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Hooman Allayee

Publications and source records attributed to Hooman Allayee.

At least 19 recordsLinked to original sources
PubMed2006

A new locus for autosomal dominant amelogenesis imperfecta on chromosome 8q24.3.

Amelogenesis imperfecta (AI) is a collective term used to describe phenotypically diverse forms of defective tooth enamel development. AI has been reported to exhibit a variety of inheritance patterns, and several loci have been identified that are associated with AI. We have performed a genome-wide scan in a large Brazilian family segregating an autosomal dominant form of AI and mapped a novel locus to 8q24.3. A maximum multipoint LOD score of 7.5 was obtained at marker D8S2334 (146,101,309 bp). The disease locus lies in a 1.9 cM (2.1 Mb) region according to the Rutgers Combined Linkage-Physical map, between a VNTR marker (at 143,988,705 bp) and the telomere (146,274,826 bp). Ten candidate genes were identified based on gene ontology and microarray-facilitated gene selection using the expression of murine orthologues in dental tissue, and examined for the presence of a mutation. However, no causative mutation was identified.

Amelogenesis Imperfecta↗
PubMed2006

Using inbred mouse strains to identify genes for complex diseases.

In recent years, genetic studies in humans have identified a handful of genes that are associated with common disorders, but our understanding of such diseases at the genetic level remains relatively rudimentary. The use of mice to dissect the complex genetic etiology of common disorders offers a viable alternative to human studies since experimental parameters, such as environmental influences, breeding scheme, and detailed phenotyping can be controlled. This review focuses on the utility of mouse genetics for identification of complex disease genes. Atherosclerosis is used as a representative example, followed by an overview for the prospects of successful gene discovery in the future.

Animals↗
PubMed2006

Nonconventional genetic risk factors for cardiovascular disease.

Despite numerous advances made in identifying the genes for rare mendelian forms of cardiovascular disease (CVD), relatively little is known about the common, complex forms at the genetic level. Moreover, most genes that have been associated with CVD, whether they are single gene forms or more common forms of the disease, have primarily been involved in biochemical pathways related to what are considered "conventional" risk factors. However, recent genetic studies have begun to identify genes and pathways associated with CVD that would not be considered to underlie conventional risk factors. In this review, we discuss the evidence for this latter notion based on recent linkage and association studies in humans. As an example, we also illustrate how a combination of mouse and human genetics led to identification of the 5-lipoxygenase pathway for CVD, with potentially important implications for its treatment and diagnosis. We conclude with a discussion of the prospects for identifying CVD genes in the future and for potentially developing more effective therapeutic strategies.

Animals↗
PubMed2006

Effect of obesity on clinical presentation and response to treatment in asthma.

Obesity is a risk factor for being diagnosed with asthma, but there is conflicting evidence on whether obesity is a risk factor for lung function abnormalities characteristic of asthma. We studied a cohort of 488 subjects, 47% of whom were obese. Obese and non-obese subjects with asthma had similar airflow limitation and bronchodilator responsiveness, but obese participants had increased sleep disturbance and gastroesophageal reflux disease, higher cytokine levels, and a trend towards increased exacerbations when treated with theophylline. Obese and non-obese asthmatics have similar lung function abnormalities, but comorbidities and altered responses to medications may significantly affect asthma control in obese people.

Acetates↗
PubMed2005

Influence of leukotriene pathway polymorphisms on response to montelukast in asthma.

RATIONALE: Interpatient variability in montelukast response may be related to variation in leukotriene pathway candidate genes. OBJECTIVE: To determine associations between polymorphisms in leukotriene pathway candidate genes with outcomes in patients with asthma receiving montelukast for 6 mo who participated in a clinical trial. METHODS: Polymorphisms were typed using Sequenom matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass array spectrometry and published methods; haplotypes were imputed using single nucleotide polymorphism-expectation maximization (SNP-EM). Analysis of variance and logistic regression models were used to test for changes in outcomes by genotype. In addition, chi(2) and likelihood ratio tests were used to test for differences between groups. Case-control comparisons were analyzed using the SNP-EM Omnibus likelihood ratio test. MEASUREMENTS: Outcomes were asthma exacerbation rate and changes in FEV(1) compared with baseline. RESULTS: DNA was collected from 252 participants: 69% were white, 26% were African American. Twenty-eight SNPs in the ALOX5, LTA4H, LTC4S, MRP1, and cysLT1R genes, and an ALOX5 repeat polymorphism were successfully typed. There were racial disparities in allele frequencies in 17 SNPs and in the repeat polymorphism. Association analyses were performed in 61 whites. Associations were found between genotypes of SNPs in the ALOX5 (rs2115819) and MRP1 (rs119774) genes and changes in FEV(1) (p < 0.05), and between two SNPs in LTC4S (rs730012) and in LTA4H (rs2660845) genes for exacerbation rates. Mutant ALOX5 repeat polymorphism was associated with decreased exacerbation rates. There was strong linkage disequilibrium between ALOX5 SNPs. Associations between ALOX5 haplotypes and risk of exacerbations were found. CONCLUSIONS: Genetic variation in leukotriene pathway candidate genes contributes to variability in montelukast response.

Acetates↗
PubMed2005

Integrating genotypic and expression data in a segregating mouse population to identify 5-lipoxygenase as a susceptibility gene for obesity and bone traits.

Forward genetic approaches to identify genes involved in complex traits such as common human diseases have met with limited success. Fine mapping of linkage regions and validation of positional candidates are time-consuming and not always successful. Here we detail a hybrid procedure to map loci involved in complex traits that leverages the strengths of forward and reverse genetic approaches. By integrating genotypic and expression data in a segregating mouse population, we show how clusters of expression quantitative trait loci linking to regions of the genome accurately reflect the underlying perturbation to the transcriptional network induced by DNA variations in genes that control the complex traits. By matching patterns of gene expression in a segregating population with expression responses induced by single-gene perturbation experiments, we show how genes controlling clusters of expression and clinical quantitative trait loci can be mapped directly. We demonstrate the utility of this approach by identifying 5-lipoxygenase as underlying previously identified quantitative trait loci in an F(2) cross between strains C57BL/6J and DBA/2J and showing that it has pleiotropic effects on body fat, lipid levels and bone density.

Animals↗
PubMed2005

A genome-wide set of congenic mouse strains derived from DBA/2J on a C57BL/6J background.

In the analysis of complex traits, congenic strains are powerful tools because they allow characterization of a single locus in the absence of genetic variation throughout the remainder of the genome. Here, we report the construction and initial characterization of a genome-wide panel of congenic strains derived from the donor strain DBA/2J on the background strain C57BL/6J. For many strains, we have carried out high-density SNP genotyping to precisely map the congenic interval and to identify any contaminating regions. Certain strains exhibit striking variation in litter size and in the ratio of females to males. We illustrate the utility of the set by "Mendelizing" the complex trait of myocardial calcification. These 65 strains cover more than 95% of the autosomal genome and should facilitate the analysis of the many genetic trait differences that have been reported between these parental strains.

Animals↗
PubMed2004

Quantitative trait loci for apolipoprotein B, cholesterol, and triglycerides in familial combined hyperlipidemia pedigrees.

OBJECTIVE: Familial combined hyperlipidemia (FCHL) is a genetically complex lipid disorder that is diagnosed in families by combinations of increased cholesterol, triglycerides, and/or apolipoprotein B (apoB) levels in patients and their first-degree relatives. Identifying the predisposing genes promises to reveal the primary risk factors and susceptibility pathways and suggest methods of prevention and treatment. As with most genetically complex disorders, a clinical definition of disease may not be the most useful phenotype for finding the complement of predisposing genes, and the quantitative traits used to define the disorder can provide important information. This is a report of a quantitative trait loci (QTL) analysis of FCHL. METHODS AND RESULTS: A full genome scan of 377 multi-allelic markers genotyped at approximately 10 centimorgan (cM) intervals was conducted in 150 sibling pairs from 22 nuclear families in FCHL pedigrees. These data were analyzed by 2 multipoint QTL linkage methods using the nonparametric and Haseman-Elston procedures of the Genehunter software. Using a criterion of P<0.001 by the nonparametric analysis, we found evidence of 2 apoB QTL at 1p21-31 (P<0.000009) and 17p11-q21 (P<0.000009), a total serum cholesterol QTL at 12p13 (P<0.0001), and a serum triglycerides QTL at 4p15-16 (P<0.0002). Using the criterion of P<0.03 for at least 2 traits at the same locus, additional evidence for cholesterol (P<0.01) and a triglycerides P<0.02) was observed at 17p11-21, as well as suggestive evidence for apoB (P<0.02) and triglycerides (P<0.01) at 4q34-35, and cholesterol (P<0.01) and triglycerides (P<0.02) and a binary FCHL trait (lod=1.5) at 16p12-13. CONCLUSIONS: QTL analyses of the traits that define FCHL are effective for localizing disease-predisposing genes.

Apolipoproteins B↗
PubMed2004

Association of the APOLIPOPROTEIN A1/C3/A4/A5 gene cluster with triglyceride levels and LDL particle size in familial combined hyperlipidemia.

The APOLIPOPROTEIN (APO)A1/C3/A4/A5 gene cluster on chromosome 11 has been hypothesized to be a modifier of plasma triglycerides in FCH. In the present study, we extended previous association analyses of the gene cluster to include APOA5, a newly discovered member of the cluster. Eight SNPs across the APOA1/C3/A4/A5 gene region were analyzed in 78 FCH probands and their normolipidemic spouses as well as in 27 Dutch FCH families. Of the individual SNPs tested in the case-control panel, the strongest evidence of association was obtained with SNPs in APOA1 (P=0.001) and APOA5 (P=0.001). A single haplotype defined by a missense mutation in APOA5 was enriched 3-fold in FCH probands when compared with the normolipidemic spouses (P=0.001) and a second haplotype was significantly enriched in the spouses (P=0.001). Family-based tests also indicated significant association of triglyceride levels and LDL particle size with the investigated SNPs of APOC3 and APOA5. These findings suggest that genetic variation in the APOA1/C3/A4/A5 gene cluster acts as a modifier of plasma triglyceride levels and LDL particle size within FCH families and furthermore indicate that a number of haplotypes may contribute to FCH.

Adult↗
PubMed2004

Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis.

BACKGROUND: Leukotrienes are inflammatory mediators generated from arachidonic acid (polyunsaturated n-6 fatty acid) by the enzyme 5-lipoxygenase. Since atherosclerosis involves arterial inflammation, we hypothesized that a polymorphism in the 5-lipoxygenase gene promoter could relate to atherosclerosis in humans and that this effect could interact with the dietary intake of competing 5-lipoxygenase substrates. METHODS: We determined 5-lipoxygenase genotypes, carotid-artery intima-media thickness, and markers of inflammation in a randomly sampled cohort of 470 healthy, middle-aged women and men from the Los Angeles Atherosclerosis Study. Dietary arachidonic acid and marine n-3 fatty acids (including a competing 5-lipoxygenase substrate that reduces the production of inflammatory leukotrienes) were measured with the use of six 24-hour recalls of food intake. RESULTS: Variant 5-lipoxygenase genotypes (lacking the common allele) were found in 6.0 percent of the cohort. Mean (+/-SE) intima-media thickness adjusted for age, sex, height, and racial or ethnic group was increased by 80+/-19 microm (95 percent confidence interval, 43 to 116; P<0.001) among carriers of two variant alleles, as compared with carriers of the common (wild-type) allele. In multivariate analysis, the increase in intima-media thickness among carriers of two variant alleles (62 microm, P<0.001) was similar in this cohort to that associated with diabetes (64 microm, P=0.01), the strongest common cardiovascular risk factor. Increased dietary arachidonic acid significantly enhanced the apparent atherogenic effect of genotype, whereas increased dietary intake of n-3 fatty acids blunted the effect. Finally, the plasma level of C-reactive protein, a marker of inflammation, was increased by a factor of 2 among carriers of two variant alleles as compared with that among carriers of the common allele. CONCLUSIONS: Variant 5-lipoxygenase genotypes identify a subpopulation with increased atherosclerosis. The observed diet-gene interactions further suggest that dietary n-6 polyunsaturated fatty acids promote, whereas marine n-3 fatty acids inhibit, leukotriene-mediated inflammation that leads to atherosclerosis in this subpopulation.

Adult↗
PubMed2004

The Collaborative Cross, a community resource for the genetic analysis of complex traits.

The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.

Animals↗
PubMed2003

Using mice to dissect genetic factors in atherosclerosis.

The genes that contribute to common, complex forms of atherosclerosis remain largely unknown. Genetic studies in humans have, for the most part, focused on identifying genes that predispose to the traditional risk factors, such as lipid levels and blood pressure, but apart from rare, single-gene disorders, there have been few successes to date. The use of mice to dissect the complex genetic etiology of atherosclerosis offers a viable alternative to human studies, because experimental parameters, such as environment, breeding scheme, and detailed phenotyping, can be controlled. Herein we review how mouse genetics can lead to the identification of genes, some of which would otherwise not have been considered as candidates for atherosclerosis, and provide an overview of the prospects for successful gene discovery in the future.

Animals↗
PubMed2003

Biochemical and genetic association of plasma apolipoprotein A-II levels with familial combined hyperlipidemia.

Apolipoprotein A-II (apoA-II) is a major protein on high-density lipoprotein (HDL) particles, and in mice, its levels are associated with triglyceride and glucose metabolism. In particular, transgenic mice overexpressing apoA-II exhibit hypertriglyceridemia, increased body fat, and insulin resistance, whereas apoA-II-null mice have decreased triglycerides and increased insulin sensitivity. Given the phenotypic overlap between familial combined hyperlipidemia (FCH) and apoA-II transgenic mice, we investigated the relationship of apoA-II to this disorder. Despite having lower HDL-cholesterol (HDL-C), FCH subjects had higher apoA-II levels compared with unaffected relatives (P<0.00016). Triglyceride and HDL-C levels were significant predictors of apoA-II, demonstrating that apoA-II variation is associated with several FCH-related traits. After adjustment for multiple covariates, there was evidence for the heritability of apoA-II levels (h2=0.15; P<0.02) in this sample. A genome scan for apoA-II levels identified significant evidence (LOD=3.1) for linkage to a locus on chromosome 1q41, coincident with a suggestive linkage for triglycerides (LOD score=1.4). Thus, this locus may have pleiotropic effects on apoA-II and FCH traits. Our results demonstrate that apoA-II is biochemically and genetically associated with FCH and may serve as a useful marker for understanding the mechanism by which FCH develops.

Adult↗
PubMed2003

Combined analysis of genome scans of dutch and finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q.

Several genomewide screens have been performed to identify novel loci predisposing to unfavorable serum lipid levels and coronary heart disease (CHD). We hypothesized that the accumulating data of these screens in different study populations could be combined to verify which of the identified loci truly harbor susceptibility genes. The power of this strategy has recently been demonstrated with other complex diseases, such as inflammatory bowel disease and asthma. We assessed the largely unknown genetic background of CHD by investigating the most common dyslipidemia predisposing to CHD, familial combined hyperlipidemia (FCHL), affecting 1%-2% of Western populations and 10%-20% of families with premature CHD. To be able to perform a combined data analysis, we unified the diagnostic criteria for FCHL and its component traits and combined the data from two genomewide scans performed in two populations, the Finns and the Dutch. As a result of our pooled data analysis, we identified three chromosomal regions, on chromosomes 2p25.1, 9p23, and 16q24.1, exceeding the statistical significance level of a LOD score >2.0. The 2p25.1 region was detected for the FCHL trait, and the 9p23 and 16q24.1 regions were detected for the low high-density lipoprotein cholesterol (HDL-C) trait. In addition, the previously recognized 1q21 region also obtained additional support in the other study sample, when the triglyceride trait was used. Analysis of the 16q24.1 region resulted in a statistically significant LOD score of 3.6 when the data from Finnish families with low HDL-C were included in the analysis. To search for the underlying gene in the 16q24.1 region, we investigated a novel functional and positional candidate gene, helix/forkhead transcription factor (FOXC2), by sequencing and by genotyping of two single-nucleotide polymorphisms in the families.

Cholesterol, HDL↗
PubMed2003

5-lipoxygenase and atherosclerosis.

PURPOSE OF REVIEW: 5-Lipoxygenase (5LO) was recently identified as a gene that makes an important contribution to atherosclerosis in mice and humans, but the underlying mechanism(s) remains unknown. RECENT FINDINGS: Studies of the 5LO pathway in other disease areas suggest that 5LO could contribute to atherosclerosis at different levels, such as lesion initiation, growth and cellular proliferation within the lesion, and/or destabilization of plaques that can lead to their rupture. SUMMARY: Recent advances in our understanding of how 5LO is involved in the atherosclerotic process will have important implications for diagnostic and therapeutic strategies in the future.

Animals↗
PubMed2002

Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice.

We previously reported the identification of a locus on mouse chromosome 6 that confers almost total resistance to atherogenesis, even on a hypercholesterolemic (LDL receptor-null) background. 5-Lipoxygenase (5-LO) is the rate-limiting enzyme in leukotriene synthesis and was among the chromosome 6 locus candidate genes that we examined. The levels of 5-LO mRNA were reduced about 5-fold in a congenic strain, designated CON6, containing the resistant chromosome 6 region derived from the CAST/Ei strain (CAST), as compared with the background C57BL/6J (B6) strain. 5-LO protein levels were similarly reduced in the CON6 mice. Sequencing of the 5-LO cDNA revealed several differences between CON6 and the B6 strain. To test the whether 5-LO is responsible for the resistant phenotype, we bred a 5-LO knockout allele onto an LDL receptor-null (LDLR(-/-)) background. On this background, the mice bred poorly and only heterozygous 5-LO knockout mice were obtained. These mice showed a dramatic decrease (>26-fold; P<0.0005) in aortic lesion development, similar to the CON6 mice. Immunohistochemistry revealed that 5-LO was abundantly expressed in atherosclerotic lesions of apoE(-/-) and LDLR(-/-) deficient mice, appearing to colocalize with a subset of macrophages but not with all macrophage-staining regions. When bone marrow from 5-LO(+/-) mice was transplanted into LDLR(-/-), there was a significant reduction in atherogenesis, suggesting that macrophage 5-LO is responsible, at least in part, for the effect on atherosclerosis. These results indicate that 5-LO contributes importantly to the atherogenic process and they provide strong presumptive evidence that reduced 5-LO expression is partly responsible for the resistance to atherosclerosis in CON6 mice.

Alleles↗
PubMed2002

Locus for elevated apolipoprotein B levels on chromosome 1p31 in families with familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCH), a common cause of premature coronary artery disease, is genetically complex and poorly understood. Recently, a major locus on chromosome 1q21-23 exhibiting highly significant linkage was identified in Finnish FCH families by use of a parametric analysis. We now report highly significant evidence of linkage (maximum LOD score 3.8, recombination fraction 0) of an important FCH phenotype, elevated apolipoprotein B (apoB) levels, to a distinctly separate locus on chromosome 1p31 in Dutch pedigrees. ApoB is the major protein on very low density and low density lipoproteins, and elevated apoB levels have been used as a surrogate trait for FCH. Additional microsatellite markers in the 1p31 region were genotyped, and evidence of linkage improved (maximum LOD score 4.7) in a multipoint analysis of two markers in the peak region. The leptin receptor gene resides within this locus and is involved in obesity and insulin/glucose homeostasis. However, there was no evidence of an association between leptin receptor and apoB levels, raising the possibility that another gene on this chromosomal region contributes to elevated apoB levels in this Dutch population. This is one of the first loci identified for apoB levels in humans and is the second major locus implicated in the genetic etiology of FCH.

Apolipoproteins B↗