ε2 and ε4 alleles have been associated with lobar intracerebral hemorrhage (ICH) in predominately... more ε2 and ε4 alleles have been associated with lobar intracerebral hemorrhage (ICH) in predominately white populations; we sought to evaluate whether this held true among black and Hispanic populations. The Ethnic/Racial Variations of Intracerebral Hemorrhage study is a prospective, multicenter case-control study of ICH among white, black, and Hispanic participants. Controls were recruited to match cases based on age, ethnicity/race, sex, and geographic location. genotyping and ICH location was determined blinded to clinical data. There were 907 cases of lobar ICH and 2,660 controls with results. Both ε (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.1-2.0, = 0.01) and ε (OR 2.0, 95% CI 1.5-2.6, < 1 × 10) were associated with lobar ICH among white participants. Among black participants, neither ε (OR 1.0, 95% CI 0.7-1.5, = 0.97) nor ε (OR 1.0, 95% CI 0.7-1.4, = 0.90) were independent risk factors for lobar ICH. Similarly, among Hispanic participants, neither ε (OR 1.0, 95% CI 0...
With the rapid adoption of high-throughput omic approaches to analyze biological samples such as ... more With the rapid adoption of high-throughput omic approaches to analyze biological samples such as genomics, transcriptomics, proteomics and metabolomics, each analysis can generate tera- to peta-byte sized data files on a daily basis. These data file sizes, together with differences in nomenclature among these data types, make the integration of these multi-dimensional omics data into biologically meaningful context challenging. Variously named as integrated omics, multi-omics, poly-omics, trans-omics, pan-omics or shortened to just ‘omics’, the challenges include differences in data cleaning, normalization, biomolecule identification, data dimensionality reduction, biological contextualization, statistical validation, data storage and handling, sharing and data archiving. The ultimate goal is toward the holistic realization of a ‘systems biology’ understanding of the biological question. Commonly used approaches are currently limited by the 3 i’s – integration, interpretation and in...
Molecular genetics & genomic medicine, Jan 19, 2018
Sensorineural hearing loss (SNHL) is a common form of hearing loss that can be inherited or trigg... more Sensorineural hearing loss (SNHL) is a common form of hearing loss that can be inherited or triggered by environmental insults; auditory neuropathy spectrum disorder (ANSD) is a SNHL subtype with unique diagnostic criteria. The genetic factors associated with these impairments are vast and diverse, but causal genetic factors are rarely characterized. A family dyad, both cochlear implant recipients, presented with a hearing history of bilateral, progressive SNHL, and ANSD. Whole-exome sequencing was performed to identify coding sequence variants shared by both family members, and screened against genes relevant to hearing loss and variants known to be associated with SNHL and ANSD. Both family members are successful cochlear implant users, demonstrating effective auditory nerve stimulation with their devices. Genetic analyses revealed a mutation (rs35725509) in the TMTC2 gene, which has been reported previously as a likely genetic cause of SNHL in another family of Northern European ...
The Journal of allergy and clinical immunology, Jan 12, 2017
Although eosinophilic esophagitis (EoE) is associated with certain gene variants, the rapidly inc... more Although eosinophilic esophagitis (EoE) is associated with certain gene variants, the rapidly increasing incidence of EoE suggests that environmental factors contribute to disease development. We tested for gene-environment interaction between EoE-predisposing polymorphisms (within TSLP, LOC283710/KLF13, CAPN14, CCL26, and TGFB) and implicated early-life factors (antibiotic use in infancy, cesarean delivery, breast-feeding, neonatal intensive care unit [NICU] admission, and absence of pets in the home). We conducted a case-control study using hospital-based cases (n = 127) and control subjects representative of the hospital catchment area (n = 121). We computed case-only interaction tests and in secondary analyses evaluated the combined and independent effects of genotype and environmental factors on the risk of EoE. Case-only analyses identified interactions between rs6736278 (CAPN14) and breast-feeding (P = .02) and rs17815905 (LOC283710/KLF13) and NICU admission (P = .02) but not...
Assess cross-sectional relationships between body mass index (BMI), waist circumference (WC), per... more Assess cross-sectional relationships between body mass index (BMI), waist circumference (WC), pericardial (PAT), visceral (VAT), and subcutaneous adipose tissue (SAT) volumes with calcified plaque (CP) in African Americans (AAs) and European Americans (EAs) with type 2 diabetes. Computed tomography measured PAT, VAT, SAT, and CP in coronary arteries (CAC), carotid arteries, and aorta. Generalized estimating equations models were fitted to test for associations between adiposity and CP, stratified by ethnicity while accounting for familial correlations. AAs (N = 753) vs. EAs (N = 562) had significantly lower PAT and VAT, despite equal or higher BMI. In multivariable models adjusting for age, gender, education, HbA1c, statins, smoking, cardiovascular disease, hypertension, nephropathy, and C-reactive protein, PAT positively associated with presence of CAC in AAs (P < 0.001), not EAs (P = 0.68; ethnicity interaction P < 0.01). Inverse associations were detected between SAT and se...
Stroke; a journal of cerebral circulation, Jan 25, 2015
Intracerebral hemorrhage has a substantial genetic component. We performed a preliminary search f... more Intracerebral hemorrhage has a substantial genetic component. We performed a preliminary search for rare coding variants associated with intracerebral hemorrhage. A total of 757 cases and 795 controls were genotyped using the Illumina HumanExome Beadchip (Illumina, Inc, San Diego, CA). Meta-analyses of single-variant and gene-based association were computed. No rare coding variants were associated with intracerebral hemorrhage. Three common variants on chromosome 19q13 at an established susceptibility locus, encompassing TOMM40, APOE, and APOC1, met genome-wide significance (P<5e-08). After adjusting for the APOE epsilon alleles, this locus was no longer convincingly associated with intracerebral hemorrhage. No gene reached genome-wide significance level in gene-based association testing. Although no coding variants of large effect were detected, this study further underscores a major challenge for the study of genetic susceptibility loci; large sample sizes are required for suff...
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2015
Genetic data suggest that IL-6 trans-signaling may have a pathogenic role in the lung; however, t... more Genetic data suggest that IL-6 trans-signaling may have a pathogenic role in the lung; however, the effects of IL-6 trans-signaling on lung effector cells have not been investigated. In this study, human airway smooth muscle (HASM) cells were treated with IL-6 (classical) or IL-6+sIL6R (trans-signaling) for 24 h and gene expression was measured by RNAseq. Intracellular signaling and transcription factor activation were assessed by Western blotting and luciferase assay, respectively. The functional effect of IL-6 trans-signaling was determined by proliferation assay. IL-6 trans-signaling had no effect on phosphoinositide-3 kinase and Erk MAP kinase pathways in HASM cells. Both classical and IL-6 trans-signaling in HASM involves activation of Stat3. However, the kinetics of Stat3 phosphorylation by IL-6 trans-signaling was different than classical IL-6 signaling. This was further reflected in the differential gene expression profile by IL-6 trans-signaling in HASM cells. Under IL-6 tr...
Objective.To investigate and refine the relationships among systemic lupus erythematosus (SLE) an... more Objective.To investigate and refine the relationships among systemic lupus erythematosus (SLE) and related autoantibodies, interferon-α (IFN-α), and various ancestral backgrounds.Methods.We investigated quantitatively defined genetic ancestry through principal component analysis in place of self-reported ancestry.Results.African ancestry was found to be associated with presence of anti-RNP antibody (p = 0.0026), and anti-RNP was correlated with high levels of IFN-α (p = 2.8 × 10−5).Conclusion.Our data support a model in which African ancestry increases the likelihood of SLE-associated autoantibody formation, which subsequently results in higher levels of serum IFN-α.
The metabolic syndrome is characterized by central obesity, dyslipidemia, elevated blood pressure... more The metabolic syndrome is characterized by central obesity, dyslipidemia, elevated blood pressure, and hyperglycemia. The Insulin Resistance Atherosclerosis Study (IRAS) Family Study recruited extended pedigrees of Hispanic descent from San Antonio, TX (SA) and San Luis Valley, CO (SLV). Thirty-five of these pedigrees (27 SA and 8 SLV) had at least 2 individuals with metabolic syndrome (216 affected individuals and 563 affected relative pairs). The prevalence of metabolic syndrome and component criteria in subjects from these pedigrees were 35% metabolic syndrome, 43% increased waist circumference, 31% hypertriglyceridemia, 69% low HDL cholesterol, 31% increased blood pressure, and 25% either increased fasting glucose or presence of diabetes. Nonparametric linkage analysis provided evidence for linkage of metabolic syndrome to 1q23-q31 (D1S518; logarithm of odds [LOD] 1.6) with significant site heterogeneity (SA LOD 2.6 and SLV LOD 0.0), and removing all individuals with diabetes re...
ε2 and ε4 alleles have been associated with lobar intracerebral hemorrhage (ICH) in predominately... more ε2 and ε4 alleles have been associated with lobar intracerebral hemorrhage (ICH) in predominately white populations; we sought to evaluate whether this held true among black and Hispanic populations. The Ethnic/Racial Variations of Intracerebral Hemorrhage study is a prospective, multicenter case-control study of ICH among white, black, and Hispanic participants. Controls were recruited to match cases based on age, ethnicity/race, sex, and geographic location. genotyping and ICH location was determined blinded to clinical data. There were 907 cases of lobar ICH and 2,660 controls with results. Both ε (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.1-2.0, = 0.01) and ε (OR 2.0, 95% CI 1.5-2.6, < 1 × 10) were associated with lobar ICH among white participants. Among black participants, neither ε (OR 1.0, 95% CI 0.7-1.5, = 0.97) nor ε (OR 1.0, 95% CI 0.7-1.4, = 0.90) were independent risk factors for lobar ICH. Similarly, among Hispanic participants, neither ε (OR 1.0, 95% CI 0...
With the rapid adoption of high-throughput omic approaches to analyze biological samples such as ... more With the rapid adoption of high-throughput omic approaches to analyze biological samples such as genomics, transcriptomics, proteomics and metabolomics, each analysis can generate tera- to peta-byte sized data files on a daily basis. These data file sizes, together with differences in nomenclature among these data types, make the integration of these multi-dimensional omics data into biologically meaningful context challenging. Variously named as integrated omics, multi-omics, poly-omics, trans-omics, pan-omics or shortened to just ‘omics’, the challenges include differences in data cleaning, normalization, biomolecule identification, data dimensionality reduction, biological contextualization, statistical validation, data storage and handling, sharing and data archiving. The ultimate goal is toward the holistic realization of a ‘systems biology’ understanding of the biological question. Commonly used approaches are currently limited by the 3 i’s – integration, interpretation and in...
Molecular genetics & genomic medicine, Jan 19, 2018
Sensorineural hearing loss (SNHL) is a common form of hearing loss that can be inherited or trigg... more Sensorineural hearing loss (SNHL) is a common form of hearing loss that can be inherited or triggered by environmental insults; auditory neuropathy spectrum disorder (ANSD) is a SNHL subtype with unique diagnostic criteria. The genetic factors associated with these impairments are vast and diverse, but causal genetic factors are rarely characterized. A family dyad, both cochlear implant recipients, presented with a hearing history of bilateral, progressive SNHL, and ANSD. Whole-exome sequencing was performed to identify coding sequence variants shared by both family members, and screened against genes relevant to hearing loss and variants known to be associated with SNHL and ANSD. Both family members are successful cochlear implant users, demonstrating effective auditory nerve stimulation with their devices. Genetic analyses revealed a mutation (rs35725509) in the TMTC2 gene, which has been reported previously as a likely genetic cause of SNHL in another family of Northern European ...
The Journal of allergy and clinical immunology, Jan 12, 2017
Although eosinophilic esophagitis (EoE) is associated with certain gene variants, the rapidly inc... more Although eosinophilic esophagitis (EoE) is associated with certain gene variants, the rapidly increasing incidence of EoE suggests that environmental factors contribute to disease development. We tested for gene-environment interaction between EoE-predisposing polymorphisms (within TSLP, LOC283710/KLF13, CAPN14, CCL26, and TGFB) and implicated early-life factors (antibiotic use in infancy, cesarean delivery, breast-feeding, neonatal intensive care unit [NICU] admission, and absence of pets in the home). We conducted a case-control study using hospital-based cases (n = 127) and control subjects representative of the hospital catchment area (n = 121). We computed case-only interaction tests and in secondary analyses evaluated the combined and independent effects of genotype and environmental factors on the risk of EoE. Case-only analyses identified interactions between rs6736278 (CAPN14) and breast-feeding (P = .02) and rs17815905 (LOC283710/KLF13) and NICU admission (P = .02) but not...
Assess cross-sectional relationships between body mass index (BMI), waist circumference (WC), per... more Assess cross-sectional relationships between body mass index (BMI), waist circumference (WC), pericardial (PAT), visceral (VAT), and subcutaneous adipose tissue (SAT) volumes with calcified plaque (CP) in African Americans (AAs) and European Americans (EAs) with type 2 diabetes. Computed tomography measured PAT, VAT, SAT, and CP in coronary arteries (CAC), carotid arteries, and aorta. Generalized estimating equations models were fitted to test for associations between adiposity and CP, stratified by ethnicity while accounting for familial correlations. AAs (N = 753) vs. EAs (N = 562) had significantly lower PAT and VAT, despite equal or higher BMI. In multivariable models adjusting for age, gender, education, HbA1c, statins, smoking, cardiovascular disease, hypertension, nephropathy, and C-reactive protein, PAT positively associated with presence of CAC in AAs (P < 0.001), not EAs (P = 0.68; ethnicity interaction P < 0.01). Inverse associations were detected between SAT and se...
Stroke; a journal of cerebral circulation, Jan 25, 2015
Intracerebral hemorrhage has a substantial genetic component. We performed a preliminary search f... more Intracerebral hemorrhage has a substantial genetic component. We performed a preliminary search for rare coding variants associated with intracerebral hemorrhage. A total of 757 cases and 795 controls were genotyped using the Illumina HumanExome Beadchip (Illumina, Inc, San Diego, CA). Meta-analyses of single-variant and gene-based association were computed. No rare coding variants were associated with intracerebral hemorrhage. Three common variants on chromosome 19q13 at an established susceptibility locus, encompassing TOMM40, APOE, and APOC1, met genome-wide significance (P<5e-08). After adjusting for the APOE epsilon alleles, this locus was no longer convincingly associated with intracerebral hemorrhage. No gene reached genome-wide significance level in gene-based association testing. Although no coding variants of large effect were detected, this study further underscores a major challenge for the study of genetic susceptibility loci; large sample sizes are required for suff...
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2015
Genetic data suggest that IL-6 trans-signaling may have a pathogenic role in the lung; however, t... more Genetic data suggest that IL-6 trans-signaling may have a pathogenic role in the lung; however, the effects of IL-6 trans-signaling on lung effector cells have not been investigated. In this study, human airway smooth muscle (HASM) cells were treated with IL-6 (classical) or IL-6+sIL6R (trans-signaling) for 24 h and gene expression was measured by RNAseq. Intracellular signaling and transcription factor activation were assessed by Western blotting and luciferase assay, respectively. The functional effect of IL-6 trans-signaling was determined by proliferation assay. IL-6 trans-signaling had no effect on phosphoinositide-3 kinase and Erk MAP kinase pathways in HASM cells. Both classical and IL-6 trans-signaling in HASM involves activation of Stat3. However, the kinetics of Stat3 phosphorylation by IL-6 trans-signaling was different than classical IL-6 signaling. This was further reflected in the differential gene expression profile by IL-6 trans-signaling in HASM cells. Under IL-6 tr...
Objective.To investigate and refine the relationships among systemic lupus erythematosus (SLE) an... more Objective.To investigate and refine the relationships among systemic lupus erythematosus (SLE) and related autoantibodies, interferon-α (IFN-α), and various ancestral backgrounds.Methods.We investigated quantitatively defined genetic ancestry through principal component analysis in place of self-reported ancestry.Results.African ancestry was found to be associated with presence of anti-RNP antibody (p = 0.0026), and anti-RNP was correlated with high levels of IFN-α (p = 2.8 × 10−5).Conclusion.Our data support a model in which African ancestry increases the likelihood of SLE-associated autoantibody formation, which subsequently results in higher levels of serum IFN-α.
The metabolic syndrome is characterized by central obesity, dyslipidemia, elevated blood pressure... more The metabolic syndrome is characterized by central obesity, dyslipidemia, elevated blood pressure, and hyperglycemia. The Insulin Resistance Atherosclerosis Study (IRAS) Family Study recruited extended pedigrees of Hispanic descent from San Antonio, TX (SA) and San Luis Valley, CO (SLV). Thirty-five of these pedigrees (27 SA and 8 SLV) had at least 2 individuals with metabolic syndrome (216 affected individuals and 563 affected relative pairs). The prevalence of metabolic syndrome and component criteria in subjects from these pedigrees were 35% metabolic syndrome, 43% increased waist circumference, 31% hypertriglyceridemia, 69% low HDL cholesterol, 31% increased blood pressure, and 25% either increased fasting glucose or presence of diabetes. Nonparametric linkage analysis provided evidence for linkage of metabolic syndrome to 1q23-q31 (D1S518; logarithm of odds [LOD] 1.6) with significant site heterogeneity (SA LOD 2.6 and SLV LOD 0.0), and removing all individuals with diabetes re...
Uploads
Papers by Carl Langefeld