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Laura Almasy

Publications and source records attributed to Laura Almasy.

At least 73 records · Page 4Linked to original sources
PubMed2004

Linkage analysis of diabetes status among hypertensive families: the Hypertension Genetic Epidemiology Network study.

Type 2 diabetes susceptibility is determined by multiple genetic and environmental factors. Genome-wide linkage scans have localized common regions, possibly harboring susceptibility genes on chromosomes 1, 2, 12, and 20. Variability in linkage findings underscores the probable genetic heterogeneity of type 2 diabetes. Thus, we conducted a genome scan of diabetes status using maximum likelihood methods that model affection status by a liability threshold model. Hypertensive sibships and their offspring and/or parents in the Hypertension Genetic Epidemiology Network study were recruited from five field centers. The diabetes phenotype was derived using the World Health Organization criteria and adjusted for race/study center, age, age2, sex, and with and without percent body fat. In total, 567 diabetic participants were identified in 437 families. Variance component linkage analysis was performed among 1,545 Caucasians and 1,608 African Americans using race-specific marker allele frequencies. We detected a quantitative trait loci (QTLs) influencing diabetes variance (logarithm of odds = 3.4) on chromosome 22, which overlaps a positive type 2 diabetes finding among Canadian Oji-Cree Indians. We also observed suggestive evidence for linkage on chromosomes 1, 2, 5, 8, 14, 17, and 19. The identification and replication of type 2 diabetes QTLs will bring us closer to the detection of functional genes that influence diabetes susceptibility.

Chromosome Mapping↗
PubMed2003

Strategy and model building in the fourth dimension: a null model for genotype x age interaction as a Gaussian stationary stochastic process.

BACKGROUND: Using univariate and multivariate variance components linkage analysis methods, we studied possible genotype x age interaction in cardiovascular phenotypes related to the aging process from the Framingham Heart Study. RESULTS: We found evidence for genotype x age interaction for fasting glucose and systolic blood pressure. CONCLUSIONS: There is polygenic genotype x age interaction for fasting glucose and systolic blood pressure and quantitative trait locus x age interaction for a linkage signal for systolic blood pressure phenotypes located on chromosome 17 at 67 cM.

Adult↗
PubMed2003

Pedigree and genotype errors in the Framingham Heart Study.

The pedigree and genotype data from the Framingham Heart Study were examined for errors. Errors in 21 of 329 pedigrees were detected with the program PREST, and of these the errors in 16 pedigrees were resolved. Genotyping errors were then detected with SIMWALK2. Five Mendelian errors were found following the pedigree corrections. Double-recombinant errors were more common, with 142 being detected at mistyping probabilities of 0.25 or greater.

Adult Children↗
PubMed2003

Evidence for bivariate linkage of obesity and HDL-C levels in the Framingham Heart Study.

BACKGROUND: Epidemiological studies have indicated that obesity and low high-density lipoprotein (HDL) levels are strong cardiovascular risk factors, and that these traits are inversely correlated. Despite the belief that these traits are correlated in part due to pleiotropy, knowledge on specific genes commonly affecting obesity and dyslipidemia is very limited. To address this issue, we first conducted univariate multipoint linkage analysis for body mass index (BMI) and HDL-C to identify loci influencing variation in these phenotypes using Framingham Heart Study data relating to 1702 subjects distributed across 330 pedigrees. Subsequently, we performed bivariate multipoint linkage analysis to detect common loci influencing covariation between these two traits. RESULTS: We scanned the genome and identified a major locus near marker D6S1009 influencing variation in BMI (LOD = 3.9) using the program SOLAR. We also identified a major locus for HDL-C near marker D2S1334 on chromosome 2 (LOD = 3.5) and another region near marker D6S1009 on chromosome 6 with suggestive evidence for linkage (LOD = 2.7). Since these two phenotypes have been independently mapped to the same region on chromosome 6q, we used the bivariate multipoint linkage approach using SOLAR. The bivariate linkage analysis of BMI and HDL-C implicated the genetic region near marker D6S1009 as harboring a major gene commonly influencing these phenotypes (bivariate LOD = 6.2; LODeq = 5.5) and appears to improve power to map the correlated traits to a region, precisely. CONCLUSIONS: We found substantial evidence for a quantitative trait locus with pleiotropic effects, which appears to influence both BMI and HDL-C phenotypes in the Framingham data.

Adult↗
PubMed2003

Genetic determinants of variation in the plasma levels of the C4b-binding protein (C4BP) in Spanish families.

The C4b-binding protein (C4BP) is a plasma glycoprotein implicated in the homeostasis of the complement and coagulation systems. It is composed of two polypeptides (alpha and beta), which form three plasma oligomers with different subunit compositions (alpha(7)beta(1), alpha(7)beta(0), and alpha(6)beta(1)). The beta chain-containing C4BP isoforms (C4BPbeta(+)isoforms) bind and inactivate protein S (PS), downregulating the activated protein C (APC)-dependent anticoagulatory pathway. Because PS deficiency is associated with recurrent thrombosis, it has been suggested that increased levels of C4BPbeta(+)isoforms might diminish the free PS plasma level, affecting the risk of developing thromboembolism. Previous work has tested this hypothesis, but no definitive conclusions were reached, mostly because nothing is known about the factors influencing the high variability in C4BP plasma levels in humans. As a part of the GAIT project, using variance component analysis, this work provides the first estimation of the relative contributions of genetic and environmental influences on the plasma levels of total C4BP and C4BPbeta(+)isoforms. Plasma levels of total C4BP and C4BPbeta(+)isoforms showed strong evidence of genetic regulation (heritability 37.7% and 42.5%, respectively). They were also affected by age, smoking, and exogenous sex hormones. Our results constitute the first step in localizing and evaluating potential quantitative trait loci that affect the plasma levels of C4BP and C4BPbeta(+). Furthermore, analysis of phenotypic and genetic correlations between C4BPbeta(+)plasma levels and the components of the APC anticoagulatory pathway (total PS, free PS, functional PS, and functional PC) suggests a genetic co-regulation of the proteins. These observations might have important implications in the individual susceptibility to thrombotic disease.

Adolescent↗
PubMed2003

A quantitative trait locus influencing free plasma protein S levels on human chromosome 1q: results from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project.

OBJECTIVE: Protein S (PS) is a component of the protein C anticoagulant system. PS deficiency is associated with myocardial infarction and venous thromboembolism, two highly prevalent causes of death in industrialized nations. As part of the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project, we conducted a genome-wide linkage screen to localize genes influencing variation in free PS (fPS) plasma levels. METHODS AND RESULTS: fPS levels were measured in 397 individuals in 21 Spanish families. A total of 363 highly informative microsatellite markers were genotyped to provide a 10-cM genetic map, and variance component linkage methods were used. A region on chromosome 1q32, flanked by markers D1S425 and D1S213, showed strong evidence of linkage with fPS levels (LOD score, 4.07; nominal P=7.5x10(-6); genome-wide P=0.0024). This region contains two positional candidate genes, the complement component 4-binding protein alpha and beta chains, which encode the principal binding protein for PS. Suggestive evidence for linkage was also observed on chromosomes 11p and 19p. CONCLUSIONS: These results represent one of the first genomic screens for quantitative variation in a component of the hemostatic pathway and provide strong evidence for a locus on chromosome 1q influencing fPS levels.

Adolescent↗
PubMed2003

Consistency of genetic analyses in longitudinal data: observations from the GAW13 Framingham Heart Study data.

This paper examines the consistency of genetic analyses across time, both in the context of replicating results from one data collection point to the next, and from the perspective of modeling longitudinal processes. This summary originates from the examination of findings from nine papers from Genetic Analysis Workshop (GAW) 13 that reported on analyses of longitudinal data of a variety of traits from the Framingham Heart Study. These analyses include both assessments of consistency of aggregate genetic effects, in the form of estimation of heritability and relative risk of disease, as well as localization of quantitative trait loci (QTLs) by genome-wide linkage screens. Consistency varied widely by trait, possibly reflecting differences in measurement error, secular trends, or underlying biological features such as genotype x age interaction. Quantitatively, comparing magnitudes of estimates across age or time, heritability estimates showed greater consistency than LOD scores. However, qualitatively, the same regions of interest were often identified in genome scans from different time points or different ages. Estimates of sibling recurrence risk, on the other hand, showed little consistency. Heritabilities were greater when participants were matched by age than when they were matched by date of examination. Multivariate approaches, either in use of multiple traits or in use of multiple measures of the same trait, appeared to provide stronger genetic signals both for relative risk and for linkage. Finally, modeling of longitudinal processes provided evidence for genotype x age interactions that may partially explain variation in results of genetic analyses across time or age.

Age Factors↗
PubMed2003

Quantitative risk factors as indices of alcoholism susceptibility.

Alcoholism is a complex disorder involving both genetic and environmental factors and interactions between them. Localizing and characterizing the genetic influences on susceptibility to alcohol dependence may provide new insights into pathology and new avenues for treatment and prevention. However, because of the complex nature of the disorder, the binary categorization of individuals as affected or unaffected may be a poor indicator of their underlying genetic susceptibility. Quantitative risk factors, or endophenotypes, that differentiate levels of severity among affected individuals and levels of susceptibility among unaffected individuals, provide one solution to this problem. Genetic studies of such quantitative risk factors in families of probands with alcohol dependence may help to disentangle the complex genetic architecture of this disorder.

Alcoholism↗
PubMed2003

The genetics of obesity in Mexican Americans: the evidence from genome scanning efforts in the San Antonio family heart study.

Recent estimates indicate that approximately 18% of the population in the United States can be considered obese (defined as a body mass index [BMI] > or = 30), and this rate is even higher among ethnic populations such as Mexican Americans. This figure becomes very significant given the strong evidence for obesity as a major risk factor for a variety of chronic diseases including type 2 diabetes mellitus and coronary heart disease. The search for genes involved in the expression of obesity has been one of the focal points of the San Antonio Family Heart Study (SAFHS), a large, family-based study to examine the genetics of risk for atherosclerosis in Mexican Americans. To date, our genome scanning effort has reported two quantitative trait loci (QTLs) with pronounced effects on the expression of a variety of obesity--related phenotypes (e.g., leptin levels, fat mass, and BMI) located on chromosomes 2 and 8. We are currently working to further refine these signals and to identify the genes and allelic variants involved. Here, we summarize the latest results from our ongoing efforts to identify obesity genes in the San Antonio Family Heart Study.

Adult↗
PubMed2003

Quantitative trait loci on chromosomes 2p, 4p, and 13q influence bone mineral density of the forearm and hip in Mexican Americans.

UNLABELLED: We performed a genome scan using BMD data of the forearm and hip on 664 individuals in 29 Mexican-American families. We obtained evidence for QTL on chromosome 4p, affecting forearm BMD overall, and on chromosomes 2p and 13q, affecting hip BMD in men. INTRODUCTION: The San Antonio Family Osteoporosis Study (SAFOS) was designed to identify genes and environmental factors that influence bone mineral density (BMD) using data from large Mexican-American families. MATERIALS AND METHODS: We performed a genome-wide linkage analysis using 416 highly polymorphic microsatellite markers spaced approximately 9.5 cM apart to locate and identify quantitative trait loci (QTL) that affect BMD of the forearm and hip. Multipoint variance components linkage analyses were done using data on all 664 subjects, as well as two subgroups of 259 men and 261 premenopausal women, from 29 families for which genotypic and phenotypic data were available. RESULTS: We obtained significant evidence for a QTL affecting forearm (radius midpoint) BMD in men and women combined on chromosome 4p near D4S2639 (maximum LOD = 4.33, genomic p = 0.006) and suggestive evidence for a QTL on chromosome 12q near locus D12S2070 (maximum conditional LOD = 2.35). We found suggestive evidence for a QTL influencing trochanter BMD on chromosome 6 (maximum LOD = 2.27), but no evidence for QTL affecting the femoral neck in men and women combined. In men, we obtained evidence for QTL affecting neck and trochanter BMD on chromosomes 2p near D2S1780 (maximum LOD = 3.98, genomic p = 0.013) and 13q near D13S788 (maximum LOD = 3.46, genomic p = 0.039), respectively. We found no evidence for QTL affecting forearm or hip BMD in premenopausal women. CONCLUSION: These results provide strong evidence that a QTL on chromosome 4p affects radius BMD in Mexican-American men and women, as well as evidence that QTL on chromosomes 2p and 13q affect hip BMD in men. Our results are consistent with some reports in humans and mice. J Bone Miner Res 2003;18:2245-2252

Adolescent↗
PubMed2003

Genome-wide linkage analysis of von Willebrand factor plasma levels: results from the GAIT project.

High plasma levels of von Willebrand factor (vWF) have been associated with the risk of thromboembolic disease. As a complex trait, this phenotype must be influenced by genetic and environmental factors. Among the genetic factors, only the ABO gene located on chromosome 9q34 has been clearly linked to the plasma levels of vWF. This locus explains about 30-40% of the genetic variability. Therefore, the source of the majority of the genetic component remains to be identified. To search for these unknown loci, we conducted a genomewide linkage screen for genes affecting normal variation in vWF levels in 21 Spanish families as part of the GAIT (Genetic Analysis of Idiopathic Thrombophilia) Project. The results showed that the strongest linkage signal (LOD =3.46, p = 0.00003) for vWF was found on chromosome 9q34 at the DNA marker D9S290, where the ABO gene is located. Additional suggestive linkage signals were found on chromosomes 2q23.2 (LOD = 1.65, p = 0.003) and 1p36.13 (LOD =1.32, p = 0.007). After refining the linkage analysis, conditional to the ABO genotype, three additional loci on chromosomes 5, 6 and 22 showed LOD scores higher than 1, suggesting the presence of other genes linked to vWF levels. Curiously, no linkage signals were detected in other chromosome regions previously associated with vWF levels (like the structural VWF gene on 12p13.2 or Lewis blood group gene on 19q13). These results indicate that these loci are not important genetic determinants of the normal variation of vWF levels. Our results indicate that the ABO locus is the major genetic determinant of the plasma levels of the vWF in Spanish population. It is possible that there are other potential regions on chromosomes 1, 2, 5, 6 and 22 that influence this thrombosis risk factor. However, the structural vWF gene itself has a very low influence (if any) on the plasma levels of vWF.

ABO Blood-Group System↗
PubMed2002

A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility.

Activated protein C resistance (APCR) is the most prevalent risk factor for thrombosis, accounting for 20% to 60% of familial thrombophilia. A mutation in the F5 gene, factor V Leiden (FVL), is a major determinant of pathological APCR in some populations. However, APCR predicts risk for thrombosis independently of FVL. This suggests that other genetic factors may influence risk of thrombosis through quantitative variation in APCR. To search for these unknown loci, we conducted a genome-wide linkage screen for genes affecting normal variation in APCR in the 21 Spanish families from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project. Conditional on FVL, the strongest linkage signal for APCR was found on chromosome 18 near D18S53. Bivariate linkage analyses with a genetically correlated trait, levels of clotting factor VIII, strengthened evidence for the chromosome 18 quantitative trait locus (QTL; logarithm of the odds [LOD], 4.5; P = 3.08 x 10(-5)). However, the region on chromosome 1 that contains the F5 structural gene showed little evidence of linkage to APCR (LOD, < 1). This indicates that apart from the FVL, the F5 locus itself plays a relatively minor role in normal variation in APCR, including the HR2 haplotype polymorphisms. A second bivariate analysis of APCR with thrombosis liability suggested that this QTL also influences the risk of thrombosis (P =.0016). These results indicate that a locus on chromosome 18 pleiotropically influences normal variation in the APCR phenotype and factor VIII (FVIII) levels as well as susceptibility to thrombosis. Importantly, there are no known thrombosis-related candidate genes in this region, implying that this QTL represents a completely novel thrombosis risk factor.

Activated Protein C Resistance↗
PubMed2002

Future research directions in idiopathic pulmonary fibrosis: summary of a National Heart, Lung, and Blood Institute working group.

Idiopathic pulmonary fibrosis (IPF) is an insidious inflammatory fibroproliferative disease whose cause and course before diagnosis are unknown, and for which existing treatments are of limited benefit. The National Heart, Lung, and Blood Institute convened a working group to develop specific recommendations for future IPF research. Inflammatory and immune processes are involved in IPF pathogenesis, and current therapeutic strategies are aimed at suppressing the inflammation. Recent data suggest that the molecular processes underlying the fibrogenesis may provide new opportunities for therapeutic intervention. Specific areas of future research recommended by the working group include studies to elucidate the etiology of IPF, to develop novel diagnostic techniques and molecular diagnostics, to establish a program for identification of molecular targets for IPF treatment and identification and generation of agonists or antagonists that inhibit fibrogenesis, to foster investigations that couple the use of new technologies (e.g., laser capture microdissection, microarrays, and mass spectroscopic analysis of proteins) with data from the human genome project, to establish a national consortium of Clinical Centers of Excellence to conduct coordinated clinical and laboratory studies of well-characterized patients and patient-derived materials, and to stimulate research to develop animal models of persistent and progressive pulmonary fibrosis for evaluation of new intervention approaches.

Humans↗
PubMed2002

Identification of a large deletion and three novel mutations in exon 13 of the factor V gene in a Spanish family with normal factor V coagulant and anticoagulant properties.

As part of the GAIT (genetic analysis of idiopathic thrombophilia) project, we analyzed polymorphisms in the factor V (FV) gene to assess their role as genetic determinants of normal phenotypic variation of hemostasis-related traits in a Spanish population. During the analysis of exon 13 polymorphisms, we detected an abnormal PCR-amplified fragment in some members of the GAIT19 family. Direct sequence analysis revealed a deletion of 108 bp in eight out of 20 individuals in this family. This deletion removes exactly 36 amino acids from the B domain of FV; thus it does not alter the reading frame of the sequence. Among the deleted amino acids there is the 4070A>G polymorphism (H1299R), which could affect the level or function of FV. In addition, in the same family we identified three novel DNA variants (L1257I, Q1317Q and T1327T) in exon 13 of the F5 gene. Despite these variants, we did not detect any differences either in the coagulant or anticoagulant traits, or in the plasma protein levels involved in the blood coagulation cascade, between the carriers compared with their non-carrier relatives. From these results, we can conclude that the mutant allele is expressed and the resultant protein is functional. Moreover, it is unlikely that the 4070A>G polymorphism, within the deletion, and the novel DNA variants alter the functional properties of the mature FV protein. Further analyses of this naturally occurring mutation and the novel DNA variants should yield useful information for the understanding of the function of the B domain of FV.

Base Sequence↗
PubMed2002

Genetic influences on aortic root size in American Indians: the Strong Heart Study .

Aortic root dilatation is a major pathophysiological mechanism for aortic regurgitation and predisposes the aortic root to dissection or rupture. However, only a small proportion of the variance of aortic root size can be explained by its known clinical and demographic correlates. The present study was undertaken to determine the heritability of echocardiographically derived aortic root diameter in the American Indian participants in the second Strong Heart Study examination. Echocardiograms were analyzed in 1373 SHS participants who had > or =1 family member in the cohort. Heritability calculations were performed by using variance component analysis as implemented in SOLAR, a computer analysis program. In a polygenic model, the variables entered and identified as covariates of larger aortic root diameter were older age, male sex, and center (P<0.001), which accounted for 35% of the overall variability of aortic root diameter. After simultaneous adjustment was made for these significant covariates, the proportion of phenotypic variance due to additive genetic contribution or residual heritability (h2) was 0.51 (SE=0.08, P<0.001). Additionally, simultaneous adjustment for height, weight, and systolic and diastolic BPs yielded slightly lower residual h2 of aortic root diameter (h2=0.44, SE=0.08, P<0.001), which accounted for 26% of the overall variance of aortic root size. Because center effects were identified as significant covariates in the analyses, h2 analyses were performed separately in Arizona, Oklahoma, and North/South Dakota centers, which confirmed that a significant proportion of the phenotypic variance of aortic root diameter is due to additive genetic contribution. Heredity explains a substantial proportion of the variability of aortic root size that is not accounted for by age, sex, body size, and blood pressure. Echocardiographic screening of family members with aortic root dilatation may identify other individuals predisposed to aortic dissection or rupture.

Aged↗