA/Cr) concentrations in basal ganglia and medial temporal regions. Volumetric measures were obtained for caudate nucleus and hippocampus. Genetic polymorphisms examined included apolipoproteins (APO) E and CI, angiotensin converting enzyme and dopamine D2 receptor TaqI genes. Age was found to be negatively correlated with hippocampal and basal ganglia volumes, but not with neurochemical values. Multiple regression analyses showed that the APOC1 polymorphism was the only variable which predicted NAA/Cr values in basal ganglia. NAA/Cr metabolites in the medial temporal lobe but not in the basal ganglia region were related with lower performance in verbal memory.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Basal Ganglia
- Caudate Nucleus
- Female
- Hippocampus
- Humans
- Magnetic Resonance Imaging
- Magnetic Resonance Spectroscopy
- Male
- Memory Disorders
- Middle Aged
- Polymorphism, Genetic
- Protons
- Temporal Lobe
We studied the distribution of two genetic polymorphisms (APOE and APOC1) in a sample of 100 subjects fulfilling the NIMH criteria for age-associated memory impairment (AAMI) and 124 controls. We found significant associations both for APOE and APOC1 loci and their combinations with the AAMI condition. The findings in our sample suggest that memory-impaired subjects as described by the NIMH may be genetically differentiated from normally aging subjects in relation to these two polymorphisms and indicate the interest of considering variations in the APOC1 gene for further studies in cognitive aging.
MeSH Terms
- Aged
- Aging
- Apolipoproteins C
- Apolipoproteins E
- Cognition
- Female
- Gene Frequency
- Genotype
- Humans
- Male
- Memory Disorders
- Middle Aged
- Polymorphism, Genetic
The present study investigated the relationship between genetic variation, MRI measurements and neuropsychological function in a sample of 58 elders exhibiting memory decline. In agreement with previous reports, we found that the epsilon4 allele of the apolipoprotein E (APOE) and the D allele of the angiotensin converting enzyme (ACE) polymorphisms negatively modulated the cognitive performance. Further, we found an association between the A allele of the apolipoprotein C1 (APOC1) polymorphism and poorer memory and frontal lobe function. No clear associations emerged between MRI measures of white matter lesions (WML) or hippocampal sulcal cavities (HSC) and the cognitive performance after controlling for age effects. Further, the degree of WML or HSC lesions was in general not predisposed genetically except for the presence of the A allele of the APOC1 polymorphism that was related to a higher severity of HSC scores. Our results suggest that WML or HSC do not represent important brain correlates of genetic influences on cognitive performance in memory impaired subjects.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Apolipoprotein C-I
- Apolipoproteins C
- Apolipoproteins E
- Brain
- Female
- Frontal Lobe
- Genotype
- Hippocampus
- Humans
- Hypertension
- Magnetic Resonance Imaging
- Male
- Memory
- Memory Disorders
- Peptidyl-Dipeptidase A
- Phenotype
- Polymorphism, Genetic