[show abstract][hide abstract] ABSTRACT: In addition to apolipoprotein E (APOE), recent large genome-wide association studies (GWASs) have identified nine other genes/loci (CR1, BIN1, CLU, PICALM, MS4A4/MS4A6E, CD2AP, CD33, EPHA1 and ABCA7) for late-onset Alzheimer's disease (LOAD). However, the genetic effect attributable to known loci is about 50%, indicating that additional risk genes for LOAD remain to be identified. In this study, we have used a new GWAS data set from the University of Pittsburgh (1291 cases and 938 controls) to examine in detail the recently implicated nine new regions with Alzheimer's disease (AD) risk, and also performed a meta-analysis utilizing the top 1% GWAS single-nucleotide polymorphisms (SNPs) with P<0.01 along with four independent data sets (2727 cases and 3336 controls) for these SNPs in an effort to identify new AD loci. The new GWAS data were generated on the Illumina Omni1-Quad chip and imputed at ~2.5 million markers. As expected, several markers in the APOE regions showed genome-wide significant associations in the Pittsburg sample. While we observed nominal significant associations (P<0.05) either within or adjacent to five genes (PICALM, BIN1, ABCA7, MS4A4/MS4A6E and EPHA1), significant signals were observed 69-180 kb outside of the remaining four genes (CD33, CLU, CD2AP and CR1). Meta-analysis on the top 1% SNPs revealed a suggestive novel association in the PPP1R3B gene (top SNP rs3848140 with P = 3.05E-07). The association of this SNP with AD risk was consistent in all five samples with a meta-analysis odds ratio of 2.43. This is a potential candidate gene for AD as this is expressed in the brain and is involved in lipid metabolism. These findings need to be confirmed in additional samples.
[show abstract][hide abstract] ABSTRACT: The major histocompatibility complex (MHC) on chromosome 6p is an established risk locus for ulcerative colitis (UC) and Crohn's disease (CD). We aimed to better define MHC association signals in UC and CD by combining data from dense single-nucleotide polymorphism (SNP) genotyping and from imputation of classical human leukocyte antigen (HLA) types, their constituent SNPs and corresponding amino acids in 562 UC, 611 CD and 1428 control subjects. Univariate and multivariate association analyses were performed, controlling for ancestry. In univariate analyses, absence of the rs9269955 C allele was strongly associated with risk for UC (P = 2.67 × 10(-13)). rs9269955 is a SNP in the codon for amino acid position 11 of HLA-DRβ1, located in the P6 pocket of the HLA-DR antigen binding cleft. This amino acid position was also the most significantly UC-associated amino acid in omnibus tests (P = 2.68 × 10(-13)). Multivariate modeling identified rs9269955-C and 13 other variants in best predicting UC vs control status. In contrast, there was only suggestive association evidence between the MHC and CD. Taken together, these data demonstrate that variation at HLA-DRβ1, amino acid 11 in the P6 pocket of the HLA-DR complex antigen binding cleft is a major determinant of chromosome 6p association with UC.
Genes and immunity 12/2011; 13(3):245-52. · 4.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: Psychotic symptoms occur in ∼40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWASs) to identify loci that (1) increase susceptibility to an AD and subsequent psychotic symptoms; or (2) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. In all, 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from Genetic and Environmental Risk in AD Consortium 1 (GERAD1), the National Institute on Aging Late-Onset Alzheimer's Disease (NIA-LOAD) family study and the University of Pittsburgh Alzheimer Disease Research Center (ADRC) GWASs. Unobserved genotypes were imputed to provide data on >1.8 million single-nucleotide polymorphisms (SNPs). Analyses in each data set were completed comparing (1) AD+P to AD-P cases, and (2) AD+P cases with controls (GERAD1, ADRC only). Aside from the apolipoprotein E (APOE) locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; 'AD+PvAD-P' P=2.85 × 10(-7); 'AD+PvControls' P=1.11 × 10(-4)). SNPs upstream of SLC2A9 (rs6834555, P=3.0 × 10(-7)) and within VSNL1 (rs4038131, P=5.9 × 10(-7)) showed strongest evidence for association with AD+P when compared with controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterized.Molecular Psychiatry advance online publication, 18 October 2011; doi:10.1038/mp.2011.125.
[show abstract][hide abstract] ABSTRACT: The risk of Alzheimer's disease (AD) is strongly determined by genetic factors and recent genome-wide association studies (GWAS) have identified several genes for the disease risk. In addition to the disease risk, age-at-onset (AAO) of AD has also strong genetic component with an estimated heritability of 42%. Identification of AAO genes may help to understand the biological mechanisms that regulate the onset of the disease. Here we report the first GWAS focused on identifying genes for the AAO of AD. We performed a genome-wide meta-analysis on three samples comprising a total of 2222 AD cases. A total of ∼2.5 million directly genotyped or imputed single-nucleotide polymorphisms (SNPs) were analyzed in relation to AAO of AD. As expected, the most significant associations were observed in the apolipoprotein E (APOE) region on chromosome 19 where several SNPs surpassed the conservative genome-wide significant threshold (P<5E-08). The most significant SNP outside the APOE region was located in the DCHS2 gene on chromosome 4q31.3 (rs1466662; P=4.95E-07). There were 19 additional significant SNPs in this region at P<1E-04 and the DCHS2 gene is expressed in the cerebral cortex and thus is a potential candidate for affecting AAO in AD. These findings need to be confirmed in additional well-powered samples.Molecular Psychiatry advance online publication, 18 October 2011; doi:10.1038/mp.2011.135.
[show abstract][hide abstract] ABSTRACT: Late-onset Alzheimer's disease (LOAD) is a multifactorial disease with the potential involvement of multiple genes. Four recent genome-wide association studies (GWAS) have found variants showing significant association with LOAD on chromosomes 6, 10, 11, 12, 14, 18, 19, and on the X chromosome. We examined a total of 12 significant SNPs from these studies to determine if the results could be replicated in an independent large case-control sample. We genotyped these 12 SNPs as well the E2/E3/E4 APOE polymorphisms in up to 993 Caucasian Americans with LOAD and up to 976 age-matched healthy Caucasian Americans. We found no statistically significant associations between the 12 SNPs and the risk of AD. Stratification by APOE*4 carrier status also failed to reveal statistically significant associations. Additional analyses were performed to examine potential associations between the 12 SNPs and age-at-onset (AAO) and disease duration among AD cases. Significant associations were observed between AAO and ZNF224/rs3746319 (P = 0.002) and KCNMA1/rs16934131 (P = 0.0066). KCNMA1/rs16934131 also demonstrated statistically significant association with disease duration (P = 0.0002). Although we have been unable to replicate the reported GWAS association with AD risk in our sample, we have identified two new associations with AAO and disease duration that need to be confirmed in additional studies.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2011; 156B(4):507-12. · 3.23 Impact Factor
[show abstract][hide abstract] ABSTRACT: Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.
[show abstract][hide abstract] ABSTRACT: In this investigation, we have carried out an autosomal genome-wide linkage analysis to map genes associated with type 2 diabetes (T2D) and five quantitative traits of blood lipids including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, and triglycerides in a unique family-based cohort from the Sikh Diabetes Study (SDS). A total of 870 individuals (526 male/344 female) from 321 families were successfully genotyped using 398 polymorphic microsatellite markers with an average spacing of 9.26 cM on the autosomes. Results of non-parametric multipoint linkage analysis using S(all) statistics (implemented in Merlin) did not reveal any chromosomal region to be significantly associated with T2D in this Sikh cohort. However, linkage analysis for lipid traits using QTL-ALL analysis revealed promising linkage signals with p≤0.005 for total cholesterol, LDL cholesterol, and HDL cholesterol at chromosomes 5p15, 9q21, 10p11, 10q21, and 22q13. The most significant signal (p = 0.0011) occurred at 10q21.2 for HDL cholesterol. We also observed linkage signals for total cholesterol at 22q13.32 (p = 0.0016) and 5p15.33 (p = 0.0031) and for LDL cholesterol at 10p11.23 (p = 0.0045). Interestingly, some of linkage regions identified in this Sikh population coincide with plausible candidate genes reported in recent genome-wide association and meta-analysis studies for lipid traits. Our study provides the first evidence of linkage for loci associated with quantitative lipid traits at four chromosomal regions in this Asian Indian population from Punjab. More detailed examination of these regions with more informative genotyping, sequencing, and functional studies should lead to rapid detection of novel targets of therapeutic importance.
PLoS ONE 01/2011; 6(6):e21188. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Fasting plasma glucose (FPG) levels correlate with cardiovascular disease and mortality in both diabetic and non-diabetic subjects. G6PC2 encodes a pancreatic islet-specific glucose-6-phosphatase-related protein and G6pc2-null mice were reported to exhibit decreased blood glucose levels. Two recent genome-wide association studies have implicated a role for G6PC2 in regulation of FPGlevels in the general European population and reported the strongest association with the rs560887 SNP. The purpose of this study was to replicate this association in our independent epidemiological samples.
DNA samples from non-Hispanic white Americans (NHWs; n = 623), Hispanic Americans (n = 410) and black Africans (n = 787) were genotyped for rs560887 using TaqMan allelic discrimination.
While no minor allele A of rs560887 was observed among blacks, its frequency was 33% in NHWs and 17.5% in Hispanics. The rs560887 minor allele was associated with reduced FPG levels in non-diabetic NHWs (p = 0.002 under an additive model). A similar trend of association was observed in non-diabetic Hispanics (p = 0.076 under a dominant model), which was more pronounced in normoglycemic subjects (p = 0.036).
Our results independently confirm the robust association of G6PC2/rs560887 with FPG levels in non-diabetic NHWs. The observed evidence for association in Hispanics warrants further studies in larger samples.
Annals of Nutrition and Metabolism 12/2009; 56(1):59-64. · 1.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: The only recognized genetic determinant of the common forms of Alzheimer's disease (AD) is the epsilon 4 allele of the apolipoprotein E gene (APOE). To identify new candidate genes, we recently performed transcriptomic analysis of 2741 genes in chromosomal regions of interest using brain tissue of AD cases and controls. From 82 differentially expressed genes, 1156 polymorphisms were genotyped in two independent discovery subsamples (n=945). Seventeen genes exhibited at least one polymorphism associated with AD risk, and following correction for multiple testing, we retained the interleukin (IL)-33 gene. We first confirmed that the IL-33 expression was decreased in the brain of AD cases compared with that of controls. Further genetic analysis led us to select three polymorphisms within this gene, which we analyzed in three independent case-control studies. These polymorphisms and a resulting protective haplotype were systematically associated with AD risk in non-APOE epsilon 4 carriers. Using a large prospective study, these associations were also detected when analyzing the prevalent and incident AD cases together or the incident AD cases alone. These polymorphisms were also associated with less cerebral amyloid angiopathy (CAA) in the brain of non-APOE epsilon 4 AD cases. Immunohistochemistry experiments finally indicated that the IL-33 expression was consistently restricted to vascular capillaries in the brain. Moreover, IL-33 overexpression in cellular models led to a specific decrease in secretion of the A beta(40) peptides, the main CAA component. In conclusion, our data suggest that genetic variants in IL-33 gene may be associated with a decrease in AD risk potentially in modulating CAA formation.
[show abstract][hide abstract] ABSTRACT: Recent genome-wide association (GWA) studies have identified several unsuspected genes associated with type 2 diabetes (T2D) with previously unknown functions. In this investigation, we have examined the role of 9 most significant SNPs reported in GWA studies: [peroxisome proliferator-activated receptor gamma 2 (PPARG2; rs 1801282); insulin-like growth factor two binding protein 2 (IGF2BP2; rs 4402960); cyclin-dependent kinase 5, a regulatory subunit-associated protein1-like 1 (CDK5; rs7754840); a zinc transporter and member of solute carrier family 30 (SLC30A8; rs13266634); a variant found near cyclin-dependent kinase inhibitor 2A (CDKN2A; rs10811661); hematopoietically expressed homeobox (HHEX; rs 1111875); transcription factor-7-like 2 (TCF7L2; rs 10885409); potassium inwardly rectifying channel subfamily J member 11(KCNJ11; rs 5219); and fat mass obesity-associated gene (FTO; rs 9939609)].
We genotyped these SNPs in a case-control sample of 918 individuals consisting of 532 T2D cases and 386 normal glucose tolerant (NGT) subjects of an Asian Sikh community from North India. We tested the association between T2D and each SNP using unconditional logistic regression before and after adjusting for age, gender, and other covariates. We also examined the impact of these variants on body mass index (BMI), waist to hip ratio (WHR), fasting insulin, and glucose and lipid levels using multiple linear regression analysis.
Four of the nine SNPs revealed a significant association with T2D; PPARG2 (Pro12Ala) [odds ratio (OR) 0.12; 95% confidence interval (CI) (0.03-0.52); p = 0.005], IGF2BP2 [OR 1.37; 95% CI (1.04-1.82); p = 0.027], TCF7L2 [OR 1.64; 95% CI (1.20-2.24); p = 0.001] and FTO [OR 1.46; 95% CI (1.11-1.93); p = 0.007] after adjusting for age, sex and BMI. Multiple linear regression analysis revealed significant association of two of nine investigated loci with diabetes-related quantitative traits. The 'C' (risk) allele of CDK5 (rs 7754840) was significantly associated with decreased HDL-cholesterol levels in both NGT (p = 0.005) and combined (NGT and T2D) (0.005) groups. The less common 'C' (risk) allele of TCF7L2 (rs 10885409) was associated with increased LDL-cholesterol (p = 0.010) in NGT and total and LDL-cholesterol levels (p = 0.008; p = 0.003, respectively) in combined cohort.
To our knowledge, this is first study reporting the role of some recently emerged loci with T2D in a high risk population of Asian Indian origin. Further investigations are warranted to understand the pathway-based functional implications of these important loci in T2D pathophysiology in different ethnicities.
BMC Medical Genetics 08/2008; 9:59. · 2.54 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recently, the transcription factor-7-like 2 (TCF7L2) gene has been identified as the most important type 2 diabetes mellitus (T2DM) susceptibility gene. Common intronic polymorphisms in this gene have been found to be strongly associated with T2DM susceptibility showing marked reproducibility in multiple populations. The purpose of this study was to confirm the reported association of six TCF7L2 variants in a Khatri Sikh diabetic sample from North India. We genotyped six-associated SNPs in a case-control sample consisting of 556 T2DM cases and 537 controls. We also examined the impact of these variants on body mass index (BMI), waist to hip ratio (WHR), fasting insulin, and glucose and lipid levels. We report replication of association of four of the six SNPs with T2DM in this Khatri Sikh sample [rs7903146, (p = 0.010); rs11196205, (p = 0.011); rs10885409, (p = 0.002) and rs4918789, (p = 0.029)], under a dominant model conferring odds ratios (ORs) of 1.39, 1.44, 1.57 and 1.36, respectively. Haplotype analysis provided further evidence of association by showing a significant difference between cases and controls as revealed by the global omnibus test (chi(2)= 19.36; p = 0.0036). Multiple linear regression analysis also revealed the risk allele carriers of three of four significant SNPs (rs7903146, rs11196205, rs10885409) to be significantly associated with increased fasting total cholesterol (p value = 0.019, 0.025, 0.006) and LDL cholesterol levels (p value = 0.021, 0.018, 0.005), respectively. Our findings confirm that the TCF7L2 gene is a major risk factor for development of T2DM in Khatri Sikhs. It also provides new information about the significant impact of TCF7L2 gene variants on plasma cholesterol levels that appear to be independent of BMI.
Annals of Human Genetics 08/2008; 72(Pt 4):499-509. · 2.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: Interferon regulatory factor 5 (IRF5) belongs to a family of transcription factors that control the transactivation of type I interferon system-related genes, as well as the expression of several other genes involved in immune response, cell signalling, cell cycle control and apoptosis. Two recent studies reported a significant association between the IRF5/rs2004640 T allele and systemic lupus erythematosus (SLE). The purpose of this study was to determine whether the reported rs2004640 T allele association could be replicated in our independent SLE case-control sample. We genotyped DNA samples from 370 white SLE-affected female subjects and 462 white healthy female controls using the TaqMan Assay-on-Demand for rs2004640, and performed a case-control genetic association analysis. Frequency of the rs2004640 T allele was significantly higher in cases than in controls (56.5% vs. 50%; P= 0.008). The odds ratio for T allele carriers was 1.68 (95% CI: 1.20 - 2.34; P= 0.003). Our results in an independent case-control sample confirm the robust association of the IRF5/rs2004640 T allele with SLE risk, and further support the relevance of the type I interferon system in the pathogenesis of SLE and autoimmunity.
Annals of Human Genetics 06/2007; 71(Pt 3):308-11. · 2.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: The gene coding for ubiquilin 1 (UBQLN1) is located near a linkage peak on chromosome 9q22.2 and it also impacts the function of presenilin proteins involved in early-onset Alzheimer's disease (AD). Recently, genetic variation in UBQLN1 has been shown to affect the risk of AD in two independent family-based samples. The purpose of this study was to confirm the reported association in a large case-control sample and to also examine the association of UBQLN1 SNPs with quantitative measures of AD progression, namely age-at-onset (AAO), disease duration and Mini-Mental State Examination (MMSE) score. We examined the associations of three SNPs in the UBQLN1 gene (intron 6/A>C, intron 8/T>C and intron 9/A>G) in up to 978 LOAD cases and 808 controls. All SNPs were in significant linkage disequilibrium (P<0.0001). While modest significant associations were observed in the single-site regression analysis, 3-site haplotype analysis revealed significant associations (P<0.0001 for overall haplotype analysis). One common haplotype (H4) defined by intron 6/A-intron 8/C-intron 9/G alleles was associated with AD risk and one less common haplotype (H5) defined by intron 6/C-intron 8/C-intron 9/A alleles was associated with protection. The adjusted odds ratios with potentially one and two copies of risk haplotype H4 were 1.5 (95% CI: 0.99-2.26; P=0.054) and 3.66 (95% CI: 1.43-9.39; P=0.007), respectively, and odds ratio for haplotype H5 carriers was 0.31 (95% CI: 0.10-0.95; P=0.0398). In addition to disease risk, the homozygosity of the risk haplotype was also associated with older AAO, longer disease duration and lower MMSE score. In summary, our data from a large case-control cohort indicate that genetic variation in the UBQLN1 gene has a modest effect on risk, AAO and disease duration of AD. Our haplotype data suggest the presence of additional putative functional variants either in the UBQLN1 gene or nearby genes and provide strong justification for additional work in this region on chromosome 9.
[show abstract][hide abstract] ABSTRACT: The gene products of the apolipoprotein A-I, A-II, A-IV, C-II, C-III, D, E and H loci have been screened by isoelectric focusing followed by immunoblotting from two Papua New Guinean populations, the Huli and the Pawaia. Only APO E and APO H revealed common polymorphisms. A putative unique A-IV variant has been identified, but due to the lack of family data it is not characterized further. Three common APO H alleles were observed in both groups with comparable frequencies. But significantly different distributions of three APO E alleles were noted in the Huli and the Pawaia. The respective frequencies of the APO E*2, APO E*3, and APO E*4 alleles were 0.154, 0.356, and 0.490 in the Huli and 0.138, 0.603, and 0.259 in the Pawaia. A strikingly high frequency of the APO E*4 allele in Papua New Guinea may provide a useful insight into the studies of genetic and environmental interactions in controlling the cholesterol levels in the general population.
American Journal of Human Biology 05/2005; 2(1):17 - 23. · 2.34 Impact Factor
[show abstract][hide abstract] ABSTRACT: To explore the association between APOE*4 and pathologically confirmed cases of the Lewy body (LB) variant of Alzheimer disease (AD).
With use of alpha-synuclein (AS) immunohistochemistry, LBs were detected in 74 of 131 (56.5%) of the AD + LB cases; the remaining 57 cases (43.5%) did not have LBs.
There were no differences in gender or age between Caucasian subjects with AD + LB or AD alone or control subjects. The APOE*4 allele frequency was highest in the AD + LB group (47.3%; 95% CI = 37.8 to 57.0%), intermediate in the AD-alone group (35.1%; 95% CI = 25.3 to 46.3%), and lowest in the control group (14.2%; 95% CI = 10.5 to 18.9%). With use of logistic regression analysis, the odds of having AD + LB vs AD alone were 2.1-fold (95% CI = 1.0 to 4.5, p = 0.055) greater in persons with an APOE*4 allele than in those without an APOE*4 allele.
The APOE*4 allele is associated with the presence of concomitant Lewy bodies in Alzheimer disease.
[show abstract][hide abstract] ABSTRACT: Although possession of the epsilon 4 allele of the apolipoprotein E gene appears to be an important biological marker for Alzheimer's disease (AD) susceptibility, strong evidence indicates that at least one additional risk gene exists on chromosome 12. Here, we describe an association of the 3'-UTR +1073 C/T polymorphism of the OLR1 (oxidised LDL receptor 1) on chromosome 12 with AD in French sporadic (589 cases and 663 controls) and American familial (230 affected sibs and 143 unaffected sibs) populations. The age and sex adjusted odds ratio between the CC+CT genotypes versus the TT genotypes was 1.56 (p=0.001) in the French sample and 1.92 (p=0.02) in the American sample. Furthermore, we have discovered a new T/A polymorphism two bases upstream of the +1073 C/T polymorphism. This +1071 T/A polymorphism was not associated with the disease, although it may weakly modulate the impact of the +1073 C/T polymorphism. Using 3'-UTR sequence probes, we have observed specific DNA protein binding with nuclear proteins from lymphocyte, astrocytoma, and neuroblastoma cell lines, but not from the microglia cell line. This binding was modified by both the +1071 T/A and +1073 C/T polymorphisms. In addition, a trend was observed between the presence or absence of the +1073 C allele and the level of astrocytic activation in the brain of AD cases. However, Abeta(40), Abeta(42), Abeta total, and Tau loads or the level of microglial cell activation were not modulated by the 3'-UTR OLR1 polymorphisms. Finally, we assessed the impact of these polymorphisms on the level of OLR1 expression in lymphocytes from AD cases compared with controls. The OLR1 expression was significantly lower in AD cases bearing the CC and CT genotypes compared with controls with the same genotypes. In conclusion, our data suggest that genetic variation in the OLR1 gene may modify the risk of AD.
Journal of Medical Genetics 07/2003; 40(6):424-30. · 5.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: Genetic variation in several genes involved in lipid metabolism is known to affect population variation in quantitative lipid risk factor profiles for coronary heart disease (CHD). The apolipoprotein A-IV gene (APOA4) is one such candidate gene. We genotyped five polymorphisms in the APOA4 gene (codon 127, codon 130, codon347, codon 360 and 3' VNTR) and investigated their impact on plasma lipid trait levels in three populations comprising 604 U.S. non-Hispanic Whites (NHWs), 408 U.S. Hispanics and 708 Nigerian Blacks. Cladistic analysis was carried out to identify 5-site haplotypes that were associated with significant phenotypic differences in each population. The distribution of APOA4 genotypes was significantly different between ethnic groups. The Africans were monomorphic for two of the five sites (codons 130 and 360), but possess a unique 12 bp insertion that was not observed in NHWs and Hispanics. Due to linkage disequilibrium between the sites, only 6 haplotypes were observed in NHWs and Hispanics, and 4 in Africans. Several gender-and ethnic-specific associations between genotypes and plasma lipid traits were observed when single sites were used. Several haplotypes were identified by cladistic analysis that may carry functional mutations that affect plasma lipid trait levels.
Annals of Human Genetics 04/2003; 67(Pt 2):107-24. · 2.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: The single-strand conformation polymorphism (SSCP) method is widely used for mutation detection. The sensitivity of the method depends on several factors, most importantly on the temperature at which electrophoresis of single-stranded DNA (ssDNA) takes place. The temperature has a profound effect on the folded conformation of ssDNA. The temperature factor is predominantly determined empirically in conventional SSCP, which can be very tedious especially when a large number of different DNA samples need to be screened. We have devised a novel SSCP method based on a vertical gradient temperature (VGT), which automatically subjects ssDNA to various temperatures in the same electrophoresis. The theory behind VGT-SSCP protocol is that when ssDNA is subjected to run in a wide range of gradient temperature, it will automatically acquire optimal resolution at an optimal temperature to distinguish between the wild type and the mutant type ssDNA. The sensitivity level of mutation detection of VGT-SSCP depends on whether the corresponding optimal secondary structure of a mutant DNA strand is within the preset gradient temperature range. In summary, the VGT-SSCP is a simple and robust nonradioactive method that is more sensitive than constant-temperature SSCP in detecting unknown mutations.
[show abstract][hide abstract] ABSTRACT: Alzheimer's disease (AD) is a complex disease with the possible involvement of several genes. The APOE*4 allele has been documented to be a major risk factor for sporadic late-onset AD, but it is neither necessary nor sufficient to cause the disease. Cathepsin G, a serine protease found commonly in the azurophillic granules of neutrophils, has been reported to possess some beta-secretase like properties, and thus may be involved in the processing of amyloid precursor protein (APP). Recently, an A-->G polymorphism has been reported in exon 4 of the cathepsin G gene, which changes the codon AAC ((125) Asp) to AGC ((125)Ser). In this study, we have investigated the association of this polymorphism with sporadic late-onset AD. We screened DNA samples from 464 late-onset AD cases and 310 age-matched controls. No significant association was seen between this polymorphism and AD. When the data were stratified by the APOE*4 carrier status, no significant difference was seen either. Our data show no effect of this cathepsin G polymorphism in AD. Characterization of additional polymorphisms in this gene may provide more conclusive answers.