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51. Genetic effect of two APOA repeat polymorphisms (kringle 4 and pentanucleotide repeats) on plasma Lp(a) levels in American Samoans

Author

Christopher E. Aston, Robert E. Ferrell, A E McAllister, K DePrince, Linda Bausserman, Kamboh Mi, and Stephen T. McGarvey

Subjects
Adult, Apolipoprotein B, Pentanucleotide Repeats, Population, Biology, Genotype, Genetics, Humans, Allele, education, Gene, Allele frequency, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Apolipoproteins A, education.field_of_study, Analysis of Variance, Polymorphism, Genetic, Middle Aged, American Samoa, Cross-Sectional Studies, Tandem Repeat Sequences, biology.protein, Repeat polymorphism, Lipoprotein(a)
Abstract

Elevated plasma lipoprotein(a) [Lp(a)] level has been established as an independent risk factor for atherosclerosis and coronary heart disease. Considerable ethnic group differences in the distribution of plasma Lp(a) levels have raised public health concerns. Recently, we have reported that Samoans have the lowest plasma Lp(a) levels of any population group. In the present investigation, we report the contribution of two apolipoprotein(a) (APOA) polymorphisms, the kringle 4 type 2 (K4) repeat and the pentanucleotide repeat (PNR), in affecting plasma Lp(a) levels in an American Samoan sample (n = 309). The K4 repeats ranged in size from 15 to 40. The common alleles contained repeats ranging from 26 to 36 with allele frequencies between 5.5% to 9.7%, and these accounted for 82% of all alleles. An inverse relationship between K4 repeat number and plasma Lp(a) level was observed for single-banded (r = -0.59, p = 0.0001) and double-banded phenotypes (r = -0.50, p = 0.0001). This polymorphism explained 60% of the variation in plasma Lp(a) level in American Samoans. For the PNR polymorphism, five different repeat alleles and eight different genotypes were identified; the most common allele was eight repeats. The *8 PNR allele was associated with a wide range of K4 repeats, the *9 PNR allele with larger K4 repeats (25-40), and the *10 PNR with smaller K4 repeats (15-24). Analysis of variance (ANOVA) revealed that the PNR polymorphism accounts for 2.1% of the variability in plasma Lp(a) levels in this sample, when the K4 repeat polymorphism was taken into account. Our data show that common polymorphisms in the APOA gene are major determinants of plasma Lp(a) variation in American Samoans.

Published
2001

52. Genetic association between APOE*4 and neuropsychiatric symptoms in patients with probable Alzheimer's disease is dependent on the psychosis phenotype

Author

Christie, D, Shofer, J, Millard, SP, Li, E, DeMichele-Sweet, MA, Weamer, EA, Kamboh, MI, Lopez, OL, Sweet, RA, Tsuang, D, Christie, D, Shofer, J, Millard, SP, Li, E, DeMichele-Sweet, MA, Weamer, EA, Kamboh, MI, Lopez, OL, Sweet, RA, and Tsuang, D

Abstract

Background: Neuropsychiatric symptoms such as psychosis are prevalent in patients with probable Alzheimer's disease (AD) and are associated with increased morbidity and mortality. Because these disabling symptoms are generally not well tolerated by caregivers, patients with these symptoms tend to be institutionalized earlier than patients without them. The identification of protective and risk factors for neuropsychiatric symptoms in AD would facilitate the development of more specific treatments for these symptoms and thereby decrease morbidity and mortality in AD. The E4 allele of the apolipoprotein E (APOE) gene is a well-documented risk factor for the development of AD. However, genetic association studies of the APOE 4 allele and BPS in AD have produced conflicting findings.Methods: This study investigates the association between APOE and neuropsychiatric symptoms in a large sample of clinically well-characterized subjects with probable AD (n=790) who were systematically evaluated using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Behavioral Rating Scale for Dementia (BRSD).Results: Our study found that hallucinations were significantly more likely to occur in subjects with no APOΕ4 alleles than in subjects with two Ε4 alleles (15% of subjects and 5% of subjects, respectively; p=.0066), whereas there was no association between the occurrence of delusions, aberrant motor behavior, or agitation and the number of Ε4 alleles. However, 94% of the subjects with hallucinations also had delusions (D+H).Conclusion: These findings suggest that in AD the Ε4 allele is differentially associated with D+H but not delusions alone. This is consistent with the hypothesis that distinct psychotic subphenotypes may be associated with the APOE allele. © 2012 Christie et al.; licensee BioMed Central Ltd.

Published
2012

53. Analysis of genetic polymorphisms in the transforming growth factor-beta1 gene and the risk of Alzheimer's disease

Author

E K Luedecking, Kamboh Mi, Mary Ganguli, Mehdi H, and Steven T. DeKosky

Subjects
Male, Candidate gene, Biology, Transfection, Exon, Gene Frequency, Alzheimer Disease, Genes, Reporter, Risk Factors, Transforming Growth Factor beta, Genotype, Genetics, Animals, Humans, Luciferase, Allele, Luciferases, Promoter Regions, Genetic, Allele frequency, Gene, Genetics (clinical), Alleles, Aged, DNA Primers, Aged, 80 and over, Reporter gene, Polymorphism, Genetic, Base Sequence, Middle Aged, Molecular biology, COS Cells, Female
Abstract

Alzheimer's disease (AD) is a complex disease involving several genetic and environmental components. Genetic studies have yet to identify all the genes involved in the pathogenesis of AD. Transforming growth factor-beta1 (TGF-beta1) is a candidate gene for AD. It is a multifunctional cytokine whose overexpression has been shown to promote the deposition of amyloid-beta peptide. The goal of this study was to investigate the association of three polymorphisms in TGF-beta1 with the risk of AD. Two of the polymorphisms are located in the 5' region at positions -800 (G--A) and -509 (C--T), and the third is in exon 5 at codon 263 (Thr--Ile). We screened DNA samples from 428 sporadic, late-onset patients and 421 controls by PCR-based assays. There was no statistically significant difference in genotype or allele frequency distributions between cases and controls for the -800 or codon 263 polymorphisms (P=0.38 and P=0.60, respectively). The overall genotype distribution at the -509 site was significantly different between cases and controls. (P=0.017). The frequency of the -509/TT genotype was significantly higher in AD patients than controls (P=0.015). We further tested whether this polymorphism may alter the regulation of the TGF-beta1 gene using dual luciferase reporter assay. We subcloned the 5' flanking region, which contained the -509 C/T polymorphic sites, in front of the firefly luciferase reporter gene in pGL-3 basic vector and co-transfected with the pRL-CMV vector containing Renilla luciferase gene as a control for transfection efficiency in COS-1 cells. The activity of each promoter allele was directly measured by the ratio of firefly luciferase activity to Renilla luciferase activity. The -509 T allele was associated with marginally higher transcriptional activity of TGF-beta compared with the -509 C allele (P=0.051). These data suggest that the -509 polymorphism of TGF-beta1 may be modestly associated with the risk of AD. However, these data should be interpreted with caution as the differences associated with the -509 alleles in both the genetic association and the transfection studies were modest.

Published
2000

54. Association analysis of PON2 genetic variants with serum paraoxonase activity and systemic lupus erythematosus

Author

Dasgupta, S, Demirci, FY, Dressen, AS, Kao, AH, Rhew, EY, Ramsey-Goldman, R, Manzi, S, Kammerer, CM, Kamboh, MI, Dasgupta, S, Demirci, FY, Dressen, AS, Kao, AH, Rhew, EY, Ramsey-Goldman, R, Manzi, S, Kammerer, CM, and Kamboh, MI

Abstract

Background: Low serum paraoxonase (PON) activity is associated with the risk of coronary artery disease, diabetes and systemic lupus erythematosus (SLE). Our prior studies have shown that the PON1/rs662 (p.Gln192Arg), PON1/rs854560 (p.Leu55Met), PON3/rs17884563 and PON3/rs740264 SNPs (single nucleotide polymorphisms) significantly affect serum PON activity. Since PON1, PON2 and PON3 share high degree of structural and functional properties, in this study, we examined the role of PON2 genetic variation on serum PON activity, risk of SLE and SLE-related clinical manifestations in a Caucasian case-control sample.Methods: PON2 SNPs were selected from HapMap and SeattleSNPs databases by including at least one tagSNP from each bin defined in these resources. A total of nineteen PON2 SNPs were successfully genotyped in 411 SLE cases and 511 healthy controls using pyrosequencing, restriction fragment length polymorphism (RFLP) or TaqMan allelic discrimination methods.Results: Our pair-wise linkage disequilibrium (LD) analysis, using an r2 cutoff of 0.7, identified 14 PON2 tagSNPs that captured all 19 PON2 variants in our sample, 12 of which were not in high LD with known PON1 and PON3 SNP modifiers of PON activity. Stepwise regression analysis of PON activity, including the known modifiers, identified five PON2 SNPs [rs6954345 (p.Ser311Cys), rs13306702, rs987539, rs11982486, and rs4729189; P = 0.005 to 2.1 × 10-6] that were significantly associated with PON activity. We found no association of PON2 SNPs with SLE risk but modest associations were observed with lupus nephritis (rs11981433, rs17876205, rs17876183) and immunologic disorder (rs11981433) in SLE patients (P = 0.013 to 0.042).Conclusions: Our data indicate that PON2 genetic variants significantly affect variation in serum PON activity and have modest effects on risk of lupus nephritis and SLE-related immunologic disorder. © 2011 Dasgupta et al; licensee BioMed Central Ltd.

Published
2011

55. Genome-wide linkage scan to identify loci associated with type 2 diabetes and blood lipid phenotypes in the sikh diabetes study

Author

Sanghera, DK, Been, LF, Ralhan, S, Wander, GS, Mehra, NK, Singh, JR, Ferrell, RE, Kamboh, MI, Aston, CE, Sanghera, DK, Been, LF, Ralhan, S, Wander, GS, Mehra, NK, Singh, JR, Ferrell, RE, Kamboh, MI, and Aston, CE

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 Sall 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. © 2011 Sanghera et al.

Published
2011

56. Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes

Author

Taylor, KE, Chung, SA, Graham, RR, Ortmann, WA, Lee, AT, Langefeld, CD, Jacob, CO, Kamboh, MI, Alarcón-Riquelme, ME, Tsao, BP, Moser, KL, Gaffney, PM, Harley, JB, Petri, M, Manzi, S, Gregersen, PK, Behrens, TW, Criswell, LA, Taylor, KE, Chung, SA, Graham, RR, Ortmann, WA, Lee, AT, Langefeld, CD, Jacob, CO, Kamboh, MI, Alarcón-Riquelme, ME, Tsao, BP, Moser, KL, Gaffney, PM, Harley, JB, Petri, M, Manzi, S, Gregersen, PK, Behrens, TW, and Criswell, LA

Abstract

Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. Recent studies have greatly expanded the number of established SLE risk alleles, but the distribution of multiple risk alleles in cases versus controls and their relationship to subphenotypes have not been studied. We studied 22 SLE susceptibility polymorphisms with previous genome-wide evidence of association (p<5×10-8) in 1919 SLE cases from 9 independent Caucasian SLE case series and 4813 independent controls. The mean number of risk alleles in cases was 15.1 (SD 3.1) while the mean in controls was 13.1 (SD 2.8), with trend p = 4×10-128. We defined a genetic risk score (GRS) for SLE as the number of risk alleles with each weighted by the SLE risk odds ratio (OR). The OR for high-low GRS tertiles, adjusted for intra-European ancestry, sex, and parent study, was 4.4 (95% CI 3.8-5.1). We studied associations of individual SNPs and the GRS with clinical manifestations for the cases: age at diagnosis, the 11 American College of Rheumatology classification criteria, and double-stranded DNA antibody (anti-dsDNA) production. Six subphenotypes were significantly associated with the GRS, most notably anti-dsDNA (ORhigh-low = 2.36, p = 9e-9), the immunologic criterion (ORhigh-low = 2.23, p = 3e-7), and age at diagnosis (ORhigh-low = 1.45, p = 0.0060). Finally, we developed a subphenotype-specific GRS (sub-GRS) for each phenotype with more power to detect cumulative genetic associations. The sub-GRS was more strongly associated than any single SNP effect for 5 subphenotypes (the above plus hematologic disorder and oral ulcers), while single loci are more significantly associated with renal disease (HLA-DRB1, OR = 1.37, 95% CI 1.14-1.64) and arthritis (ITGAM, OR = 0.72, 95% CI 0.59-0.88). We did not observe significant associations for other subphenotypes, for individual loci or the sub-GRS. Thus our analysis categorizes SLE subphenotypes into three groups: those ha

Published
2011

57. Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production

Author

Chung, SA, Taylor, KE, Graham, RR, Nititham, J, Lee, AT, Ortmann, WA, Jacob, CO, Alarcón-Riquelme, ME, Tsao, BP, Harley, JB, Gaffney, PM, Moser, KL, Petri, M, Demirci, FY, Kamboh, MI, Manzi, S, Gregersen, PK, Langefeld, CD, Behrens, TW, Criswell, LA, Chung, SA, Taylor, KE, Graham, RR, Nititham, J, Lee, AT, Ortmann, WA, Jacob, CO, Alarcón-Riquelme, ME, Tsao, BP, Harley, JB, Gaffney, PM, Moser, KL, Petri, M, Demirci, FY, Kamboh, MI, Manzi, S, Gregersen, PK, Langefeld, CD, Behrens, TW, and Criswell, LA

Abstract

Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, n = 811) and anti-dsDNA autoantibody negative (anti-dsDNA -, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, p = 2.0E-20) compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, p = 2.4E-04), with pheterogeneity<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti-dsDNA + SLE and were not associated with anti-dsDNA - SLE. In conclusion, we identified differential genetic associations with SLE based on anti-dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti-dsDNA - SLE.

Published
2011

58. APOE and Alzheimer disease: a major gene with semi-dominant inheritance

Author

Genin, E, Hannequin, D, Wallon, D, Sleegers, K, Hiltunen, M, Combarros, O, Bullido, M, Engelborghs, S, De Deyn, P, Berr, C, Pasquier, F, Dubois, B, Tognoni, G, Fiévet, N, Brouwers, N, Bettens, K, Arosio, B, Coto, E, Del Zompo, M, Mateo, I, Epelbaum, J, Frank Garcia, A, Helisalmi, S, Porcellini, E, Pilotto, A, Forti, P, Ferri, R, Scarpini, E, Siciliano, G, Solfrizzi, V, Sorbi, S, Spalletta, G, Valdivieso, F, Vepsäläinen, S, Alvarez, V, Bosco, P, Mancuso, M, Panza, F, Nacmias, B, Bossù, P, Hanon, O, Piccardi, P, Annoni, G, Seripa, D, Galimberti, D, Licastro, F, Soininen, H, Dartigues, J, Kamboh, M, Van Broeckhoven, C, Lambert, J, Amouyel, P, Campion, D, Bullido, MJ, ANNONI, GIORGIO, Kamboh, MI, Lambert, JC, Campion, D., Genin, E, Hannequin, D, Wallon, D, Sleegers, K, Hiltunen, M, Combarros, O, Bullido, M, Engelborghs, S, De Deyn, P, Berr, C, Pasquier, F, Dubois, B, Tognoni, G, Fiévet, N, Brouwers, N, Bettens, K, Arosio, B, Coto, E, Del Zompo, M, Mateo, I, Epelbaum, J, Frank Garcia, A, Helisalmi, S, Porcellini, E, Pilotto, A, Forti, P, Ferri, R, Scarpini, E, Siciliano, G, Solfrizzi, V, Sorbi, S, Spalletta, G, Valdivieso, F, Vepsäläinen, S, Alvarez, V, Bosco, P, Mancuso, M, Panza, F, Nacmias, B, Bossù, P, Hanon, O, Piccardi, P, Annoni, G, Seripa, D, Galimberti, D, Licastro, F, Soininen, H, Dartigues, J, Kamboh, M, Van Broeckhoven, C, Lambert, J, Amouyel, P, Campion, D, Bullido, MJ, ANNONI, GIORGIO, Kamboh, MI, Lambert, JC, and Campion, D.

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.Molecular Psychiatry advance online publication, 10 May 2011; doi:10.1038/mp.2011.52.

Published
2011

59. A novel mutation in the apolipoprotein E gene (APOE*4 Pittsburgh) is associated with the risk of late-onset Alzheimer's disease

Author

John Hardy, Jordi Pérez-Tur, Christopher E. Aston, Kamboh Mi, Emre Kokmen, Robert E. Ferrell, and Steven T. DeKosky

Subjects
Apolipoprotein E, Adult, Male, medicine.medical_specialty, Proline, Population, Apolipoprotein E4, Mutation, Missense, Biology, Gastroenterology, Apolipoproteins E, Alzheimer Disease, Leucine, Reference Values, Risk Factors, Internal medicine, medicine, Missense mutation, Humans, Registries, Allele, Age of Onset, education, Polymorphism, Single-Stranded Conformational, Aged, Genetics, Aged, 80 and over, education.field_of_study, General Neuroscience, Single-strand conformation polymorphism, Odds ratio, Exons, Middle Aged, medicine.disease, United States, Amino Acid Substitution, Female, Alzheimer's disease, Age of onset
Abstract

Using a combination of polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP) and DNA sequencing techniques, we identified a unique missense mutation (T-->C) in exon 3 of the APOE gene which resulted in the substitution of pro-28 for leu-28. We screened 1118 White cases of late-onset (>60 years) Alzheimer's disease (AD) from three independent centers (Pittsburgh = 489, Indiana = 319, Mayo Clinic Rochester = 310) and 1123 controls (607 clinically assessed and 516 individuals randomly ascertained from the general population). Two of the 1123 control subjects had the pro-28 mutation (0.18%). However, this mutation was observed in heterozygous state in 2.66, 2.51 and 1.94% of the AD cases from Pittsburgh, Indiana and Mayo Clinic Rochester, respectively, with an overall frequency of 2.42%. All individuals with this mutation were carriers of the APOE*4 allele and hence the mutation was denoted as APOE*4 Pittsburgh (APOE*4P). Compared with the non-E*4P carriers, the E*4P carriers were associated with an increased risk of AD (odds ratio (OR) 13.2) and this risk remained significant even after adjusting for the known effect of APOE*4 (OR 5.4). The risk associated with the E*4P/E*4 combination was about five times (OR 29.1) the risk attributed to APOE*4 carriers alone (OR 5.7). Our data indicates that the new mutation most likely exists in cis-orientation with APOE*4 and is associated with increased risk of developing AD.

Published
1999

60. Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus

Author

Taylor, KE, Remmers, EF, Lee, AT, Ortmann, WA, Plenge, RM, Tian, C, Chung, SA, Nititham, J, Hom, G, Kao, AH, Demirci, FY, Kamboh, MI, Petri, M, Manzi, S, Kastner, DL, Seldin, MF, Gregersen, PK, Behrens, TW, Criswell, LA, Taylor, KE, Remmers, EF, Lee, AT, Ortmann, WA, Plenge, RM, Tian, C, Chung, SA, Nititham, J, Hom, G, Kao, AH, Demirci, FY, Kamboh, MI, Petri, M, Manzi, S, Kastner, DL, Seldin, MF, Gregersen, PK, Behrens, TW, and Criswell, LA

Abstract

Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. A polymorphism in the STAT4 gene has recently been established as a risk factor for SLE, but the relationship with specific SLE subphenotypes has not been studied. We studied 137 SNPs in the STAT4 region genotyped in 4 independent SLE case series (total n = 1398) and 2560 healthy controls, along with clinical data for the cases. Using conditional testing, we confirmed the most significant STAT4 haplotype for SLE risk. We then studied a SNP marking this haplotype for association with specific SLE subphenotypes, including autoantibody production, nephritis, arthritis, mucocutaneous manifestations, and age at diagnosis. To prevent possible type-I errors from population stratification, we reanalyzed the data using a subset of subjects determined to be most homogeneous based on principal components analysis of genome-wide data. We confirmed that four SNPs in very high LD (r2 = 0.94 to 0.99) were most strongly associated with SLE, and there was no compelling evidence for additional SLE risk loci in the STAT4 region. SNP rs7574865 marking this haplotype had a minor allele frequency (MAF) = 31.1% in SLE cases compared with 22.5% in controls (OR = 1.56, p = 10-16). This SNP was more strongly associated with SLE characterized by double-stranded DNA autoantibodies (MAF = 35.1%, OR = 1.86, p<10-19), nephritis (MAF = 34.3%, OR = 1.80, p<10-11), and age at diagnosis<30 years (MAF = 33.8%, OR = 1.77, p<10-13). An association with severe nephritis was even more striking (MAF = 39.2%, OR = 2.35, p<10 -4 in the homogeneous subset of subjects). In contrast, STAT4 was less strongly associated with oral ulcers, a manifestation associated with milder disease. We conclude that this common polymorphism of STAT4 contributes to the phenotypic heterogeneity of SLE, predisposing specifically to more severe disease.

Published
2008

61. Plasma apolipoprotein A-I, apolipoprotein B, and lipoprotein(a) concentrations in normoglycemic Hispanics and non-Hispanic whites from the San Luis Valley, Colorado

Author

Christopher E. Aston, Marian Rewers, Richard F. Hamman, and Kamboh Mi

Subjects
Adult, Male, medicine.medical_specialty, Colorado, Apolipoprotein B, Epidemiology, Coronary Disease, Apolipoproteins A, White People, Quantitative Trait, Heritable, Risk Factors, Internal medicine, Blood plasma, medicine, Humans, Apolipoprotein A-I/Apolipoprotein B, Aged, Apolipoproteins B, biology, Apolipoprotein A-I, business.industry, nutritional and metabolic diseases, Lipoprotein(a), Hispanic or Latino, Middle Aged, Non-Hispanic whites, Coronary heart disease, Endocrinology, biology.protein, lipids (amino acids, peptides, and proteins), Female, business, Lipoprotein
Abstract

Lower levels of plasma apolipoprotein (apo) A-I and higher levels of apoB, lipoprotein(a) (Lp(a)), and the ratio of apoB to apoA-I are considered to be independent risk factors for coronary heart disease. To examine race differences in the distributions of plasma levels of apoA-I, apoB, and Lp(a), the authors have determined quantitative levels of these traits in 252 nondiabetic Hispanics and 459 nondiabetic non-Hispanic whites (NHWs) from the San Luis Valley, Colorado. Hispanic men and women, respectively, had significantly higher plasma apoB levels (p0.003; p0.01) and the ratio of apoB to apoA-I (p0.003; p0.0003) than their NHW counterparts. Plasma Lp(a) concentrations were also significantly higher in Hispanic men (p0.003) and apoA-I levels were significantly lower in Hispanic women (p0.0003) than NHW men and women, respectively. Overall, the threshold points of apoA-I (120 mg/dl), apoB (120 mg/dl), and Lp(a) (25 mg/dl) were higher in Hispanics than in NHWs for apoA-I (22.8 vs. 15.7%), apoB (16.9 vs. 9.9%), and Lp(a) (18.6 vs. 12.4%). These data suggest that the quantitative risk profile for coronary heart disease with respect to these three quantitative traits is not favorable for Hispanics compared with that for NHWs in the San Luis Valley, Colorado.

Published
1998

62. Influence of two apo A4 polymorphisms at codons 347 and 360 on non-fasting plasma lipoprotein-lipids and apolipoproteins in Asian Indians

Author

S. Vasisht, Nilmani Saha, Kamboh Mi, and G Wang

Subjects
Adult, Male, medicine.medical_specialty, Apolipoprotein B, Adolescent, Genotype, Lipoproteins, Biology, chemistry.chemical_compound, Internal medicine, medicine, Humans, Allele, Codon, Apolipoproteins A, Aged, DNA Primers, Genetics, Polymorphism, Genetic, Triglyceride, Haplotype, Lipid metabolism, DNA, Middle Aged, Lipids, Endocrinology, Apolipoproteins, chemistry, Low-density lipoprotein, biology.protein, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, Lipoprotein
Abstract

Apolipoprotein A-IV (apo A-IV, protein; apo A4, gene) is a major constituent of triglyceride-rich and high-density lipoprotein particles and may, therefore, play an important role in lipid metabolism. We studied the distribution of two apo A4 polymorphisms at codons 347 (alleles A and T) and 360 (alleles 1 and 2) in relation to plasma lipoprotein-lipid and apolipoprotein levels in 176 non-fasting male blood donors from New Delhi, Northern India. The frequencies of the T allele at codon 347 and the 2 allele at codon 360 were 0.12 and 0.03 respectively. Carriers of the T allele (AT and TT genotypes) had significantly lower plasma total cholesterol (P0.04) and low density lipoprotein (LDL)-cholesterol (P 0.02) levels than individuals homozygous for the A allele (AA genotype). The codon 347 polymorphism explained 2.2 and 2.6% of the phenotypic variation in total cholesterol and LDL-cholesterol, respectively. The 2 allele at codon 360 was associated with marginally reduced plasma LDL-cholesterol (P0.09) and increased triglyceride (P 0.05) levels compared to the 1 allele. To further elucidate the combined effects of the two polymorphism we constructed two-site haplotypes. The haplotype data showed a stronger influence and explained 3.0 and 5.2% of the phenotypic variation in total cholesterol and LDL-cholesterol, respectively. The two uncommon haplotypes, T1 and A2, were associated with 24.2 and 23.5 mg:dl lower total cholesterol and 22.5 and 42.0 mg:dl lower LDL-cholesterol levels, respectively. The accentuated effect of apo A4 polymorphisms on non-fasting plasma cholesterol suggest that apo A-IV may play an important role in regulating the postprandial metabolism of lipoproteins. © 1997 Elsevier Science Ireland Ltd.

Published
1997

63. Quantitative effects of the apolipoprotein E polymorphism in a biracial sample of 9-10-year-old girls

Author

Kamboh Mi, Dharambir K. Sanghera, Sue Y. S. Kimm, Christopher E. Aston, Robert E. Ferrell, and A E McAllister

Subjects
Apolipoprotein E, medicine.medical_specialty, Waist, Apolipoprotein B, Genotype, Black People, Coronary Artery Disease, White People, Cohort Studies, chemistry.chemical_compound, Apolipoproteins E, Skin fold, Risk Factors, Internal medicine, medicine, Humans, Obesity, Allele, Child, Alleles, Triglycerides, Apolipoproteins B, biology, Anthropometry, Apolipoprotein A-I, Cholesterol, business.industry, Cholesterol, HDL, Cholesterol, LDL, Endocrinology, chemistry, biology.protein, lipids (amino acids, peptides, and proteins), Female, Disease Susceptibility, Cardiology and Cardiovascular Medicine, business, Cohort study
Abstract

Genetic polymorphism at the apolipoprotein E locus (APOE) has been shown to have a significant impact on quantitative risk factors for coronary artery disease (CAD) in diverse populations. However, despite the recognition that atherosclerosis begins in childhood and that genetic factors are related to the initial stages of atherosclerosis, prior studies were carried out mostly on adults and little attention has been paid to genetic risk factors for CAD in children. We have examined the impact of APOE polymorphism on quantitative risk factors for CAD (apoAI, apoB, TC, LDL-C, HDL-C and TG) in a sample of 647 African American and 573 White 9-10-year-old girls who were enrolled in the National Heart, Lung and Blood Institute Growth and Healthy Study. The frequencies of the APOE*2, APOE*3 and APOE*4 alleles were 0.09, 0.76 and 0.15 in Whites and 0.11, 0.70 and 0.19 in African Americans, respectively. The APOE*2 allele was significantly associated with lower mean levels of LDL-C and apoB and the APOE*4 allele with higher levels of LDL-C and apoB in both racial groups. Variation in maturation stage, body fat and fat patterning, as assessed by skin fold measures and waist/hip ratio, accounted for a significant proportion of the variation in quantitative CAD risk factors.

Published
1996

64. Genetic effect of apolipoprotein(a) and apolipoprotein E polymorphisms on plasma quantitative risk factors for coronary heart disease in American black women

Author

Rhobert W. Evans, Kamboh Mi, and Christopher E. Aston

Subjects
Apolipoprotein E, Adult, medicine.medical_specialty, Apolipoprotein B, Black People, Coronary Disease, Quantitative trait locus, chemistry.chemical_compound, Random Allocation, Apolipoproteins E, Risk Factors, Internal medicine, Blood plasma, Genotype, medicine, Humans, Allele, Child, Alleles, Apolipoproteins A, Apolipoproteins B, Analysis of Variance, Polymorphism, Genetic, biology, Cholesterol, Endocrinology, Phenotype, chemistry, biology.protein, lipids (amino acids, peptides, and proteins), Female, Cardiology and Cardiovascular Medicine, Lipoprotein
Abstract

The distributions of plasma total cholesterol, apolipoproteins A-I and B and lipoprotein(a) levels as well as genetic typings of apolipoprotein(a) and apolipoprotein E were determined in a randomly selected sample of American Black women (mean age 22.2 +/- 6.5 years) . Mean plasma levels of cholesterol, apolipoprotein A-I, apolipoprotein B and lipoprotein(a) were 184.5 +/- 3.0 mg/dl, 138.0 +/- 3.1 mg/dl, 79.5 +/- 1.8 mg/dl and 24.5 +/- 1.5 mg/dl, respectively. Plasma lipoprotein (a) levels correlated significantly with apolipoprotein B and cholesterol. The contribution of apolipoprotein (a) and apolipoprotein E polymorphisms in affecting these quantitative traits was evaluated. The apolipoprotein(a) locus was extremely polymorphic with 27 alleles, while the 3 common alleles were observed in the apolipoprotein E gene. The frequencies of the APOE*2, APOE* and APOE*4 alleles were 0.094, 0.674 and 0.232, respectively. An inverse relationship was observed between the size of apolipoprotein(a) isoforms and lipoprotein(a) levels (r = 0.37; P = 0.0001). The apolipoprotein E polymorphism revealed a significant genotypic effect on apolipoprotein B (P = 0.0008) and cholesterol (P= 0.005) levels; these concentrations were lower in the APOE 2-3 genotype and higher in the 3-4 and 4-4 genotypes compared with the common 3-3 genotype. The apolipoprotein E polymorphism explained 15.8% and 6.3% of the phenotypic variance in apolipoprotein B and cholesterol levels, respectively. This study demonstrates that genetics play an important role in determining quantitative risk factors for coronary heart disease among American Black women.

Published
1995

65. Heterogeneity of the apolipoprotein H*3 allele and its role in affecting the binding of apolipoprotein H (beta 2-glycoprotein I) to anionic phospholipids

Author

McIntyre Ja, Wagenknecht Dr, and Kamboh Mi

Subjects
Adult, Anions, Male, medicine.drug_class, Immunoblotting, Phospholipid, Phosphatidylserines, Monoclonal antibody, Binding, Competitive, Cofactor, chemistry.chemical_compound, Genetics, medicine, Humans, Allele, Gene, Genetics (clinical), Alleles, Glycoproteins, biology, Racial Groups, Antibodies, Monoclonal, Molecular biology, Apolipoproteins, chemistry, Polyclonal antibodies, beta 2-Glycoprotein I, Child, Preschool, Immunoglobulin G, biology.protein, Female, Antibody, Isoelectric Focusing, Apolipoprotein H
Abstract

Apolipoprotein H (apoH, protein; APOH, gene) has been implicated as a necessary cofactor for the binding of certain autoimmune antiphospholipid antibodies to anionic phospholipids. APOH exhibits genetically determined structural polymorphism with the occurrence of four alleles. Recently three IgG1k monoclonal antibodies (mAb) to human apoH, designated 3G9, 1B4, and 3D11, have been produced. The mAb 3D11 does not recognize apoH bound to anionic phospholipids in contrast to mAb 3G9 and 1B4, which recognize free and phospholipid-bound apoH. In this investigation we have determined the reactivity of the three mAb with four APOH allele products and the binding ability of these allele products with anionic phospholipids. The mAb 3G9 and 1B4, like the polyclonal anti-apoH, were equally reactive with all four allelic products, but the 3D11 recognized only the APOH*3 allele product. In the 159 APOH*3 carriers tested from five ethnic groups, the reactivity of mAb 3D11 was observed with all the Chinese but none of the African blacks. For the U.S. whites and Polynesians 89% and 75%, respectively, of the APOH*3 allele products were recognized by 3D11, while 87% of the U.S. blacks with this allele had no 3D11 reactivity. These data show that the APOH*3 allele, originally identified as a single entity by the polyclonal anti-apoH, is heterogeneous with at least one distinct variation based on mAb 3D11 reactivity. Our data also demonstrate that the apoH from certain homozygous APOH*3 individuals is unable to bind to anionic phospholipids. Such ethnic-specific apoH variations could play a significant role in the binding properties of autoimmune antiphospholipid antibodies to anionic phospholipids.

Published
1995

66. Role of common genetic polymorphisms in the LDL receptor gene in affecting plasma cholesterol levels in the general population

Author

Y I Ahn, Richard F. Hamman, Kamboh Mi, Christopher E. Aston, and Robert E. Ferrell

Subjects
Male, medicine.medical_specialty, Linkage disequilibrium, Population, Molecular Sequence Data, Familial hypercholesterolemia, Biology, Linkage Disequilibrium, chemistry.chemical_compound, Apolipoproteins E, Gene Frequency, Internal medicine, medicine, Humans, education, Allele frequency, Alleles, education.field_of_study, Polymorphism, Genetic, Base Sequence, Cholesterol, Hispanic or Latino, medicine.disease, Endocrinology, chemistry, Receptors, LDL, LDL receptor, lipids (amino acids, peptides, and proteins), Female, Restriction fragment length polymorphism, Cardiology and Cardiovascular Medicine, Lipoprotein
Abstract

A large number of rare mutations in the low-density lipoprotein (LDL) receptor gene cause the autosomal dominant disorder familial hypercholesterolemia. In addition, a number of common DNA polymorphisms have been identified in the LDL receptor gene, but their significance in affecting plasma cholesterol levels in the general population has not been studied widely. We investigated the role of two common DNA polymorphisms, Ava II (exon 13) and Nco I (exon 18), at the LDL receptor locus in affecting plasma lipid profiles in normolipidemic Hispanics (n = 385) and non-Hispanic whites (NHWs; n = 543) from the San Luis Valley, Colorado. While the distribution of the Nco I polymorphism was comparable between Hispanics and NHWs, the allele frequencies at the Ava II restriction site differed significantly between the two ethnic groups (P < .001). The Ava II and Nco I polymorphisms were in linkage disequilibrium (P < .05) in both Hispanics and NHWs. Both polymorphisms revealed a gender-specific effect on total and LDL cholesterol (LDL-C) confined to women only in both ethnic groups. The AVA II polymorphism was associated significantly with total cholesterol and LDL-C in NHW women (P = .001 and P = .014) and in Hispanic women (P = .011 and P = .057). The effect of the Nco I polymorphism was significant on total cholesterol and LDL-C (P = .019 and P = .035) in Hispanic women only. Although a similar trend was observed in NHW women, the effect was not significant at the 5% level.(ABSTRACT TRUNCATED AT 250 WORDS)

Published
1994

67. Association of lipoprotein lipase gene variation with the physiological components of the insulin-resistance syndrome in the population of the San Luis Valley, Colorado

Author

Kamboh Mi, Y I Ahn, Robert E. Ferrell, and Richard F. Hamman

Subjects
Blood Glucose, medicine.medical_specialty, Colorado, Genotype, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Population, Molecular Sequence Data, HindIII, Polymerase Chain Reaction, White People, chemistry.chemical_compound, Insulin resistance, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, Insulin, education, Triglycerides, Advanced and Specialized Nursing, Lipoprotein lipase, education.field_of_study, Triglyceride, biology, Base Sequence, business.industry, Cholesterol, HDL, Genetic Variation, DNA, Hispanic or Latino, Syndrome, medicine.disease, Lipoprotein Lipase, Endocrinology, Cross-Sectional Studies, chemistry, Multigene Family, biology.protein, Insulin Resistance, business, Polymorphism, Restriction Fragment Length
Abstract

OBJECTIVE To cross-sectionally evaluate the presence of clustering of the insulin-resistance syndrome components. Tests were conducted for association of the Hind III restriction site polymorphism at the lipoprotein lipase locus with clustering of the physiological components of the insulin resistance syndrome. RESEARCH DESIGN AND METHODS DNA samples of 370 normoglycemic Hispanics and 520 normoglycemic non-Hispanic whites from the San Luis Valley, Colorado, were amplified by the polymerase chain reaction. Lipids and glucose were determined by the standard procedures. Cross-tabulation and χ2 analysis were used. RESULTS The insulin-resistance syndrome components (elevated fasting insulin, reduced high-density lipoprotein cholesterol, and elevated triglycerides) appeared together in individuals of this population sample more often than expected by chance. Individuals in the population with the (+/+) lipoprotein lipase-HindIII restriction of fragment-length polymorphism genotype were more likely to have elevated fasting insulin and triglycerides and a reduced high-density lipoproteincholesterol level than subjects with the (+/−) genotype (odds ratio = 2.3, 95% confidence interval 1.38–3.98). CONCLUSIONS As expected from the physiological function of lipoprotein lipase, the primary association of lipoprotein lipase genotypes is with triglyceride and high-density lipoprotein-cholesterol levels. This appears to be the first reported genetic association with the insulin-resistance syndrome and may reflect genotype specific differences in the regulation of lipoprotein lipase by insulin.

Published
1993

68. A simplified method for screening the apolipoprotein E polymorphism

Author

June E. Eichner, L.H. Kuller, Robert E. Ferrell, and Kamboh Mi

Subjects
Apolipoprotein E, Adult, Chromatography, Polymorphism, Genetic, Isoelectric focusing, Polyacrylamide, Biology, Middle Aged, Molecular biology, chemistry.chemical_compound, Apolipoproteins E, chemistry, Cardiovascular Diseases, Risk Factors, Genetics, Humans, Female, Genetic Testing, Longitudinal Studies, Isoelectric Focusing, Apolipoprotein e polymorphism, Genetics (clinical)
Abstract

A simple method for screening populations for the apolipoprotein E polymorphism which involves isoelectric focusing of delipidated samples on polyacrylamide gels of pH 4.5–5.8 followed by immunoblotting using a double-antibody technique is presented. The method is a synthesis of two previously published procedures and works well on samples that have been stored for as long as 15 years.

Published
1991

69. Bleomycin hydrolase is associated with risk of sporadic Alzheimer's disease

Author

Kamboh Mi, Susana E. Montoya, Christopher E. Aston, John S. Lazo, Robert E. Ferrell, and Steven T. DeKosky

Subjects
Heterozygote, Polymorphism, Genetic, business.industry, Homozygote, Bleomycin hydrolase, Disease, Biology, Cysteine Endopeptidases, Apolipoproteins E, Text mining, Gene Frequency, Alzheimer Disease, Case-Control Studies, Genetics, Cancer research, Humans, Regression Analysis, Genetic Predisposition to Disease, business
Published
1998

72. Association between ACT polymorphism and Alzheimer's disease

Author

C. E. Aston, Steven T. DeKosky, and Kamboh Mi

Subjects
Genetics, Polymorphism, Genetic, Genotype, alpha 1-Antichymotrypsin, business.industry, Genetic Carrier Screening, Association (object-oriented programming), Apolipoprotein E4, Disease, Apolipoproteins E, Gene Frequency, Alzheimer Disease, Reference Values, Polymorphism (computer science), Humans, Medicine, Neurology (clinical), business, Alleles
Published
1998

75. Relationship of serum paraoxonase 1 activity and paraoxonase 1 genotype to risk of systemic lupus erythematosus.

Author

Tripi LM, Manzi S, Chen Q, Kenney M, Shaw P, Kao A, Bontempo F, Kammerer C, and Kamboh MI

Abstract

OBJECTIVE: Low serum paraoxonase 1 (PON1) activity determined with paraoxon as substrate has been found to be associated with coronary artery disease. This study was undertaken to examine the relationship of PON1 activity and genotype to risk of systemic lupus erythematosus (SLE). METHODS: The impact of 7 PON1 single-nucleotide polymorphisms (SNPs) was analyzed in relation to PON1 activity, SLE risk, lupus nephritis, antiphospholipid antibody (aPL) positivity, and carotid vascular disease in 380 SLE patients (334 white, 46 black) and 497 controls (455 white, 42 black). RESULTS: Compared with findings in controls, PON1 activity with paraoxon substrate was reduced both in white lupus patients (mean +/- SEM 618.9 +/- 24.0 units/liter versus 719.6 +/- 24.6 units/liter; P = 0.007) and in black lupus patients (991.1 +/- 82.7 units/liter versus 1,164.3 +/- 101.4 units/liter; P = 0.2711). Low PON1 activity in SLE was not associated with the occurrence of aPL, carotid vascular disease, or the use of immunosuppressive drugs. In multiple regression analyses, the Q192R SNP was found to be independently associated with PON1 activity and explained 28% and 41% of the variation in PON1 activity in white patients and black patients, respectively. Stratification of the lupus sample by presence (n = 81) or absence (n = 247) of renal disease revealed significant associations with 3 promoter SNPs, with odds ratios of 3.82 (95% confidence interval [95% CI] 1.49-9.82, P = 0.005), 3.41 (95% CI 1.35-8.61, P = 0.009), and 2.17 (95% CI 1.01-4.68, P = 0.049). CONCLUSION: To our knowledge, this is the first study to assess the role of PON1 activity in SLE risk in a large biracial sample from the US. Our data indicate that low PON1 activity determined with paraoxon substrate is independently associated with SLE and that certain PON1 SNPs are associated with lupus nephritis. [ABSTRACT FROM AUTHOR]

Published
2006
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78. Ethnic variation in vitamin D-binding protein (GC): a review of isoelectric focusing studies in human populations

Author

Robert E. Ferrell and Kamboh Mi

Subjects
Genetic Markers, Genetics, Polymorphism, Genetic, integumentary system, Isoelectric focusing, Vitamin D-binding protein, Vitamin D-Binding Protein, Black People, Population genetics, Locus (genetics), Biology, White People, Phenotype, Asian People, Gene Frequency, Genetic marker, Genetic variation, Ethnicity, Humans, Isoelectric Focusing, Allele, Allele frequency, Alleles, Genetics (clinical)
Abstract

Since the discovery in 1977 that the GC1 gene could be resolved into two common subcomponents on an isoelectric focusing (IEF) gel, a large number of ethnic groups have been screened to analyze the extent of genetic variation in human populations. Using the IEF technique, approximately 50,000 individuals from 160 different populations have been tested for the GC polymorphism. A marked variation in common GC suballele frequencies in different geographic areas seems to correlate with skin pigmentation and intensity of sun light. Pigmented (black) and keratinized (yellowish) skin type populations have a relatively high frequency of the GC*IF allele as compared to white skin populations. By comparison non-pigmented and non-keratinized white skin populations are generally characterized by having the maximum values of the GC*IS allele. The anthropologic significance of the GC locus has been enhanced further by detecting additional unique GC variants which provide useful information about evolutionary links between different populations. However, the presence of some electrophoretically identical unique variants in genetically and geographically distinct populations demand further investigation of these allelic variants to shed more light on their origins.

Published
1986

79. Genetic studies of low abundance human plasma proteins VIII. Inherited structural variation in antithrombin III

Author

Kamboh Mi and Robert E. Ferrell

Subjects
Genetics, Heterozygote, Polymorphism, Genetic, Isoelectric focusing, Antithrombin III, Homozygote, Antithrombin, Black People, Population genetics, Biology, United States, White People, Structural variation, White (mutation), Phenotype, Polymorphism (computer science), medicine, Humans, Isoelectric Focusing, Allele, Allele frequency, Alleles, Genetics (clinical), medicine.drug
Abstract

Genetically determined structural polymorphism of antithrombin III has been observed using ultra narrow pH polyacrylamide isoelectric focusing gels, followed by immunoblotting. The products of three alleles at the antithrombin III structural locus have been detected in normal U.S. white and black blood donors. The frequencies of the three alleles, AT III* 1, AT III* 2 and AT III* 3, respectively, are: 0.878, 0.103, 0.019 in whites and 0.916, 0.068, 0.016 in blacks. Family data from a large number of families establish an autosomal codominant pattern of inheritance of the three alleles.

Published
1988

80. Genetic Studies of Human Apolipoproteins

Author

B Sepehrnia, Kamboh Mi, and Robert E. Ferrell

Subjects
Genetics, Gene product, Isoelectric focusing, Apolipoprotein C-II, Population genetics, lipids (amino acids, peptides, and proteins), Biology, Structural locus, Allele, Allele frequency, Phenotype, Genetics (clinical)
Abstract

Using a simple and rapid one-dimensional isoelectric focusing technique followed by immunoblotting, we have detected genetic polymorphism of human apolipoprotein C-II (APO C-II) in normal unfractionated plasma samples of individuals of black ancestry. Two common autosomal codominantly expressed alleles, designated APO C-II*1 and APO C-II*2, at the APO C-II structural locus have been observed with frequencies of 0.975 and 0.025 in US blacks and 0.943 and 0.049 in Nigerian blacks. In addition, the gene product of a rare allele designated APO C-II*3 was observed in a single Nigerian black. Apart from a single example of an APO C-II 2-1 phenotype in plasma samples from 187 whites, which was electrophoretically identical to the 2-1 phenotype observed in blacks, it appears that APO C-II*2 is a unique black marker of potential importance in anthropogenetic and atherosclerosis studies.

Published
1988

81. Genetic studies of human apolipoproteins. V. A novel rapid procedure to screen apolipoprotein E polymorphism

Author

Kamboh Mi, B Kottke, and Robert E. Ferrell

Subjects
Apolipoprotein E, biology, Isoelectric focusing, QD415-436, Cell Biology, Biochemistry, Molecular biology, Primary and secondary antibodies, chemistry.chemical_compound, Endocrinology, chemistry, Polyclonal antibodies, biology.protein, Alkaline phosphatase, Ultracentrifuge, Nitrocellulose, Neuraminidase
Abstract

A simple and new method has been developed to detect apolipoprotein E polymorphism directly from plasma or serum without prior ultracentrifugation and delipidation. The method combines the use of dialyzed plasma or serum samples with or without neuraminidase treatment followed by monodimensional isoelectric focusing in simple or 3 M urea gels at a constant low power and progressively increasing voltage over a 3-hr period, and finally protein blotting to a nitrocellulose membrane. Apolipoprotein E phenotypes are identified immunologically using a double antibody reaction, the primary antibody being a monospecific, polyclonal goat anti-apolipoprotein E, and the secondary antibody being a rabbit anti-goat IgG conjugated with alkaline phosphatase. The method was employed to screen apolipoprotein E polymorphism in two white populations in the United States. The frequency values are comparable to those reported previously by other investigators using conventional detection methods. The procedure is simple, accurate, suitable for large scale epidemiologic, clinical, and genetic studies.

Published
1988

82. Meta-analysis of genetic association with diagnosed Alzheimer’s disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing

Author

Kunkle, BW, Grenier-Boley, B, Sims, R, Bis, JC, Naj, AC, Boland, A, Vronskaya, M, Van Der Lee, SJ, Amlie-Wolf, A, Bellenguez, C, Frizatti, A, Chouraki, V, Martin, ER, Sleegers, K, Badarinarayan, N, Jakobsdottir, J, Hamilton-Nelson, KL, Aloso, R, Raybould, R, Chen, Y, Kuzma, AB, Hiltunen, M, Morgan, T, Ahmad, S, Vardarajan, BN, Epelbaum, J, Hoffmann, P, Boada, M, Beecham, GW, Garnier, JG, Harold, D, Fitzpatrick, AL, Valladares, O, Moutet, ML, Gerrish, A, Smith, AV, Qu, L, Bacq, D, Denning, N, Jian, X, Zhao, Y, Zompo, MD, Fox, NC, Grove, ML, Choi, SH, Mateo, I, Hughes, JT, Adams, HH, Malamon, J, Garcia, FS, Patel, Y, Brody, JA, Dombroski, B, Naranjo, MCD, Daniilidou, M, Eiriksdottir, G, Mukherjee, S, Wallon, D, Uphill, J, Aspelund, T, Cantwell, LB, Garzia, F, Galimberti, D, Hofer, E, Butkiewics, M, Fin, B, Scarpini, E, Sarnowski, C, Bush, W, Meslage, S, Kornhuber, J, White, CC, Song, Y, Barber, RC, Engelborghs, S, Pichler, S, Voijnovic, D, Adams, PM, Vandenberghe, R, Mayhaus, M, Cupples, LA, Albert, MS, De Deyn, PP, Gu, W, Himali, JJ, Beekly, D, Squassina, A, Hartmann, AM, Orellana, A, Blacker, D, Rodriguez-Rodriguez, E, Lovestone, S, Garcia, ME, Doody, RS, Fernadez, CM, Sussams, R, Lin, H, Fairchild, TJ, Benito, YA, Holmes, C, Comic, H, Frosch, MP, Thonberg, H, Maier, W, Roschupkin, G, Ghetti, B, Giedraitis, V, Kawalia, A, Li, S, Huebinger, RM, Kilander, L, Moebus, S, Hernández, I, Kamboh, MI, Brundin, R, Turton, J, Yang, Q, Katz, MJ, Concari, L, Lord, J, Beiser, AS, Keene, CD, Helisalmi, S, Kloszewska, I, Kukull, WA, Koivisto, AM, Lynch, A, Tarraga, L, Larson, EB, Haapasalo, A, Lawlor, B, Mosley, TH, Lipton, RB, Solfrizzi, V, Gill, M, Longstreth, WT, Montine, TJ, Frisardi, V, Ortega-Cubero, S, Rivadeneira, F, Petersen, RC, Deramecourt, V, Ciaramella, A, Boerwinkle, E, Reiman, EM, Fievet, N, Caltagirone, C, Rotter, JI, Reisch, JS, Hanon, O, Cupidi, C, Uitterlinden, AG, Royall, DR, Dufouil, C, Maletta, RG, Moreno-Grau, S, Sano, M, Brice, A, Cecchetti, R, St George-Hyslop, P, Ritchie, K, Tsolaki, M, Tsuang, DW, Dubois, B, Craig, D, Wu, CK, Soininen, H, Avramidou, D, Albin, RL, Fratiglioni, L, Germanou, A, Apostolova, LG, Keller, L, Koutroumani, M, Arnold, SE, Panza, F, Gkatzima, O, Asthana, S, Hannequin, D, Whitehead, P, Atwood, CS, Caffarra, P, Hampel, H, Baldwin, CT, Lannfelt, L, Rubinsztein, DC, Barnes, LL, Pasquier, F, Frölich, L, Barral, S, McGuinness, B, Beach, TG, Johnston, JI, Becker, JT, Passmore, P, Bigio, EH, Schott, JM, Bird, TD, Warren, JD, Boeve, BF, Lupton, MK, Bowen, JD, Proitsi, P, Boxer, A, Powell, JF, Burke, Kauwe, JK, Burns, JM, Mancuso, M, Buxbaum, JD, Bonuccelli, U, Cairns, NJ, McQuillin, A, Cao, C, Livingston, G, Carlson, CS, Bass, NJ, Carlsson, CM, Hardy, J, Carney, RM, Bras, J, Carrasquillo, MM, Guerreiro, R, Allen, M, Chui, HC, Fisher, E, Cribbs, DH, Masullo, C, Crocco, EA, DeCarli, C, Bisceglio, G, Dick, M, Ma, L, Duara, R, Graff-Radford, NR, Evans, DA, Hodges, A, Faber, KM, Scherer, M, Fallon, KB, Riemenschneider, M, Fardo, DW, Heun, R, Farlow, MR, Ferris, S, Leber, M, Foroud, TM, Heuser, I, Galasko, DR, Giegling, I, Gearing, M, Hüll, M, Geschwind, DH, Gilbert, Morris, J, Green, RC, Mayo, K, Growdon, JH, Feulner, T, Hamilton, RL, Harrell, LE, Drichel, D, Honig, LS, Cushion, TD, Huentelman, MJ, Hollingworth, P, Hulette, CM, Hyman, BT, Marshall, R, Jarvik, GP, Meggy, A, Abner, E, Menzies, G, Jin, LW, Leonenko, G, Jun, G, Grozeva, D, Karydas, A, Russo, G, Kaye, JA, Kim, R, Jessen, F, Kowall, NW, Vellas, B, Kramer, JH, Vardy, E, LaFerla, FM, Jöckel, KH, Lah, JJ, Dichgans, M, Leverenz, JB, Mann, D, Levey, AI, Pickering-Brown, S, Lieberman, AP, Klopp, N, Lunetta, KL, Wichmann, HE, Lyketsos, CG, Morgan, K, Marson, DC, Brown, K, Martiniuk, F, Medway, C, Mash, DC, Nöthen, MM, Masliah, E, Hooper, NM, McCormick, WC, Daniele, A, McCurry, SM, Bayer, A, McDavid, AN, Gallacher, J, McKee, AC, Van Den Bussche, H, Mesulam, M, Brayne, C, Miller, BL, Riedel-Heller, S, Miller, CA, Miller, JW, Al-Chalabi, A, Morris, JC, Shaw, CE, Myers, AJ, Wiltfang, J, O’Bryant, S, Coto, E, Olichney, JM, Alvarez, V, Parisi, JE, Singleton, AB, Paulson, HL, Collinge, J, Perry, W, Mead, S, Peskind, E, Rosser, M, Pierce, A, Ryan, N, Poon, WW, Nacmias, B, Potter, H, Sorbi, S, Quinn, JF, Sacchinelli, E, Raj, A, Spalletta, G, Raskind, M, Bossù, P, Reisberg, B, Clarke, R, Reitz, C, and S, AD

Subjects
2 Aetiology, Aging, Prevention, Human Genome, 4202 Epidemiology, 42 Health Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, 3101 Biochemistry and Cell Biology, Alzheimer's Disease, 3105 Genetics, 3. Good health, Brain Disorders, Clinical Research, FOS: Biological sciences, Neurological, Acquired Cognitive Impairment, Genetics, 2.1 Biological and endogenous factors, Dementia, 31 Biological Sciences
Abstract

Introduction Late-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly 1 , and risk is partially driven by genetics 2 . Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS) 3–8 . To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci ( IQCK , ACE , ADAM10 , and ADAMTS1 ). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants ( P = 1.32 × 10 −7 ) indicating that additional rare variants remain to be identified.

83. An Improved Method for Complement Subcomponent C1R Typing

Author

Kamboh, MI and Ferrell, RE

Abstract

An improved method has been developed for the reliable classification of different C1R genetic variant forms from human serum or plasma. The method combines the use of neuraminidase-digested samples followed by monodimensional isoelectric focusing in the pH range 5 to 8 followed by immunoblotting. The method yields a simple pattern, with one major band in homozygote and two major bands in heterozygote cases.

Published
1990
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84. Three F XIIIA gene loci?

Author

Robert E. Ferrell and Kamboh Mi

Subjects
Antiserum, Genetic linkage, Isoelectric focusing, Protein subunit, Structural gene, Genetics, Chromosome, In situ hybridization, Biology, Gene, Molecular biology, Genetics (clinical)
Abstract

Recently, Sebetan (1988) has reported the existence of three distinct structural gene loci controlling the synthesis of the A subunit of coagulation factor XIII (FXIIIA). This is a very provocative report without having any substantial evidence that the three observed isoelectric focusing (IEF)/immunoblotting patterns correspond to the products of three F XIIIA genes, as the author has postulated. Both the protein and DNA sequence studies strongly support the existence of a single FXI I IA structural gene (Ichinose et al. 1986); this is supported by segregation data using protein and DNA polymorphisms (Board 1979; Zoghbi et al. 1988). In situ hybridization of the placental F XIIIA eDNA to human chromosomes reveals a single site of hybridization on chromosome 6p. The three distinct patterns observed by Sebetan (1988) using commercial antiserum appear to be the result of crosscontamination of other plasma proteins along with FXIIIA. Over the past few years, we have used FXI I IA antiserum from one commercial source for our IEF-immunoblotting studies. The early lots showed highly specificity for FXI I IA but later lots also yielded non-specific reactions; using more recent lots, we could not detect any FXI I IA IEF-immunoblot patterns but rather encountered entirely different non-specific immunolocalized patterns. The contamination problem with commercial antisera is not an unusual one. In our own experience with IEF/immunoblotting studies using more than 50 different antisera, we have found that, in several cases, the commercial antisera was non-specific and, in some cases, failed to react with the protein to which it was theoretically raised. When we encounter such problems, we consider and test several other possible factors rather than wholly relying on the resuits obtained using commercial antisera. Sebetan's own observations that, except for the well-established FXI I IA polymorphism, he could not detect the gene products of the other two proposed loci in platelet lysates contradict his findings. In addition to plasma, the FXI I IA polypeptide is expressed in platelets, megakaryocytes and placental tissues; F XIIIA from these various sources are indistinguishable by biochemical criteria. If, in fact, there are multiple FXI I IA gene products, they should have also been detected in platelets because the transglutaminase activity of the subunit is essential for normal clot formation. The conclusion reached by Sebetan is a rather hasty one and he should have performed additional relevant biochemical and genetic tests to confirm his findings. In our opinion, the following tests would have been appropriate: (1) use of FXII IA antiserum from multiple commercial sources; (2) use of purified FXIIIA; (3) use of FXII IA subunit transglutaminase activity as a functional stain; (4) use of linkage studies between the postulated loci and other chromosome 6p markers; (5) possible use of other tissues where F XIIIA activity has been localized.

Published
1989

85. Review : Genetics of apolipoprotein H (β2-glycoprotein I) and anionic phospholipid binding.

Author

Kamboh, MI and Mehdi, H.

Abstract

Apolipoprotein H (apoH; also known as β2-glycoprotein I), is an essential cofactor for the binding of certain antiphospholipid antibodies (APA) to anionic phospholipid. The gene coding for apoH is polymorphic, with the occurrence of several common alleles in the general population. This genetically determined variation can effect the binding of apoH to anionic phospholipids and consequently the production of APA. Our group has identified two common mutations at codons 306 (Cys → Gly) and 316 (Trp → Ser) in the fifth domain of apoH which affect the binding of apoH to anionic phospholipids (phosphatidylserine or cardiolipin). ApoH from serum samples homozygous for each of these mutations or compound heterozygotes for both mutations showed no binding with anionic phospholipids on ELISA. In vitro mutagenesis and transient expression of these mutations in COS-1 cells followed by cardiolipin binding studies confirmed that Gly306 and Ser316 are causative mutations. Our data indicate that the fifth domain of apoH is essential for anionic phospholipid binding and genetically determined variation in this domain can affect the production of apoH-dependent APA. [ABSTRACT FROM PUBLISHER]

Published
1998
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86. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX.

Author

Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S, Lee AT, Chung SA, Ferreira RC, Pant PV, Ballinger DG, Kosoy R, Demirci FY, Kamboh MI, Kao AH, Tian C, Gunnarsson I, Bengtsson AA, Rantapää-Dahlqvist S, and Petri M

Abstract

Background: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility genes; there is strong evidence for the existence of additional risk loci.Methods: We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden.Results: Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case-control series (rs13277113; odds ratio, 1.39; P=1x10(-10)) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3x10(-11)).Conclusions: We identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM-ITGAX region. [ABSTRACT FROM AUTHOR]

Published
2008
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87. APOE and Alzheimer disease: a major gene with semi-dominant inheritance

Author

Genin, Emmanuelle, Hannequin, Didier, Wallon, David, Sleegers, Kristel, Hiltunen, Mikko, Combarros Pascual, Onofre, Bullido, María Jesús, Brouwers, Nathalie, Bettens, Karolien, Berr, Claudine, Pasquier, Florence, Dubois, Bruno, DeKosky, Steven T., Tognoni, Gloria, Fiévet, Nathalie, Engelborghs, Sebastiaan, Arosio, Beatrice, Coto García, Elicer, Deyn, Peter De, Zompo, Maria Del, Mateo Fernández, José Ignacio, Epelbaum, Jacques, Frank García, Ana, Helisalmi, Seppo, Porcellini, Elisa, Pilotto, Alberto, Forti, Paola, Ferri, Raffaele, Scarpini, Elio, Siciliano, Gabriele, Solfrizzi, Vincenzo, Sorbi, Sandro, Spalletta, Gianfranco, Ravaglia, Giovanni, Valdivieso Amato, Fernando, Vepsäläinen, Saila, Álvarez, Victoria, Bosco, Paolo, Mancuso, Michelangelo, Panza, Francesco, Nacmias, Benedetta, Bossù, Paola, Hanon, Olivier, Piccardi, Paola, Annoni, Giorgio, Seripa, Davide, Galimberti, Daniela, Licastro, Federico, Soininen, Hilkka, Dartigues, Jean-François, Tzourio, Christophe, Van Broeckhoven, Christine, Kamboh, M. Ilyas, Alpérovitch, Annick, Lambert, Jean Charles, Amouyel, Philippe, Campion, Dominique, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, Vrije Universiteit Brussel, Universidad de Cantabria, Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, Bullido MJ, Engelborghs S, De Deyn P, Berr C, Pasquier F, Dubois B, Tognoni G, Fiévet N, Brouwers N, Bettens K, Arosio B, Coto E, Del Zompo M, Mateo I, Epelbaum J, Frank-Garcia A, Helisalmi S, Porcellini E, Pilotto A, Forti P, Ferri R, Scarpini E, Siciliano G, Solfrizzi V, Sorbi S, Spalletta G, Valdivieso F, Vepsäläinen S, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Hanon O, Piccardi P, Annoni G, Seripa D, Galimberti D, Licastro F, Soininen H, Dartigues JF, Kamboh MI, Van Broeckhoven C, Lambert JC, Amouyel P, Campion D., Genin, E, Hannequin, D, Wallon, D, Sleegers, K, Hiltunen, M, Combarros, O, Bullido, M, Engelborghs, S, De Deyn, P, Berr, C, Pasquier, F, Dubois, B, Tognoni, G, Fiévet, N, Brouwers, N, Bettens, K, Arosio, B, Coto, E, Del Zompo, M, Mateo, I, Epelbaum, J, Frank Garcia, A, Helisalmi, S, Porcellini, E, Pilotto, A, Forti, P, Ferri, R, Scarpini, E, Siciliano, G, Solfrizzi, V, Sorbi, S, Spalletta, G, Valdivieso, F, Vepsäläinen, S, Alvarez, V, Bosco, P, Mancuso, M, Panza, F, Nacmias, B, Bossù, P, Hanon, O, Piccardi, P, Annoni, G, Seripa, D, Galimberti, D, Licastro, F, Soininen, H, Dartigues, J, Kamboh, M, Van Broeckhoven, C, Lambert, J, Amouyel, P, and Campion, D

Subjects
Apolipoprotein E, APOE, Alzheimer, genetics, lifetime risks, epidemiology, Male, Heredity, Genotype, Epidemiology, Apolipoprotein E4, Apolipoprotein E3, Physiology, Genome-wide association study, Biology, Article, Cellular and Molecular Neuroscience, Alzheimer Disease, Odds Ratio, Humans, GWAS, Genetic Predisposition to Disease, genetics, Allele, Risk factor, Molecular Biology, ALZHEIMER, Alleles, Aged, Genetics, Medicine(all), Incidence, ALZHEIMER’S DISEASE, Case-control study, Age Factors, Odds ratio, Middle Aged, Major gene, United States, Psychiatry and Mental health, lifetime risks, Case-Control Studies, Female, Human medicine, France, APOE
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.Molecular Psychiatry advance online publication, 10 May 2011; doi:10.1038/mp.2011.52.

Published
2011

88. The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study

Author

Rudolph E. Tanzi, Dominique Campion, Brit Maren Michaud Schjeide, Diana Zelenika, Lars Lannfelt, Nathalie Fievet, Paola Forti, M. Ilyas Kamboh, Antonio González-Pérez, Hilkka Soininen, Elicer Coto, Steven T. DeKosky, Victoria Alvarez, Carmen Antúnez, Karolien Bettens, Margaret A. Pericak-Vance, Michelangelo Mancuso, Jacques Epelbaum, Kristel Sleegers, Federico Licastro, Giorgio Annoni, Florence Pasquier, Gianfranco Spalletta, Claudine Berr, Florence Richard, Christine Van Broeckhoven, Ana Frank-García, Lars Bertram, Mikko Hiltunen, Daniela Galimberti, Jean-Charles Lambert, Philippe Marambaud, Elisa Porcellini, Maria Del Zompo, Seppo Helisalmi, Nathalie Brouwers, Ignacio Mateo, Corinne Lendon, Gabriele Siciliano, David M. A. Mann, Fernando Valdivieso, Annick Alpérovitch, Jean-François Dartigues, Paola Piccardi, Jesús López-Arrieta, Alberto Pilotto, Mercè Boada, Olivier Hanon, Elio Scarpini, Vilmentas Giedraitis, Didier Hannequin, Benedetta Nacmias, Onofre Combarros, Giovanni Ravaglia, Mark Lathrop, Christophe Tzourio, Paola Bossù, María J. Bullido, Martin Ingelsson, Sandro Sorbi, Paolo Bosco, Philippe Amouyel, Vincenzo Solfrizzi, Sebastiaan Engelborghs, Beatrice Arosio, Francesco Panza, Marc Delepine, Saila Vepsäläinen, Jonathan L. Haines, Peter Paul De Deyn, Gary W. Beecham, Agustín Ruiz, Davide Seripa, Gloria Tognoni, Raffaele Ferri, Lambert JC, Sleegers K, González-Pérez A, Ingelsson M, Beecham GW, Hiltunen M, Combarros O, Bullido MJ, Brouwers N, Bettens K, Berr C, Pasquier F, Richard F, Dekosky ST, Hannequin D, Haines JL, Tognoni G, Fiévet N, Dartigues JF, Tzourio C, Engelborghs S, Arosio B, Coto E, De Deyn P, Del Zompo M, Mateo I, Boada M, Antunez C, Lopez-Arrieta J, Epelbaum J, Schjeide BM, Frank-Garcia A, Giedraitis V, Helisalmi S, Porcellini E, Pilotto A, Forti P, Ferri R, Delepine M, Zelenika D, Lathrop M, Scarpini E, Siciliano G, Solfrizzi V, Sorbi S, Spalletta G, Ravaglia G, Valdivieso F, Vepsäläinen S, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Hanon O, Piccardi P, Annoni G, Mann D, Marambaud P, Seripa D, Galimberti D, Tanzi RE, Bertram L, Lendon C, Lannfelt L, Licastro F, Campion D, Pericak-Vance MA, Soininen H, Van Broeckhoven C, Alpérovitch A, Ruiz A, Kamboh MI, Amouyel P., Lambert, J, Sleegers, K, González Pérez, A, Ingelsson, M, Beecham, G, Hiltunen, M, Combarros, O, Bullido, M, Brouwers, N, Bettens, K, Berr, C, Pasquier, F, Richard, F, Dekosky, S, Hannequin, D, Haines, J, Tognoni, G, Fiévet, N, Dartigues, J, Tzourio, C, Engelborghs, S, Arosio, B, Coto, E, De Deyn, P, Del Zompo, M, Mateo, I, Boada, M, Antunez, C, Lopez Arrieta, J, Epelbaum, J, Schjeide, B, Frank Garcia, A, Giedraitis, V, Helisalmi, S, Porcellini, E, Pilotto, A, Forti, P, Ferri, R, Delepine, M, Zelenika, D, Lathrop, M, Scarpini, E, Siciliano, G, Solfrizzi, V, Sorbi, S, Spalletta, G, Ravaglia, G, Valdivieso, F, Vepsäläinen, S, Alvarez, V, Bosco, P, Mancuso, M, Panza, F, Nacmias, B, Bossù, P, Hanon, O, Piccardi, P, Annoni, G, Mann, D, Marambaud, P, Seripa, D, Galimberti, D, Tanzi, R, Bertram, L, Lendon, C, Lannfelt, L, Licastro, F, Campion, D, Pericak Vance, M, Soininen, H, Van Broeckhoven, C, Alpérovitch, A, Ruiz, A, Kamboh, M, Amouyel, P, Clinical sciences, and Neurology

Subjects
Apolipoprotein E, Male, CALHM1, Calcium Channels/genetics, Apolipoprotein E4, Single-nucleotide polymorphism, Biology, Article, polymorphism, Alzheimer Disease/epidemiology, Alzheimer Disease, Genetic variation, Genotype, Humans, Apolipoprotein E4/genetics, Allele, Age of Onset, Polymorphism, Genetic/genetics, Alleles, apolipoprotein E, Aged, Medicine(all), Genetics, Aged, 80 and over, Membrane Glycoproteins, Polymorphism, Genetic, General Neuroscience, Haplotype, Age at onset, General Medicine, Membrane Glycoproteins/genetics, Alzheimer's disease, Middle Aged, Psychiatry and Mental health, Clinical Psychology, Case-Control Studies, Female, Human medicine, Calcium Channels, Geriatrics and Gerontology, Age of onset
Abstract

The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the epsilon 4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age of onset by interacting with the effect of the epsilon 4 allele of the APOE gene.

Published
2010

89. Multi-analyte proteomic analysis identifies blood-based neuroinflammation, cerebrovascular and synaptic biomarkers in preclinical Alzheimer's disease.

Author

Zeng X, Lafferty TK, Sehrawat A, Chen Y, Ferreira PCL, Bellaver B, Povala G, Kamboh MI, Klunk WE, Cohen AD, Lopez OL, Ikonomovic MD, Pascoal TA, Ganguli M, Villemagne VL, Snitz BE, and Karikari TK

Subjects
Humans, Male, Female, Aged, Aged, 80 and over, Amyloid beta-Peptides blood, Amyloid beta-Peptides metabolism, Synapses metabolism, Middle Aged, tau Proteins blood, tau Proteins metabolism, Alzheimer Disease blood, Alzheimer Disease metabolism, Alzheimer Disease diagnosis, Biomarkers blood, Proteomics methods, Neuroinflammatory Diseases blood
Abstract

Background: Blood-based biomarkers are gaining grounds for the detection of Alzheimer's disease (AD) and related disorders (ADRDs). However, two key obstacles remain: the lack of methods for multi-analyte assessments and the need for biomarkers for related pathophysiological processes like neuroinflammation, vascular, and synaptic dysfunction. A novel proteomic method for pre-selected analytes, based on proximity extension technology, was recently introduced. Referred to as the NULISAseq CNS disease panel, the assay simultaneously measures ~ 120 analytes related to neurodegenerative diseases, including those linked to both core (i.e., tau and amyloid-beta (Aβ)) and non-core AD processes. This study aimed to evaluate the technical and clinical performance of this novel targeted proteomic panel., Methods: The NULISAseq CNS disease panel was applied to 176 plasma samples from 113 individuals in the MYHAT-NI cohort of predominantly cognitively normal participants from an economically underserved region in southwestern Pennsylvania, USA. Classical AD biomarkers, including p-tau181, p-tau217, p-tau231, GFAP, NEFL, Aβ40, and Aβ42, were independently measured using Single Molecule Array (Simoa) and correlations and diagnostic performances compared. Aβ pathology, tau pathology, and neurodegeneration (AT(N) statuses) were evaluated with [ 11 C] PiB PET, [ 18 F]AV-1451 PET, and an MRI-based AD-signature composite cortical thickness index, respectively. Linear mixed models were used to examine cross-sectional and Wilcoxon rank sum tests for longitudinal associations between NULISA and neuroimaging-determined AT(N) biomarkers., Results: NULISA concurrently measured 116 plasma biomarkers with good technical performance (97.2 ± 13.9% targets gave signals above assay limits of detection), and significant correlation with Simoa assays for the classical biomarkers. Cross-sectionally, p-tau217 was the top hit to identify Aβ pathology, with age, sex, and APOE genotype-adjusted AUC of 0.930 (95%CI: 0.878-0.983). Fourteen markers were significantly decreased in Aβ-PET + participants, including TIMP3, BDNF, MDH1, and several cytokines. Longitudinally, FGF2, IL4, and IL9 exhibited Aβ PET-dependent yearly increases in Aβ-PET + participants. Novel plasma biomarkers with tau PET-dependent longitudinal changes included proteins associated with neuroinflammation, synaptic function, and cerebrovascular integrity, such as CHIT1, CHI3L1, NPTX1, PGF, PDGFRB, and VEGFA; all previously linked to AD but only reliable when measured in cerebrospinal fluid. The autophagosome cargo protein SQSTM1 exhibited significant association with neurodegeneration after adjusting age, sex, and APOE ε4 genotype., Conclusions: Together, our results demonstrate the feasibility and potential of immunoassay-based multiplexing to provide a comprehensive view of AD-associated proteomic changes, consistent with the recently revised biological and diagnostic framework. Further validation of the identified inflammation, synaptic, and vascular markers will be important for establishing disease state markers in asymptomatic AD., (© 2024. The Author(s).)

Published
2024
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90. CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET.

Author

Nho K, Risacher SL, Apostolova LG, Bice PJ, Brosch JR, Deardorff R, Faber K, Farlow MR, Foroud T, Gao S, Rosewood T, Kim JP, Nudelman K, Yu M, Aisen P, Sperling R, Hooli B, Shcherbinin S, Svaldi D, Jack CR Jr, Jagust WJ, Landau S, Vasanthakumar A, Waring JF, Doré V, Laws SM, Masters CL, Porter T, Rowe CC, Villemagne VL, Dumitrescu L, Hohman TJ, Libby JB, Mormino E, Buckley RF, Johnson K, Yang HS, Petersen RC, Ramanan VK, Ertekin-Taner N, Vemuri P, Cohen AD, Fan KH, Kamboh MI, Lopez OL, Bennett DA, Ali M, Benzinger T, Cruchaga C, Hobbs D, De Jager PL, Fujita M, Jadhav V, Lamb BT, Tsai AP, Castanho I, Mill J, Weiner MW, and Saykin AJ

Subjects
Aged, Aged, 80 and over, Animals, Female, Humans, Male, Mice, Amyloid beta-Peptides metabolism, Apolipoprotein E4 genetics, Apolipoprotein E4 metabolism, Disease Models, Animal, Polymorphism, Single Nucleotide, Alzheimer Disease genetics, Alzheimer Disease diagnostic imaging, Alzheimer Disease metabolism, Cytochrome P-450 CYP1B1 genetics, Cytochrome P-450 CYP1B1 metabolism, Endophenotypes, Genome-Wide Association Study, Positron-Emission Tomography methods, tau Proteins metabolism, tau Proteins genetics
Abstract

Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD., (© 2024. The Author(s).)

Published
2024
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91. Associations of endogenous estrogens, plasma Alzheimer's disease biomarkers, and APOE4 carrier status on regional brain volumes in postmenopausal women.

Author

Wugalter KA, Schroeder RA, Thurston RC, Wu M, Aizenstein HJ, Cohen AD, Kamboh MI, Karikari TK, Derby CA, and Maki PM

Abstract

Background: Women carrying the APOE4 allele are at greater risk of developing Alzheimer's disease (AD) from ages 65-75 years compared to men. To better understand the elevated risk conferred by APOE4 carrier status among midlife women, we investigated the separate and interactive associations of endogenous estrogens, plasma AD biomarkers, and APOE4 carrier status on regional brain volumes in a sample of late midlife postmenopausal women., Methods: Participants were enrolled in MsBrain, a cohort study of postmenopausal women ( n  = 171, mean age = 59.4 years, mean MoCA score = 26.9; race = 83.2% white, APOE4 carriers = 40). Serum estrone (E1) and estradiol (E2) levels were assessed using liquid chromatography-tandem mass spectrometry. APOE genotype was determined using TaqMan SNP genotyping assays. Plasma AD biomarkers were measured using single molecule array technology. Cortical volume was measured and segmented by FreeSurfer software using individual T1w MPRAGE images. Multiple linear regression models were conducted to determine whether separate and interactive associations between endogenous estrogen levels, plasma AD biomarkers (Aβ42/Aβ40, Aβ42/p-tau181), and APOE4 carrier status predict regional brain volume (21 regions per hemisphere, selected a priori ); and, whether significant interactive associations between estrogens and AD biomarkers on brain volume differed by APOE4 carrier status., Results: There was no main effect of APOE4 carrier status on regional brain volumes, endogenous estrogen levels, or plasma AD biomarkers. Estrogens did not associate with regional brain volumes, except for positive associations with left caudal middle frontal gyrus and fusiform volumes. The interactive association of estrogens and APOE4 carrier status on brain volume was not significant for any region. The interactive association of estrogens and plasma AD biomarkers predicted brain volume of several regions. Higher E1 and E2 were more strongly associated with greater regional brain volumes among women with a poorer AD biomarker profile (lower Aβ42/40, lower Aβ42/p-tau181 ratios). In APOE4 -stratified analyses, these interactions were driven by non- APOE4 carriers., Conclusion: We demonstrate that the brain volumes of postmenopausal women with poorer AD biomarker profiles benefit most from higher endogenous estrogen levels. These findings are driven by non- APOE4 carriers, suggesting that APOE4 carriers may be insensitive to the favorable effects of estrogens on brain volume in the postmenopause., Competing Interests: RT reported receiving personal fees from Astellas Pharma, Bayer, Hello Therapeutics, Happify Health, and Vira Health outside the submitted work. HA reported receiving personal fees from Eisai outside the submitted work. PM reported receiving personal fees from Astellas Pharma, Bayer, Estrigenix, Alloy, and MidiHealth outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wugalter, Schroeder, Thurston, Wu, Aizenstein, Cohen, Kamboh, Karikari, Derby and Maki.)

Published
2024
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92. Apolipoprotein E and Alzheimer's disease pathology in African American older adults.

Author

Royse SK, Snitz BE, Hill AV, Reese AC, Roush RE, Kamboh MI, Bertolet M, Saeed A, Lopresti BJ, Villemagne VL, Lopez OL, Reis SE, Becker JT, and Cohen AD

Subjects
Aged, Aged, 80 and over, Female, Humans, Male, Alleles, Apolipoprotein E4 genetics, Apolipoproteins E genetics, Brain diagnostic imaging, Brain pathology, Genetic Association Studies, White, Alzheimer Disease genetics, Alzheimer Disease pathology, Amyloid beta-Peptides metabolism, Black or African American genetics, Positron-Emission Tomography, tau Proteins genetics
Abstract

The apolipoprotein-E4 (APOE*4) and apolipoprotein-E2 (APOE*2) alleles are more common in African American versus non-Hispanic white populations, but relationships of both alleles with Alzheimer's disease (AD) pathology among African American individuals are unclear. We measured APOE allele and β-amyloid (Aβ) and tau using blood samples and positron emission tomography (PET) images, respectively. Individual regression models tested associations of each APOE allele with Aβ or tau PET overall, stratified by racialized group, and with a racialized group interaction. We included 358 older adults (42% African American) with Aβ PET, 134 (29% African American) of whom had tau PET. APOE*4 was associated with higher Aβ in non-Hispanic white (P < 0.0001), but not African American (P = 0.64) participants; racialized group modified the association between APOE*4 and Aβ (P < 0.0001). There were no other racialized group differences. These results suggest that the association of APOE*4 and Aβ differs between African American and non-Hispanic white populations. Other drivers of AD pathology in African American populations should be identified as potential therapeutic targets., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024. Published by Elsevier Inc.)

Published
2024
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93. Genetic associations with psychosis and affective disturbance in Alzheimer's disease.

Author

Antonsdottir IM, Creese B, Klei L, DeMichele-Sweet MAA, Weamer EA, Garcia-Gonzalez P, Marquie M, Boada M, Alarcón-Martín E, Valero S, Liu Y, Hooli B, Aarsland D, Selbaek G, Bergh S, Rongve A, Saltvedt I, Skjellegrind HK, Engdahl B, Andreassen OA, Borroni B, Mecocci P, Wedatilake Y, Mayeux R, Foroud T, Ruiz A, Lopez OL, Kamboh MI, Ballard C, Devlin B, Lyketsos C, and Sweet RA

Abstract

Introduction: Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or irritability, AD+A). This study's goal was to identify the genetic architecture of AD+P and AD+A, as well as their genetically correlated phenotypes., Methods: Genome-wide association meta-analysis of 9988 AD participants from six source studies with participants characterized for AD+P AD+A, and a joint phenotype (AD+A+P)., Results: AD+P and AD+A were genetically correlated. However, AD+P and AD+A diverged in their genetic correlations with psychiatric phenotypes in individuals without AD. AD+P was negatively genetically correlated with bipolar disorder and positively with depressive symptoms. AD+A was positively correlated with anxiety disorder and more strongly correlated than AD+P with depressive symptoms. AD+P and AD+A+P had significant estimated heritability, whereas AD+A did not. Examination of the loci most strongly associated with the three phenotypes revealed overlapping and unique associations., Discussion: AD+P, AD+A, and AD+A+P have both shared and divergent genetic associations pointing to the importance of incorporating genetic insights into future treatment development., Highlights: It has long been known that psychotic and affective symptoms are often comorbid in individuals diagnosed with Alzheimer's disease. Here we examined for the first time the genetic architecture underlying this clinical observation, determining that psychotic and affective phenotypes in Alzheimer's disease are genetically correlated.Nevertheless, psychotic and affective phenotypes in Alzheimer's disease diverged in their genetic correlations with psychiatric phenotypes assessed in individuals without Alzheimer's disease. Psychosis in Alzheimer's disease was negatively genetically correlated with bipolar disorder and positively with depressive symptoms, whereas the affective phenotypes in Alzheimer's disease were positively correlated with anxiety disorder and more strongly correlated than psychosis with depressive symptoms.Psychosis in Alzheimer's disease, and the joint psychotic and affective phenotype, had significant estimated heritability, whereas the affective in AD did not.Examination of the loci most strongly associated with the psychotic, affective, or joint phenotypes revealed overlapping and unique associations., Competing Interests: The authors declare no conflicts of interest. Author disclosures are available in the supporting information., (© 2024 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Published
2024
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94. Alzheimer blood biomarkers: practical guidelines for study design, sample collection, processing, biobanking, measurement and result reporting.

Author

Zeng X, Chen Y, Sehrawat A, Lee J, Lafferty TK, Kofler J, Berman SB, Sweet RA, Tudorascu DL, Klunk WE, Ikonomovic MD, Pfister A, Zetterberg H, Snitz BE, Cohen AD, Villemagne VL, Pascoal TA, Kamboh MI, Lopez OI, Blennow K, and Karikari TK

Subjects
Humans, Research Design standards, Amyloid beta-Peptides blood, Specimen Handling standards, Specimen Handling methods, tau Proteins blood, Alzheimer Disease blood, Alzheimer Disease diagnosis, Biomarkers blood, Biological Specimen Banks standards
Abstract

Alzheimer's disease (AD), the most common form of dementia, remains challenging to understand and treat despite decades of research and clinical investigation. This might be partly due to a lack of widely available and cost-effective modalities for diagnosis and prognosis. Recently, the blood-based AD biomarker field has seen significant progress driven by technological advances, mainly improved analytical sensitivity and precision of the assays and measurement platforms. Several blood-based biomarkers have shown high potential for accurately detecting AD pathophysiology. As a result, there has been considerable interest in applying these biomarkers for diagnosis and prognosis, as surrogate metrics to investigate the impact of various covariates on AD pathophysiology and to accelerate AD therapeutic trials and monitor treatment effects. However, the lack of standardization of how blood samples and collected, processed, stored analyzed and reported can affect the reproducibility of these biomarker measurements, potentially hindering progress toward their widespread use in clinical and research settings. To help address these issues, we provide fundamental guidelines developed according to recent research findings on the impact of sample handling on blood biomarker measurements. These guidelines cover important considerations including study design, blood collection, blood processing, biobanking, biomarker measurement, and result reporting. Furthermore, the proposed guidelines include best practices for appropriate blood handling procedures for genetic and ribonucleic acid analyses. While we focus on the key blood-based AD biomarkers for the AT(N) criteria (e.g., amyloid-beta [Aβ]40, Aβ42, Aβ42/40 ratio, total-tau, phosphorylated-tau, neurofilament light chain, brain-derived tau and glial fibrillary acidic protein), we anticipate that these guidelines will generally be applicable to other types of blood biomarkers. We also anticipate that these guidelines will assist investigators in planning and executing biomarker research, enabling harmonization of sample handling to improve comparability across studies., (© 2024. The Author(s).)

Published
2024
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95. Sex-dependent alterations in hippocampal connectivity are linked to cerebrovascular and amyloid pathologies in normal aging.

Author

Schweitzer N, Li J, Thurston RC, Lopresti B, Klunk WE, Snitz B, Tudorascu D, Cohen A, Kamboh MI, Halligan-Eddy E, Iordanova B, Villemagne VL, Aizenstein H, and Wu M

Subjects
Male, Female, Humans, Amyloid beta-Peptides metabolism, Brain pathology, Amyloid, Aging, Positron-Emission Tomography, Magnetic Resonance Imaging, Hippocampus pathology, Alzheimer Disease pathology, Cognitive Dysfunction pathology
Abstract

Introduction: Compared to males, females have an accelerated trajectory of cognitive decline in Alzheimer's disease (AD). The neurobiological factors underlying the more rapid cognitive decline in AD in females remain unclear. This study explored how sex-dependent alterations in hippocampal connectivity over 2 years are associated with cerebrovascular and amyloid pathologies in normal aging., Methods: Thirty-three females and 21 males 65 to 93 years of age with no cognitive impairment performed a face-name associative memory functional magnetic resonance imaging (fMRI) task with a 2-year follow-up. We acquired baseline carbon 11-labeled Pittsburgh compound B ([ 11 C]PiB) positron emission tomography (PET) and T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) MRI to quantify amyloid β (Aβ) burden and white matter hyperintensity (WMH) volume, respectively., Results: Males had increased hippocampal-prefrontal connectivity over 2 years, associated with greater Aβ burden. Females had increased bilateral hippocampal functional connectivity, associated with greater WMH volume., Discussion: These findings suggest sex-dependent compensatory mechanisms in the memory network in the presence of cerebrovascular and AD pathologies and may explain the accelerated trajectory of cognitive decline in females., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Published
2024
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96. Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome.

Author

Gorijala P, Aslam MM, Dang LT, Xicota L, Fernandez MV, Sung YJ, Fan KH, Feingold E, Surace EI, Chhatwal JP, Hom CL, Hartley SL, Hassenstab J, Perrin RJ, Mapstone M, Zaman SH, Ances BM, Kamboh MI, Lee JH, and Cruchaga C

Subjects
Adult, Humans, Genetic Risk Score, Apolipoproteins E genetics, Phenotype, Biomarkers cerebrospinal fluid, Cognition, Memory Disorders, Amyloid beta-Peptides cerebrospinal fluid, Alzheimer Disease diagnosis, Down Syndrome genetics, Cognitive Dysfunction diagnosis
Abstract

Introduction: This study aimed to investigate the influence of the overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers., Methods: AD polygenic risk scores (PRS) were tested for association with DS-related traits., Results: The AD risk PRS was associated with disease status in several cohorts of sporadic late- and early-onset and familial late-onset AD, but not in familial early-onset AD or DS. On the other hand, lower DS Mental Status Examination memory scores were associated with higher PRS, independent of intellectual disability and APOE (PRS including APOE, PRS APOE , p = 2.84 × 10 -4 ; PRS excluding APOE, PRS nonAPOE , p = 1.60 × 10 -2 ). PRS APOE exhibited significant associations with Aβ42, tTau, pTau, and Aβ42/40 ratio in DS., Discussion: These data indicate that the AD genetic architecture influences cognitive and CSF phenotypes in DS adults, supporting common pathways that influence memory decline in both traits., Highlights: Examination of the polygenic risk of AD in DS presented here is the first of its kind. AD PRS influences memory aspects in DS individuals, independently of APOE genotype. These results point to an overlap between the genes and pathways that leads to AD and those that influence dementia and memory decline in the DS population. APOE ε4 is linked to DS cognitive decline, expanding cognitive insights in adults., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Published
2024
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97. Association Between β-Amyloid Accumulation and Incident Dementia in Individuals 80 Years or Older Without Dementia.

Author

Lopez OL, Villemagne VL, Chang YF, Cohen AD, Klunk WE, Mathis CA, Pascoal T, Ikonomovic MD, Rowe C, Dore V, Snitz BE, Lopresti BJ, Kamboh MI, Aizenstein HJ, and Kuller LH

Subjects
Humans, Aged, 80 and over, Australia, Educational Status, Life Style, Amyloid beta-Peptides, Alzheimer Disease diagnostic imaging, Alzheimer Disease epidemiology
Abstract

Background and Objectives: While the highest prevalence of dementia occurs in individuals older than 80 years, most imaging studies focused on younger populations. The rates of β-amyloid (Aβ) accumulation and the effect of Alzheimer disease (AD) pathology on progression to dementia in this age group remain unexplored. In this study, we examined the relationship between changes in Aβ deposition over time and incident dementia in nondemented individuals followed during a period of 11 years., Methods: We examined 94 participants (age 85.9 + 2.8 years) who had up to 5 measurements of Pittsburgh compound-B (PiB)-PET and clinical evaluations from 2009 to 2020. All 94 participants had 2 PiB-PET scans, 76 participants had 3 PiB-PET scans, 18 participants had 4 PiB-PET scans, and 10 participants had 5 PiB-PET scans. The rates of Aβ deposition were compared with 120 nondemented individuals younger than 80 years (69.3 ± 5.4 years) from the Australian Imaging, Biomarker, and Lifestyle (AIBL) study who had 3 or more annual PiB-PET assessments., Results: By 2020, 49% of the participants developed dementia and 63% were deceased. There was a gradual increase in Aβ deposition in all participants whether they were considered Aβ positive or negative at baseline. In a Cox model controlled for age, sex, education level, APOE-4 allele, baseline Mini-Mental State Examination, and mortality, short-term change in Aβ deposition was not significantly associated with incident dementia (HR 2.19 (0.41-11.73). However, baseline Aβ burden, cortical thickness, and white matter lesions volume were the predictors of incident dementia. Aβ accumulation was faster ( p = 0.01) in the older cohort (5.6%/year) when compared with AIBL (4.1%/year). In addition, baseline Aβ deposition was a predictor of short-term change (mean time 1.88 years)., Discussion: There was an accelerated Aβ accumulation in cognitively normal individuals older than 80 years. Baseline Aβ deposition was a determinant of incident dementia and short-term change in Aβ deposition suggesting that an active Aβ pathologic process was present when these participants were cognitively normal. Consequently, age may not be a limiting factor for the use of the emergent anti-Aβ therapies.

Published
2024
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98. Meta-analysis of age-related cognitive decline reveals a novel locus for the attention domain and implicates a COVID-19-related gene for global cognitive function.

Author

Acharya V, Fan KH, Snitz BE, Ganguli M, DeKosky ST, Lopez OL, Feingold E, and Kamboh MI

Subjects
Humans, SARS-CoV-2, Cognition physiology, Attention, Apolipoprotein E4 genetics, Neuropsychological Tests, COVID-19 genetics, Cognitive Dysfunction genetics
Abstract

Introduction: Cognitive abilities have substantial heritability throughout life, as shown by twin- and population-based studies. However, there is limited understanding of the genetic factors related to cognitive decline in aging across neurocognitive domains., Methods: We conducted a meta-analysis on 3045 individuals aged ≥65, derived from three population-based cohorts, to identify genetic variants associated with the decline of five neurocognitive domains (attention, memory, executive function, language, visuospatial function) and global cognitive decline. We also conducted gene-based and functional bioinformatics analyses., Results: Apolipoprotein E (APOE)4 was significantly associated with decline of memory (p = 5.58E-09) and global cognitive function (p = 1.84E-08). We identified a novel association with attention decline on chromosome 9, rs6559700 (p = 2.69E-08), near RASEF. Gene-based analysis also identified a novel gene, TMPRSS11D, involved in the activation of SARS-CoV-2, to be associated with the decline in global cognitive function (p = 4.28E-07)., Discussion: Domain-specific genetic studies can aid in the identification of novel genes and pathways associated with decline across neurocognitive domains., Highlights: rs6559700 was associated with decline of attention. APOE4 was associated with decline of memory and global cognitive decline. TMPRSS11D, a gene involved in the activation of SARS-CoV-2, was implicated in global cognitive decline. Cognitive domain abilities had both unique and shared molecular pathways across the domains., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Published
2023
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99. Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer's disease risk.

Author

Aslam MM, Fan KH, Lawrence E, Bedison MA, Snitz BE, DeKosky ST, Lopez OL, Feingold E, and Kamboh MI

Subjects
Humans, Genome-Wide Association Study, Apolipoproteins E genetics, Genotype, Polymorphism, Genetic, Apolipoprotein E4 genetics, Alzheimer Disease genetics
Abstract

The APOE 2/3/4 polymorphism is the greatest genetic risk factor for Alzheimer's disease (AD). This polymorphism is also associated with variation in plasma ApoE level; while APOE*4 lowers, APOE*2 increases ApoE level. Lower plasma ApoE level has also been suggested to be a risk factor for incident dementia. To our knowledge, no large genome-wide association study (GWAS) has been reported on plasma ApoE level. This study aimed to identify new genetic variants affecting plasma ApoE level as well as to test if baseline ApoE level is associated with cognitive function and incident dementia in a longitudinally followed cohort of the Ginkgo Evaluation of Memory (GEM) study. Baseline plasma ApoE concentration was measured in 3031 participants (95.4% European Americans (EAs)). GWAS analysis was performed on 2580 self-identified EAs where both genotype and plasma ApoE data were available. Lower ApoE concentration was associated with worse cognitive function, but not with incident dementia. As expected, the risk for AD increased from E2/2 through to E4/4 genotypes (P for trend = 4.8E-75). In addition to confirming the expected and opposite associations of APOE*2 (P = 4.73E-79) and APOE*4 (P = 8.73E-12) with ApoE level, GWAS analysis revealed nine additional independent signals in the APOE region, and together they explained about 22% of the variance in plasma ApoE level. We also identified seven new loci on chromosomes 1, 4, 5, 7, 11, 12 and 20 (P range = 5.49E-08 to 5.36E-10) that explained about 9% of the variance in ApoE level. Plasma ApoE level-associated independent variants, especially in the APOE region, were also associated with AD risk and amyloid deposition in the brain, indicating that genetically determined ApoE level variation may be a risk factor for developing AD. These results improve our understanding of the genetic determinants of plasma ApoE level and their potential value in affecting AD risk., (© 2023. The Author(s).)

Published
2023
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100. Plasma biomarkers identify older adults at risk of Alzheimer's disease and related dementias in a real-world population-based cohort.

Author

Ferreira PCL, Zhang Y, Snitz B, Chang CH, Bellaver B, Jacobsen E, Kamboh MI, Zetterberg H, Blennow K, Pascoal TA, Villemagne VL, Ganguli M, and Karikari TK

Subjects
Humans, Aged, Amyloid beta-Peptides, Glial Fibrillary Acidic Protein, Apolipoprotein E4, Biomarkers, tau Proteins, Alzheimer Disease diagnosis
Abstract

Introduction: Plasma biomarkers-cost effective, non-invasive indicators of Alzheimer's disease (AD) and related disorders (ADRD)-have largely been studied in clinical research settings. Here, we examined plasma biomarker profiles and their associated factors in a population-based cohort to determine whether they could identify an at-risk group, independently of brain and cerebrospinal fluid biomarkers., Methods: We measured plasma phosphorylated tau181 (p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid beta (Aβ)42/40 ratio in 847 participants from a population-based cohort in southwestern Pennsylvania., Results: K-medoids clustering identified two distinct plasma Aβ42/40 modes, further categorizable into three biomarker profile groups: normal, uncertain, and abnormal. In different groups, plasma p-tau181, NfL, and GFAP were inversely correlated with Aβ42/40, Clinical Dementia Rating, and memory composite score, with the strongest associations in the abnormal group., Discussion: Abnormal plasma Aβ42/40 ratio identified older adult groups with lower memory scores, higher dementia risks, and higher ADRD biomarker levels, with potential implications for population screening., Highlights: Population-based plasma biomarker studies are lacking, particularly in cohorts without cerebrospinal fluid or neuroimaging data. In the Monongahela-Youghiogheny Healthy Aging Team study (n = 847), plasma biomarkers associated with worse memory and Clinical Dementia Rating (CDR), apolipoprotein E ε4, and greater age. Plasma amyloid beta (Aβ)42/40 ratio levels allowed clustering participants into abnormal, uncertain, and normal groups. Plasma Aβ42/40 correlated differently with neurofilament light chain, glial fibrillary acidic protein, phosphorylated tau181, memory composite, and CDR in each group. Plasma biomarkers can enable relatively affordable and non-invasive community screening for evidence of Alzheimer's disease and related disorders pathophysiology., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Published
2023
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