Association Study On The Cognitiverelated Gene Polymorphism With Cognition Status In Guangxi Bama Longlived Population

PARTⅠ CORRELATION BETWEEN LIPID METABOLISMRELATED GENE APOE AND CETP AND COGNITION STATUS IN BAMA LONG-LIVED POPULATIONBackground: Currently, there are four hypotheses to interpret the onset of cognition impairment diseases such as Alzheimer’s disease(AD): cholinergic hypothesis, amyloid cascade, tau and cholesterol metabolism hypothesis. APOE gene encodes apolipoprotein Apo E, an important carrier of cholesterol in the brain, which participates in the repairing mechanism of brain cells. Researches have shown that individuals who carry ε4 increase the risk of cognition impairment, individual risk of late onset and sporadic AD is higher in homozygous ε4, with a dose-dependant pattern. CETP plays a key role in the process of reverse cholesterol transport and is an important regulatory protein in lipid metabolism. Both CETP and APOE genes involve in the central nervous system homeostasis and the regulation of cholesterol, which may correlate with cognition impairment and AD risk,and other kinds of cognitive decline.Objective: To investigate the cognitive situation of Bama Zhuang long-lived group, and the correlation of APOE and the CETP I405 V polymorphism with their cognitive situation.Methods: Two groups were enrolled from Guangxi Bama area included: Bama long-lived group(BLG, n=645, aged 90 and above), Bama control group( BCG, n=674, aged 60-75); another group from Hezhou area(700 kilometers far away Bama county), Hezhou control group(HCG, n= 662, aged 60-77). MMSE scale was used to evaluate their cognitive levels, improved multi-temperature ligase detection reaction(i MLDR) method was employed to genotype APOE rs429358, rs7412 and CETP rs5882 loci. Lipid levels, blood pressure, BMI, FPG, and chest, waist and hip circumference were imputed as the baseline data. Association analyses were performed between the SNPs and MMSE.Results:1. General information: TC, LDL-C, Apo B of BLG were lower than the other two groups, TG level in BLG was lower than BCG, HDL-C level of BLG was similar to BCG but lower than HCG.2. Cognitive decline rate of BLG was 49.6%, which was higher than the other two groups. The MMSE total score in BLG showed no difference as compared to other two groups, when compared to BCG, BLG was weak in memory. In other items of MMSE, BLG and the other two groups showed no difference.3. APOE genotype and allele frequencies: the major genotype and allele of APOE were E3/3 and ε3, the frequency of ε4 allele in BLG was lower than HCG( P<0.05). 4. The E4/X(+) genotype frequency in dyslipidemia subgroup was significantly higher than the normal lipid subgroup( P < 0.05). Compared with E4/X(-), E4/X(+) genotype carriers had higher TC, LDL- C( P <0.01).5. In general population, MMSE total score in E4/X(+) genotype carriers were lower than those of E4/X(-), In BLG, E4/X(+) genotype carriers had bad orientation than those of E4/X(-), In male, BCG and HCG,E4/X(+) genotype carriers had poorer concentration ability than those of E4/X(-), in HCG, E4/X(+) genotype carriers had poorer memory than those of E4/X(-)( P < 0.05);contrarily, in BCG, MMSE total score and concentration in E4/X(+) genotype carriers were higher than those of E4/X(-), and in male, E4/X(+) genotype carriers had good orientation than those of E4/X(-). 6. Under the situation of BMI>24, dyslipidemia or hypertension, compared with ε3 allele( E3/3 genotype) carriers, APOE ε2 allele( E2/2, E2/3 or E2/4 genotypes) carriers had higher cognitive dimension; in the illiterate population, as compared with the E3/3 genotype, APOE ε4 allele( E3/4 and E4/4 genotypes) carriers had higher risk of cognitive impairment. 7. The major genotype and allele of CETP rs5882 were heterozygous GA and A allele. In male, the frequency of GG genotype in BLG was highest, and G allele frequency in BLG and BCG were significantly higher than that of HCG, but no obvious difference was noted in BLG and BCG.8. In female, CETP rs5882 G allele carriers had higher plasma level of Apo AI, In HCG,G allele had lower plasma level of Apo B, in general population and BLG, G allele had higher plasma level of Apo AI/Apo B( P < 0.05).9. In general population, when compared with A allele(AA/GA genotypes), CETP rs5882 G allele carriers(GA/GG genotypes) had higher orientation dimension, in BLG, G allele carriers had better concentration function and memory( P < 0.05);but in male, G allele carriers was weak in orientation and expression, in BLG, G allele carriers had bad memory.10. After APOE gene is stratified, in the ε4 allele carriers, CETP G allele related with higher memory dimension in general population and males, higher orientation dimension in male and better concentration dimension in female.Conclusions: 1. APOE E4(+) genotype was disadvantageous to lipid levels, and beneficial to maintain cognition except BCG, the frequency of ε4 allele in BLG was lower than HCG, this may be the reason why BLG had better cognition maintenance.2. Environmental factors such as obesity, dyslipidemia hypertension and education background may interact with different genotypes of APOE, as compared with ε3 allele, APOE ε2 allele is beneficial for cognition while ε4 allele is susceptible to cognitive impairment.3. In male, the frequencies of CETP rs5882 GG genotype and G allele in BLG were significantly higher than those of BCG and HCG, G allele has higher Apo AI/Apo B level and better concentration function in BLG, so it may serve as a protective factor for the cognition of BLG. 4. APOE and CETP genes may affect cognitive level through the regulation of serum lipid levels, the interaction between APOE ε4 allele and CETP G allele may reduce the risk of APOE ε4 allele for cognitive impairment.PARTⅡ CORRELATION BETWEEN BRAIN DERIVED NEURAL NUTRITION FACTOR BDNF GENE AND NEUROTRANSMITTER COMT GENE AND COGNITION STATUS IN BAMA LONG-LIVED POPULATIONBackground: Cognition is the process human brain receives outside world information, thinking and dealing with it, which is mainly dominate by prefrontal cortex and temporal lobe, it can not do without the normal work of the neurons and synapses, and the neurotrophic factors effect on nutrition, migration, proliferation and differentiation of neurons, and is close with a variety of neurotransmitter and its synthesis, transport and degradation. BDNF is indispensable medium in memory process and it is high expressed in hippocampus, playing an important role in the survival, differentiation, growth and development of neurons. COMT is the main catabolism enzyme to catecholamine neurotransmitters such as dopamine(DA), norepinephrine, and epinephrine. If DA in synaptic cleft of neurons is less degraded, DA concentration is increased, so it is advantageous for cognition such as working, learning, memory and examination.Objective: To explore the correlation of cognitive levels in long-lived group and the polymorphisms of BDNF rs6265 and COMT rs4680.Methods: IMLDR method was employed to genotype of BDNF rs6265 and COMT rs4680, association analyses were conducted among genotypes and lipid levels, blood pressure, BMI, FPG and other indicators. ANCOVA was used to analyze the correlation between BDNF and COMT different genotypes with MMSE.Results: 1. BDNF rs6265 genotype and allele frequencies: the major genotype and allele were GA genotype and G allele, the frequencies of GG genotype and G allele in BLG were higher than HCG( P<0.05).2. In BLG, when compared with BDNF rs6265 A allele, the major G allele had higher TC, HDL-C, Apo AI and Apo AI/Apo B levels( P<0.05).3. In general population, when compared with A allele, BDNF G allele carriers had better performance in orientation, in male and BLG, G allele carriers had higher MMSE total score and orientation; on the contrary, in female, compared with A allele, G allele carriers had weaker MMSE total score and language skills, in male, G allele carriers is inferior in orientation and memory, in BLG their concentration dimension was under average, in BCG their language skills were poorer.4. After APOE is stratified, in the ε4 allele carriers, BDNF A allele related with higher concentration dimension in male; in non- ε4 allele carriers, BDNF A allele related with higher MMSE total score and orientation and language skills in general population, expression in male, MMSE total score and language skills in female, but also related with lower MMSE total score and orientation in male.5. COMT 472 G>A genotype and allele frequencies: the major genotype and allele were wild type GG genotype and wild type G allele. In female, GG genotype frequency in BLG was significantly lower than BCG and HCG( P = 0.044). 6. In BLG, when compare with COMT GG genotype, GA/AA genotypes had lower Apo B level and higher FBG, BMI and SBP levels.7. When compare with COMT G allele, A allele carriers had weaker memory and language skills in general population and bad orientation in BLG, but at the same time A allele carriers had higher MMSE total scores in BLG, better memory in male and excellent language skills in female( P<0.05).8. In dyslipidemia population, When GG genotype as reference, COMT AA genotype was protective factor to cognition, OR=1.69( P = 0.003).9. After APOE gene is stratified, in the ε4 allele carriers, COMT A allele related with lower concentration dimension in male; in non-ε4 allele carriers,COMT A allelerelated with better memory in general population and males, better language skills in females, but at the same time related with lower language skills in general population.Conclusions: 1. BDNF rs6265 GG genotype and G allele in BLG was higher than HCG but there was no significant difference between BLG and BCG, when compared with A allele, BDNF G allele carriers have higher level of HDL-C, Apo AI and Apo AI/Apo B, at the same time, G allele carriers have better orientation dimension and MMSE total scores, that’s maybe another reason for BLG have good cognition maintenance. 2. In BLG, COMT rs5882 G allele carriers have lower levels of FBG, BMI, SBP and good concentration, which contribute to maintain their cognition levels.PART III CORRELATION BETWEEN COGNITIVE GENEGENE INTERACTIONS AND COGNITIVE IMPAIRMENTBackground: Cognition is a complex phenotype, influenced by the individual environmental conditions, education, social and economic status, life experiences and physical diseases, regulated by the combination of multiple genes.Objective: To find the best model in the interaction between APOE rs429358, APOE rs7412, CETP rs5882, BDNF rs6265, COMT rs4680, 5 SNPs, in order to investigate the relativity between them and the cognition impairment.Methods: GMDR software was used to explore the best gene-gene interaction model, after that, the result was put in the logistic regression model to validate the GMDR results.Results: The best genetic model in the interaction of above 4 genes was not associated with the cognition status of the research popultion.Conclusions: Interactions between APOE rs429358, APOE rs7412, CETP rs5882, BDNF rs6265 and COMT rs4680 polymorphic loci are not associated with cognition impairment of the research population.