APOE Rs429358 Research Articles

Central obesity in males affected by a dyslipidemia-associated genetic polymorphism on APOA1/C3/A4/A5 gene cluster

Background:Central obesity is a rising epidemic, and often occurs in parallel with dyslipidemia. Furthermore, enhancement of ectopic fat deposition has been observed in both human studies and animal models of altered lipidemic control. Though APOA1/C3/A4/A5 genetic polymorphisms are associated with dyslipidemia, their effect on central obesity is less known.Method:The anthropometric and metabolic parameters were taken from obese (body mass index (BMI) ⩾25 kg m−2) and non-obese healthy (BMI <25) Taiwanese patients at the initiation weight-loss intervention and 6 months later. The effects of APOA1/C3/A4/A5 genetic polymorphisms were analyzed cross-sectionally and longitudinally. Gender contributions were specifically examined.Patients:Three hundred and ninety-eight participants (obese n=262; non-obese healthy n=136) were recruited in total, and 130 obese patients underwent weight-loss treatments.Results:APOA5 rs662799 minor allele carriage was associated with unfavorable metabolic profiles in obese but not non-obese individuals at baseline. Further analysis identified gender–genotype interactions in waist-hip ratio (WHR), and that one rs662799 minor allele increased 0.032 WHR unit in obese males as analyzed by linear regression adjusted for age, BMI and plasma triglyceride (TG) (95% confidence interval (CI)=0.014–0.050, P=0.001). The rs662799-associated WHR elevation resulted in increased frequency of central obesity (WHR ⩾1.0) in rs662799 carrying obese males as analyzed by binary logistic regression adjusted for age, BMI and plasma TG (odds ratio=6.52, 95% CI=1.87–22.73, P=0.003). In contrast, APOA5 rs662799 and central obesity were no longer correlated 6 months into weight-loss treatments, owing to significant WHR reductions in male rs662799 minor allele carriers (P=0.001). Meanwhile, hypertriglyceridemia was more prevalent in both male and female obese rs662799 minor allele carriers at baseline (males, P=0.034, females, P=0.007).Conclusion:This study highlights the gender-specific and weight-sensitive effects of APOA5 rs662799 on central obesity in Taiwanese individuals, and that these effects are dyslipidemia-independent and weight-loss responsive.

Association of Genetic Variants Influencing Lipid Levels with Coronary Artery Disease in Japanese Individuals

Background/ObjectiveIn Japanese populations, we performed a replication study of genetic loci previously identified in European-descent populations as being associated with lipid levels and risk of coronary artery disease (CAD).MethodsWe genotyped 48 single nucleotide polymorphisms (SNPs) from 22 candidate loci that had previously been identified by genome-wide association (GWA) meta-analyses for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and/or triglycerides in Europeans. We selected 22 loci with 2 parallel tracks from 95 reported loci: 16 significant loci (p<1×10−30 in Europeans) and 6 other loci including those with suggestive evidence of lipid associations in 1292 GWA-scanned Japanese samples. Genotyping was done in 4990 general population samples, and 1347 CAD cases and 1337 controls. For 9 SNPs, we further examined CAD associations in an additional panel of 3052 CAD cases and 6335 controls.Principal FindingsSignificant lipid associations (one-tailed p<0.05) were replicated for 18 of 22 loci in Japanese samples, with significant inter-ethnic heterogeneity at 4 loci–APOB, APOE-C1, CETP, and APOA5–and allelic heterogeneity. The strongest association was detected at APOE rs7412 for LDL-C (p = 1.3×10−41), CETP rs3764261 for HDL-C (p = 5.2×10−24), and APOA5 rs662799 for triglycerides (p = 5.8×10−54). CAD association was replicated and/or verified for 4 loci: SORT1 rs611917 (p = 1.7×10−8), APOA5 rs662799 (p = 0.0014), LDLR rs1433099 (p = 2.1×10−7), and APOE rs7412 (p = 6.1×10−13).ConclusionsOur results confirm that most of the tested lipid loci are associated with lipid traits in the Japanese, further indicating that in genetic susceptibility to lipid levels and CAD, the related metabolic pathways are largely common across the populations, while causal variants at individual loci can be population-specific.

Pleiotropy and allelic heterogeneity in the TOMM40-APOE genomic region related to clinical and metabolic features of hepatitis C infection

Hepatitis C virus (HCV) modulates host lipid metabolism as part of its lifecycle and is dependent upon VLDL for co-assembly and secretion. HCV dyslipidemia is associated with steatosis, insulin resistance, IL28B genotype and disease progression. Apolipoprotein E (ApoE) is an important lipid transport protein, a key constituent of VLDL, and is involved in immunomodulation. Our aims were to determine the role of APOE regional polymorphisms on host lipids, IL28B genotype and disease severity in chronic HCV (CHC) patients. The study cohort included 732 CHC patients with available DNA for genotype determination of four polymorphisms in the chromosome 19 region that encompasses the TOMM40, APOE and APOC1 genes. Serum lipid analysis and apolipoproteins levels were measured using an immunoturbidimetric assay. APOE rs7412 polymorphism (capturing the ε2 isoform) was significantly associated with serum ApoE levels in both Caucasians and African-American patients (p=2.3×10(-11)) and explained 7% of variance in serum ApoE. Among IL28B-CC patients (n=196), the rs429358 (defines ε4 isoform) and TOMM40 '523' S polymorphisms were associated with 12% of variance in ApoB levels. Patients homozygous for the APOE ε3 isoform had a greater than twofold increased odds of F2-F4 fibrosis (p=1.8×10(-5)), independent of serum lipid and lipoprotein levels. There were no associations between APOE polymorphisms and serum HDL-C, APO-CIII and triglycerides. In CHC patients, genetic heterogeneity in the APOE/TOMM40 genomic region is significantly associated with variation in serum ApoE and ApoB levels, and also with fibrosis suggesting a pleiotropic attribute of this genomic region.

Association study of candidate gene polymorphisms with amnestic mild cognitive impairment in a Chinese population.

To investigate the relationship between amnestic mild cognitive impairment (aMCI) and candidate gene polymorphisms in a Chinese population, 116 aMCI patients and 93 normal controls were recruited. Multi-dimensional neuropsychological tests were used to extensively assess the cognitive functions of the subjects. MassARRAY and iPLEX systems were used to measure candidate single nucleotide polymorohisms (SNPs) and analyse allelic, genotypic or haplotypic distributions. The scores of the neuropsychological tests were significantly lower for the aMCI patients than for the normal controls. The distributions of SNPs relating to the amyloid cascade hypothesis (TOMM40 rs157581 G and TOMM40 rs2075650 G), to the cholesterol metabolism hypothesis (ApoE rs429358 C, LDLR rs11668477 G and CH25H rs7091822 T and PLAU rs2227564 CT) and to the tau hypothesis (MAPT/STH rs242562 GG) in aMCI were significantly different than those in normal controls. Interactions were also found in aMCI amongst SNPs in LDLR rs11668477, PLAU rs2227564, and TOMM40 rs157581, between SNPs in TOMM40 rs157580 and BACE2 rs9975138. The study suggests that aMCI is characterised by memory impairment and associated with SNPs in three systems relating to the pathogenesis of AD-those of the amyloid cascade, tau and cholesterol metabolism pathways. Interactions were also observed between genes in the amyloid pathway and between the amyloid and cholesterol pathways.

Association of PICALM Gene with Late-Onset Alzheimer's Disease in Korean Population (P05.073)

Objective: We aimed to investigate the association of top associated variants in GWAS with Alzheimer9s disease (AD) in Korean population. Background AD is the most common cause of neurodegenerative adult-onset dementia. Recent genome-wide association studies (GWAS) have discovered several AD susceptibility loci. However, the identified susceptibility loci are substantially inconsistent across GWAS of Caucasian population. Design/Methods: We selected single nucleotide polymorphisms (SNPs) selected from 12 genes (ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, LRAT, MS4A6A, PCDH11X, and PICALM) that had genome-wide significance in recent GWAS and additional tag SNPs in each gene using the HapMap Asian (CHB and JPT) samples, and genotyped in 290 AD cases from all regions of South Korea and 554 unrelated controls from the same region. All subjects were Korean population. Case-control analyses were performed to study association with AD susceptibility, while cases-only analyses were used to study association with age at onset. Results: Three SNPs (rs429358 in APOE, rs2075650 in APOE, and rs677909 in PICALM) were associated with AD susceptibility after correction for multiple testing. After adjustment of APOE gene, only PICALM SNP rs677909 remained significant after Bonferroni correction (OR = 0.629, 95% CI = 0.488 – 0.81, uncorrected p = 0.0003, log additive model). However, 6 additional PICALM SNPs, 3 ABCA7 SNPs, and one APOE, CD33, and BIN1 SNPs each had significant uncorrected p values. There was no significant association for age at onset after correction for multiple testing. Conclusions: Our results confirm the association of PICALM gene (encoding phosphatidylinositol-binding protein) in addition to APOE gene with AD susceptibility in Korean population but show limited association of other susceptibility loci with AD. All AD susceptibility loci were not associated with age at onset of AD in Korean population. Supported by: A grant of the Korea Healthcare technology R & D Project, Ministry of Health and Welfare, Republic of Korea (A092042). This study was also partially supported by a grant of the Korea Healthcare technology R & D Project, Ministry of Health and Welfare, Republic of Korea (A102065). Disclosure: Dr. Chung has nothing to disclose. Dr. Lee has nothing to disclose. Dr. Kim has nothing to disclose. Dr. You has nothing to disclose. Dr. Kim has nothing to disclose. Dr. Koh has nothing to disclose.

Analysis of LIPC ‐514C&gt;T and APOA5 ‐1131T&gt;C polymorphisms in Mexican Mestizos and Mexican Amerindians

Description of frequencies and haplotypes in Mexican Mestizo (MM) and Mexican Amerindian (MA) populations, of two SNPs implicated in lipid metabolism, which have been associated to lipid levels in white populations. For this purpose we analyzed DNA extracted from blood samples of 372 MA and 300 MM that participated in the Mexican Genome Diversity Project by allelic discrimination, we also constructed haplotypes and identified tag SNPs.ResultsThe frequency for LIPC rs1800588 was 0.430 in MM and 0.262 in MA, whereas for APOA5 rs662799 the frequency was 0.168 in MM and 0.262 in MA. Three haplotypes (&gt;5%) were identified on the LIPC region on MM, one of them including the rs1800588 (8.3%). Six haplotypes (&gt;5%) were identified on the APOA5 region. The rs662799 SNP was included in haplotypes showing similar frequencies in MM and MA (14% and 14.8% respectively). The APOA5 rs662799 is in high LD with tag SNPs that are present in BUD13 and ZNF259. The LIPC rs1077834, that has been associated to higher high density lipoprotein concentrations in white populations, showed high linkage desequilibrium with our SNP of interest.ConclusionsThe genetic information obtained from this study will be useful in future studies where associations between lipid metabolism phenotypes, environmental factors, and disease onset need to be determine in Mexican population. Source of research support CONACYT.

Association of gene variants with lipid levels in response to fenofibrate is influenced by metabolic syndrome status

ObjectiveFenofibrate therapy reduces serum triglycerides (TG) and increases high-density lipoprotein-cholesterol (HDL-C) and thus addresses the atherogenic dyslipidemia associated with metabolic syndrome (MetS). Our hypothesis is that genetic factors contribute to the variability of lipid response to fenofibrate differently in subjects with MetS and without MetS. MethodsWe investigated the association in 25 candidate genes with lipid responses to a 3-weeks trial on fenofibrate in subjects with and without MetS. We employed growth curve mixed models to generate the response phenotypes to fenofibrate in TG, HDL-C, and low-density lipoprotein-cholesterol (LDL-C) and examined the genetic associations accounting for family dependencies. ResultsAfter correcting for multiple testing (p<0.05) and accounting for significant differences in the association effect sizes between subjects with and without MetS (p<0.05), variants of APOA5 (rs662799) and APOE (rs429358) were associated with HDL-C and LDL-C responses in MetS subjects, while APOA4 (rs675) was associated with TG response in non-MetS subjects. There was also suggestive evidence that MetS may interact with APOA4 (p=0.017), APOA5 (p=0.06), and APOE (p=0.09) to the variation to lipid responses. ConclusionsGenetic effects that contributed to the variability of lipid responses to fenofibrate may differ in subjects with and without MetS. This research may provide guidance for more personalized and effective therapies.

Gene-nutrient interactions and gender may modulate the association between ApoA1 and ApoB gene polymorphisms and metabolic syndrome risk

ObjectiveDyslipidemia is a key feature of the metabolic syndrome (MetS), which is determined by both genetic and dietary factors. MethodsWe determined the relationships between ApoA1 and ApoB polymorphisms and MetS risk, and whether dietary fat modulates this in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n=1754). ResultsApoB rs512535 and ApoA1 rs670 major G allele homozygotes had increased MetS risk (OR 1.65 [CI 1.24, 2.20], P=0.0006; OR 1.42 [CI 1.08, 1.87], P=0.013), which may be, partly, explained by their increased abdominal obesity and impaired insulin sensitivity (P<0.05) but not dyslipidemia. Interestingly these associations derived primarily from the male GG homozygotes (ApoB rs512535 OR 1.92 [CI 1.31, 2.81], P=0.0008; ApoA1 rs670 OR 1.50 [CI 1.05, 2.12], P=0.024). MetS risk was exacerbated among the habitual high-fat consumers (>35% energy) (ApoB rs512535 OR 2.00 [CI 1.14, 3.51], P=0.015; OR 1.58 [CI 1.11, 2.25], P=0.012 for ApoA1 rs670). In addition a high monounsaturated fat (MUFA) intake (>14% energy) increased MetS risk (OR 1.89 [CI 1.08, 3.30], P=0.026 and OR 1.57 [CI 1.10, 2.40], P=0.014 for ApoB rs512535 and ApoA1 rs670, respectively). MetS risk was abolished among the habitual low-fat consumers (<35% energy). Saturated and polyunsaturated fat intake did not modulate MetS risk. ConclusionApoB rs512535 and ApoA1 rs670 may influence MetS risk. Apparent modulation of these associations by gender and dietary fat composition suggests novel gene-gender-diet interactions.

Exploring genetic determinants of plasma total cholesterol levels and their predictive value in a longitudinal study

Background Plasma total cholesterol (TC) levels are highly genetically determined. Although ample evidence of genetic determination of separate lipoprotein cholesterol levels has been reported, using TC level directly as a phenotype in a relatively large broad-gene based association study has not been reported to date. Methods and results We genotyped 361 single nucleotide polymorphisms (SNPs) across 243 genes based on pathways potentially relevant to cholesterol metabolism in 3575 subjects that were examined thrice over 11 years. Twenty-three SNPs were associated with TC levels after adjustment for multiple testing. We used 12 of them (rs7412 and rs429358 in APOE, rs646776 in CELSR2, rs1367117 in APOB, rs6756629 in ABCG5, rs662799 in APOA5, rs688 in LDLR, rs10889353 in DOCK7, rs2304130 in NCAN, rs3846662 in HMGCR, rs2275543 in ABCA1, rs7275 in SMARCA4) that were confirmed in previous candidate association or genome-wide-association studies to define a gene risk score (GRS). Average TC levels increased from 5.23 ± 0.82 mmol/L for those with 11 or less cholesterol raising alleles to 6.03 ± 1.11 mmol/L for those with 18 or more ( P for trend < 0.0001). The association with TC levels was slightly stronger when the weighted GRS that weighted the magnitude of allelic effects was used. Conclusion A panel of common genetic variants in the genes pivotal in cholesterol metabolism could possibly help identify those people who are at risk of high cholesterol levels.

GAB2 gene does not modify the risk of Alzheimer's disease in Spanish APOE 4 carriers.

The genetic basis of Alzheimer's disease (AD) is being analyzed in multiple whole genome association studies (WGAS). The GAB2 gene has been proposed as a modifying factor of APOE epsilon 4 allele in a recent case-control WGAS conducted in the US. Given the potential application of these novel results in AD diagnostics, we decided to make an independent replication to examine the GAB2 gene effect in our series. We are conducting a multicenter population-based study of AD in Spain. We analyzed a total of 1116 Spanish individuals. Specifically, 521 AD patients, 475 controls from the general population and 120 neurologically-normal elderly controls (NNE controls). We have genotyped GAB2 (rs2373115 G/T) and APOE rs429358 (SNP112)/rs7412 (SNP158) polymorphisms using real time-PCR technologies. As previously reported in Spain, APOE epsilon 4 allele was strongly associated with AD in our series (OR=2.88 [95% C.I. 2.16- 3.84], p=7.38E-11). Moreover, a large effect for epsilone 4/epsilone 4 genotype was also observed (OR=14.45 [95% C.I., 3.34-125.2], p=1.8E-6). No difference between the general population and the NNE controls series were observed for APOE genotypes (P > 0.61). Next, we explored GAB2 rs2373115 SNP singlelocus association using different genetic models and comparing AD versus controls or NNE controls. No evidence of association with AD was observed for this GAB2 marker (p > 0.17). To evaluate GAB2-APOE genegene interactions, we stratified our series according to APOE genotype and case-control status, in accordance with the original studies. Again, no evidence of genetic association with AD was observed in any strata of GAB2-APOE loci pair (p > 0.34). GAB2 rs2373115 marker does not modify the risk of Alzheimer's disease in Spanish APOE epsilon 4 carriers.

Polygenic determinants of severe hypertriglyceridemia

Recent genome-wide association (GWA) studies have identified new genetic determinants of complex quantitative traits, including plasma triglyceride (TG). We hypothesized that common variants associated with mild TG variation identified in GWA studies would also be associated with severe hypertriglyceridemia (HTG). We studied 132 patients of European ancestry with severe HTG (fasting plasma TG > 10 mmol/l), who had no mutations found by resequencing of candidate genes, and 351 matched normolipidemic controls. We determined genotypes for: GALNT2 rs4846914, TBL2/MLXIPL rs17145738, TRIB1 rs17321515, ANGPTL3 rs12130333, GCKR rs780094, APOA5 rs3135506 (S19W), APOA5 rs662799 (-1131T > C), APOE (isoforms) and LPL rs328 (S447X). We found that: (i) genotypes, including those of APOA5 S19W, APOA5 -1131T > C, APOE, GCKR, TRIB1 and TBL2/MLXIPL, were significantly associated with severe HTG; (ii) odds ratios for these genetic variables were significant in both univariate and multivariate regression analyses, irrespective of the presence or absence of diabetes or obesity; (iii) a significant fraction-about one-quarter-of the explained variation in disease status was associated with these genotypes. Therefore, common SNPs (single nucleotide polymorphisms) that are associated with mild TG variation in GWA studies of normolipidemic subjects are also associated with severe HTG. Our findings are consistent with the emerging model of a complex genetic trait. At the extremes of a quantitative trait, such as severe HTG, are found the cumulative contributions of both multiple rare alleles with large genetic effects and common alleles with small effects.