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1.  Association of cardiovascular risk factors with disease severity in cerebral cavernous malformation type 1 subjects with the common Hispanic mutation 
Cerebral Cavernous Malformations (CCM) are enlarged vascular lesions affecting 0.1 to 0.5% of the population worldwide and causing hemorrhagic strokes, seizures, and neurological deficits. Familial CCM type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and is characterized by multiple brain lesions whose number and size increase with age. The number of lesions varies widely for unknown reasons, even among carriers of similar ages with the same mutation. The purpose of this study was to investigate whether cardiovascular (CV) risk factors influence potential markers of familial CCM1 disease severity, such as lesion count and history of intracerebral hemorrhage.
We analyzed baseline data from 185 Hispanic subjects, enrolled in the Brain Vascular Malformation Consortium (BVMC) study between June 2010 and March 2013. All subjects were carriers of the founder Q455X “Common Hispanic Mutation” (CHM) in the KRIT1 gene, and had a clinical diagnosis of CCM or had an affected first or second degree relative with CCM. We performed a cross-sectional study, collecting detailed clinical information of CCM1-CHM subjects and cerebral susceptibility-weighted magnetic resonance imaging to assess lesion count. Linear or logistic regression analysis of log-lesion count or history of intracerebral hemorrhage and CV risk factors (age, gender, obesity, diabetes, hypertension, hyperlipidemia and smoking status) and related quantitative traits (body mass index, glycosylated hemoglobin levels, blood pressure, lipid levels and pack-years of cigarette smoking) was performed accommodating familial clustering.
CCM1-CHM subjects were mainly female (63.8%) and symptomatic at presentation (63.2%). Lesion count was highly variable (mean ± SD: 57.7 ± 110.6; range: 0–713); 90% of CCM1-CHM subjects had multiple lesions at enrollment. Age (p < 0.001) was positively correlated with lesion count and male gender (P=0.035) was associated with a greater number of lesions. Obesity (P=0.001) and higher body mass index (P=0.002) were associated with fewer lesions. No association with hypertension was detected, however, systolic blood pressure (P=0.002) was associated with fewer lesions. No significant association with lesion count was observed for diabetes, hyperlipidemia, smoking status or for related quantitative traits. History of intracerebral hemorrhage was not significantly associated with any CV risk factors; however, we found borderline associations of hemorrhage with obesity (P=0.062), systolic blood pressure (P=0.083) and pack-years of cigarette smoking (P=0.055). After correction for multiple testing, age and obesity remained significantly associated with lesion count in CCM1-CHM subjects.
These results suggest that several CV risk factors explain some of the variability in lesion count in Hispanic CCM1-CHM subjects. Although age, gender, obesity, body mass index and systolic blood pressure may influence familial CCM1 disease severity, further longitudinal studies in larger sample sizes are essential to confirm these findings.
PMCID: PMC3995158  PMID: 24401931
cerebrovascular disease; familial cerebral cavernous malformations type 1 (CCM1); common Hispanic mutation; disease severity; brain lesion count; intracerebral hemorrhage; cardiovascular risk factors
2.  Severity score for hereditary hemorrhagic telangiectasia 
A disease severity score in hereditary hemorrhagic telangiectasia (HHT) would be a useful tool for assessing burden of disease and for designing clinical trials. Here, we propose the first known HHT severity score, the HHT-score.
Demographics and disease characteristics were collected for the first 525 HHT patients recruited to the HHT Project of the Brain Vascular Malformation Consortium (BVMC). HHT-score was calculated based on presence of: organ arteriovenous malformations (maximum 3 points); chronic bleeding (maximum 2 points); and severe organ involvement (maximum 2 points). Points were summed and patients categorized as having mild (0–2), moderate (3–4) or severe (5–7) disease. The occurrence of “any adverse outcome” was evaluated for association with HHT-score categories.
The frequency of “any adverse outcome” was significantly different across the three groups (49.6% in mild, 65.8% in moderate and 89.5% in severe, p < 0.001). Adjusting for age and gender, the risk of “any adverse outcome” was higher in the moderate (OR = 1.84, 95% CI: 1.15-2.95, p = 0.011) and severe groups (OR = 9.16, 95% CI: 1.99-42.09, p = 0.004) compared to the mild.
We have taken the first steps toward creating a global measure of disease severity in HHT. While the initial results are promising, further validation of the HHT-score is still required.
PMCID: PMC4302697
Hereditary Hemorrhagic Telangiectasia (HHT); Osler-Weber-Rendu; Arteriovenous Malformation (AVM); Bleeding; Disease severity; Severity score
3.  eQTL and receptor pharmacology implicate Arg1 and the GABA-A receptor as therapeutic targets in neuroblastoma 
Cell reports  2014;9(3):1034-1046.
The development of targeted therapeutics for neuroblastoma, the third most common tumor in children, has been limited by a poor understanding of growth signaling mechanisms unique to the peripheral nerve precursors from which tumors arise. In this study, we combined genetics with gene expression analysis in the peripheral sympathetic nervous system to implicate arginase 1 and GABA signaling in tumor formation in vivo. In human neuroblastoma cells, either blockade of ARG1 or benzodiazepine-mediated activation of GABA-A receptors induced apoptosis and inhibited mitogenic signaling through AKT and MAPK. These results suggest that ARG1 and GABA influence both neural development and neuroblastoma, and that benzodiazepines in clinical use may have potential for neuroblastoma therapy.
PMCID: PMC4251494  PMID: 25437558
4.  Polymorphisms in ACVRL1 and Endoglin genes are not associated with sporadic and HHT related brain AVMs in Dutch patients 
Translational stroke research  2012;4(3):375-378.
We aimed to replicate the association of the IVS3-35A>G polymorphism in the activin receptor-like kinase (ACVRL) 1 gene and the 207G>A polymorphism in the endoglin (ENG) gene with sporadic brain arteriovenous malformations (BAVM) in Dutch BAVM patients. In addition, we assessed whether these polymorphisms contribute to the risk of BAVM in patients with hereditary haemorrhagic telangiectasia type 1 (HHT1). We genotyped 143 Dutch sporadic BAVM patients and 360 healthy volunteers for four variants in the ACVRL1 gene including IVS3-35A>G and two variants in the ENG gene including 207G>A. Differences in allele and genotype frequencies between sporadic BAVM patients and controls and their combined effect were analysed with a likelihood ratio test. Furthermore, we compared the allele and genotype frequencies between 24 HHT1 patients with a BAVM with those of a relative with HHT1 without a BAVM in a matched pair analysis using Wilcoxon signed rank test. No significant differences in allele frequency were found between sporadic BAVM cases and controls or between HHT1 patients with and without BAVM for any of the polymorphisms or the combination of ACVRL1 and ENG polymorphisms. Meta-analysis of the current and the two previous studies for the ACVRL1 IVS3-35A polymorphism showed a persisting association between the ACVRL1 IVS3-35A polymorphism and risk of sporadic BAVM (OR 1.86; 95% CI 1.32–2.61, p<0.001). We did not replicate the previously found association between a polymorphism in ACVRL1 IVS3-35A>G and BAVM in Dutch patients. However, meta-analysis did not rule out a possible effect.
PMCID: PMC4038301  PMID: 24323303
Arteriovenous malformations; Etiology; Genetics; Neurogenetics; Cerebrovascular disease
5.  G Protein-Coupled Receptor 124 (GPR124) Gene Polymorphisms and Risk of Brain Arteriovenous Malformation 
Translational stroke research  2012;3(4):418-427.
Abnormal endothelial proliferation and angiogenesis may contribute to brain arteriovenous malformation (BAVM) formation. G protein-coupled receptor 124 (GPR124) mediates embryonic CNS angiogenesis; thus we investigated the association of single nucleotide polymorphisms (SNPs) and haplotypes in GPR124 with risk of BAVM. Ten tagging SNPs spanning 39 kb of GPR124 were genotyped in 195 Caucasian BAVM patients and 243 Caucasian controls. SNP and haplotype association with risk of BAVM was screened using χ2 analysis. Associated variants were further evaluated using multivariable logistic regression, adjusting for age and sex. The minor alleles of 3 GPR124 SNPs adjacent to exon 2 and localized to a 16 kb region of high linkage disequilibrium were associated with reduced risk of BAVM (rs7015566 A, P=0.001; rs7823249 T, P=0.014; rs12676965 C, P=0.007). SNP rs7015566 (intron 1) remained associated after permutation testing (additive model P=0.033). Haplotype analysis revealed a significant overall association (χ2=12.55, 4 df, P=0.014); 2 haplotypes (ATCC, P=0.006 and GGCT, P=0.008) were associated with risk of BAVM. We genotyped a known synonymous SNP (rs16887051) in exon 2, however genotype frequency did not differ between cases and controls. Sequencing of conserved GPR124 regions revealed a novel indel polymorphism in intron 2. Immunohistochemistry confirmed GPR124 expression in the endothelium with no qualitative difference in expression between BAVM cases and controls. SNP rs7015566 mapping to intron 1 of GPR124 was associated with BAVM susceptibility among Caucasians. Future work is focused on investigating this gene region.
PMCID: PMC3544200  PMID: 23329986
Angiogenesis; Genetics; Intracerebral hemorrhage; Risk factor; Vascular malformation
6.  A Genome-Wide Investigation of Copy Number Variation in Patients with Sporadic Brain Arteriovenous Malformation 
PLoS ONE  2013;8(10):e71434.
Brain arteriovenous malformations (BAVM) are clusters of abnormal blood vessels, with shunting of blood from the arterial to venous circulation and a high risk of rupture and intracranial hemorrhage. Most BAVMs are sporadic, but also occur in patients with Hereditary Hemorrhagic Telangiectasia, a Mendelian disorder caused by mutations in genes in the transforming growth factor beta (TGFβ) signaling pathway.
To investigate whether copy number variations (CNVs) contribute to risk of sporadic BAVM, we performed a genome-wide association study in 371 sporadic BAVM cases and 563 healthy controls, all Caucasian. Cases and controls were genotyped using the Affymetrix 6.0 array. CNVs were called using the PennCNV and Birdsuite algorithms and analyzed via segment-based and gene-based approaches. Common and rare CNVs were evaluated for association with BAVM.
A CNV region on 1p36.13, containing the neuroblastoma breakpoint family, member 1 gene (NBPF1), was significantly enriched with duplications in BAVM cases compared to controls (P = 2.2×10−9); NBPF1 was also significantly associated with BAVM in gene-based analysis using both PennCNV and Birdsuite. We experimentally validated the 1p36.13 duplication; however, the association did not replicate in an independent cohort of 184 sporadic BAVM cases and 182 controls (OR = 0.81, P = 0.8). Rare CNV analysis did not identify genes significantly associated with BAVM.
We did not identify common CNVs associated with sporadic BAVM that replicated in an independent cohort. Replication in larger cohorts is required to elucidate the possible role of common or rare CNVs in BAVM pathogenesis.
PMCID: PMC3789669  PMID: 24098321
7.  Mitochondrial DNA sequence variation is associated with free-living activity energy expenditure in the elderly 
Biochimica et Biophysica Acta  2012;1817(9):1691-1700.
The decline in activity energy expenditure underlies a range of age-associated pathological conditions, neuromuscular and neurological impairments, disability, and mortality. The majority (90%) of the energy needs of the human body are met by mitochondrial oxidative phosphorylation (OXPHOS). OXPHOS is dependent on the coordinated expression and interaction of genes encoded in the nuclear and mitochondrial genomes. We examined the role of mitochondrial genomic variation in free-living activity energy expenditure (AEE) and physical activity levels (PAL) by sequencing the entire (~16.5 kilobases) mtDNA from 138 Health, Aging, and Body Composition Study participants. Among the common mtDNA variants, the hypervariable region 2 m.185G>A variant was significantly associated with AEE (p=0.001) and PAL (p=0.0005) after adjustment for multiple comparisons. Several unique nonsynonymous variants were identified in the extremes of AEE with some occurring at highly conserved sites predicted to affect protein structure and function. Of interest is the p.T194M, CytB substitution in the lower extreme of AEE occurring at a residue in the Qi site of complex III. Among participants with low activity levels, the burden of singleton variants was 30% higher across the entire mtDNA and OXPHOS complex I when compared to those having moderate to high activity levels. A significant pooled variant association across the hypervariable 2 region was observed for AEE and PAL. These results suggest that mtDNA variation is associated with free-living AEE in older persons and may generate new hypotheses by which specific mtDNA complexes, genes, and variants may contribute to the maintenance of activity levels in late life.
PMCID: PMC3389152  PMID: 22659402
metabolic rate; energy expenditure; mitochondria; mtDNA; oxidative phosphorylation; DNA sequencing
8.  BDNF Val66Met Polymorphism Predicts Worse Functional Outcome After Surgery in Unruptured Brain Arteriovenous Malformation Patients 
Background and Purpose
The Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) is associated with decreased BDNF secretion and poor outcome after acute neurological injury. We hypothesized that the Met allele is associated with worsening of functional outcome after brain arteriovenous malformation (BAVM) resection.
341 surgically-treated BAVM patients with outcome data were genotyped for Val66Met. Outcome was change in modified Rankin Scale (mRS) preoperatively versus postoperatively, dichotomized into poor (change>0) or good outcome (change≤0). Likelihood ratio test for interactions and logistic regression analysis were performed.
A significant interaction (p=0.03) of Val66Met genotype and hemorrhagic presentation existed; thus, ruptured and unruptured patients were considered separately. The Met allele was associated with increased risk of poor outcome among patients presenting unruptured (OR=2.15, 95% CI=1.02–4.55, p=0.045) but not ruptured (OR=0.54, 95% CI=0.19–1.53, p=0.25), adjusting for covariates.
The Val66Met polymorphism is associated with worsened surgical outcome in unruptured BAVM patients, a group that currently has no good risk predictors. Further studies replicating these findings are needed.
PMCID: PMC3431194  PMID: 22773554
Brain-derived neurotrophic factor; Genetics; Arteriovenous Malformations; Outcomes; Surgery
9.  Brain arteriovenous malformation multiplicity predicts diagnosis of Hereditary Hemorrhagic Telangiectasia: Quantitative assessment 
To quantitatively estimate the relationship between multiplicity of brain arteriovenous malformations (bAVMs) and the diagnosis of hereditary hemorrhagic telangiectasia (HHT).
We combined databases from two large North American bAVM referral centers, including demographics, clinical presentation and angiographic characteristics, and compared HHT patients with non-HHT patients. Logistic regression analysis was performed to quantify the association between bAVM multiplicity and odds of HHT diagnosis. Sensitivity, specificity, positive and negative predictive value (PPV, NPV), and positive and negative likelihood ratios (LR) were calculated to determine accuracy of bAVM multiplicity for screening HHT.
Prevalence of HHT was 2.8% in the combined group. bAVM multiplicity was present in 39% of HHT patients and was highly associated with diagnosis of HHT in univariate (OR=83, 95% CI:40–173, P<0.0001) and multivariable (OR=87, 95% CI: 38–195, P<0.001) models, adjusting for age at presentation (P=0.013), non-symptomatic presentation (P=0.029) and cohort site (P=0.021). bAVM multiplicity alone was associated with high specificity (99.2%, 95%CI: 98.7–99.6%) and NPV (98.3%, 95% CI: 97.6–98.8%), and low sensitivity (39.3%, 95% CI: 26.5–53.2%) and PPV (59.5%, 95% CI: 42.1–75.2%). Positive and negative LR was 51 and 0.61, respectively, for diagnosis of HHT. HHT bAVMs were also more often smaller in size (<3 cm), non-eloquent in location and associated with superficial venous drainage, compared to non-HHT bAVMs.
Multiplicity of bAVMs is highly predictive of the diagnosis of HHT. The presence of multiple bAVMs should alert the clinician to the high probability of HHT and lead to comprehensive investigation for this diagnosis.
PMCID: PMC3727386  PMID: 22034007
arteriovenous malformation; hereditary hemorrhagic telangiectasia; brain
10.  Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity 
Aging cell  2009;8(4):460-472.
The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF), including 293 long-lived cases (lifespan ≥ 92 years (y), mean ± standard deviation (SD) = 95.3 ± 2.2y) and 603 average-lifespan controls (lifespan ≤ 79y, mean=75.7 ± 2.6y). Variants were selected for genotyping using a haplotype tagging approach. We found a modest excess of variants nominally associated with longevity. We then replicated nominally significant variants in two additional Caucasian cohorts containing both males and females: the Cardiovascular Health Study (CHS) and Ashkenazi Jewish Centenarians (AJC). An intronic single nucleotide polymorphism (SNP) in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (odds ratio (OR)=0.78 (95% confidence interval (CI)=0.68-0.89), adjusted p=0.043); two intronic SNPs in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR=1.35, 95% CI=1.15-1.57, adjusted p=0.0093). Conclusion: common variants in several insulin/IGF1 pathway genes are associated with human lifespan.
PMCID: PMC3652804  PMID: 19489743
IGF1; longevity; gene; SNP; AKT1; FOXO3A
11.  Mitochondrial DNA sequence variation and risk of pancreatic cancer 
Cancer Research  2011;72(3):686-695.
Although the mitochondrial genome exhibits high mutation rates, common mitochondrial DNA (mtDNA) variation has not been consistently associated with pancreatic cancer. Here, we comprehensively examined mitochondrial genomic variation by sequencing the mtDNA of participants (cases=286, controls=283) in a San Francisco Bay Area pancreatic cancer case-control study. Five common variants were associated with pancreatic cancer at nominal statistical significance (p<0.05) with the strongest finding for mt5460g in the ND2 gene (odds ratio (OR)=3.9, 95% confidence interval (CI)=1.5–10; p=0.004) which encodes an A331T substitution. Haplogroup K was nominally associated with reduced pancreatic cancer risk (OR = 0.32, CI=0.13–0.76; p=0.01) when compared with the most common haplogroup, H. A total of 19 haplogroup-specific rare variants yielded nominal statistically significant associations (p<0.05) with pancreatic cancer risk, with the majority observed in genes involved in oxidative phosphorylation. Weighted-sum statistics were used to identify an aggregate effect of variants in the 22 mitochondrial tRNAs on pancreatic cancer risk (p=0.02). While the burden of singleton variants in the HV2 and 12S RNA regions was three times higher among European haplogroup N cases than controls, the prevalence of singleton variants in ND4 and ND5 was two to three times higher among African haplogroup L cases than in controls. Together, the results of this study provide evidence that aggregated common and rare variants and the accumulation of singleton variants are important contributors to pancreatic cancer risk.
PMCID: PMC3271167  PMID: 22174369
Pancreatic cancer; mitochondrial DNA; oxidative phosphorylation; DNA sequencing; epidemiology
12.  Gene expression profiling of blood in brain arteriovenous malformation patients 
Translational stroke research  2011;2(4):575-587.
Brain arteriovenous malformations (BAVMs) are an important cause of intracranial hemorrhage (ICH) in young adults. Gene expression profiling of blood has led to the identification of stroke biomarkers, and may help identify BAVM biomarkers and illuminate BAVM pathogenesis. It is unknown whether blood gene expression profiles differ between 1) BAVM patients and healthy controls, or 2) unruptured and ruptured BAVM patients at presentation. We characterized blood transcriptional profiles in 60 subjects (20 unruptured BAVM, 20 ruptured BAVM, and 20 healthy controls) using Affymetrix whole genome expression arrays. Expression differences between groups were tested by ANOVA, adjusting for potential confounders. Genes with absolute fold change ≥ 1.2 (false discovery rate corrected p ≤ 0.1) were selected as differentially expressed and evaluated for over-representation in KEGG biological pathways (p ≤ 0.05). Twenty-nine genes were differentially expressed between unruptured BAVM patients and controls, including 13 which may be predictive of BAVM. Patients with ruptured BAVM compared to unruptured BAVM differed in expression of 1490 genes, with over-representation of genes in 8 pathways including MAPK, VEGF, Wnt signaling and several inflammatory pathways. These results suggest clues to the pathogenesis of BAVM and/or BAVM rupture and point to potential biomarkers or new treatment targets.
PMCID: PMC3241209  PMID: 22184505
arteriovenous malformation; blood; gene expression; intracranial hemorrhage; microarray analysis
13.  Contemporary Human Genetic Strategies in Aging Research 
Ageing research reviews  2010;10(2):191-200.
Human aging is a complex, multifactorial process influenced by a number of genetic and non-genetic factors. This article first reviews genetic strategies for human aging research and considers the advantages and disadvantages of each. We then discuss the issue of phenotypic definition for genetic studies of aging, including longevity/life span, as well as disease-free survival and other endophenotypes. Finally, we argue that extensions of this area of research, including incorporation of gene × environment interactions, multivariate phenotypes, integration of functional genomic annotations, and exploitation of orthology – many of which are already initiated and ongoing – are critical to advancing this field.
PMCID: PMC3043164  PMID: 20709627
14.  Angiopoietin-Like 4 (ANGPTL4) Gene Polymorphisms and Risk of Brain Arteriovenous Malformations 
Brain arteriovenous malformations (BAVM) are high-flow vascular lesions prone to intracranial hemorrhage (ICH). Abnormal angiogenesis is a key characteristic of BAVM tissue. Angiopoietin-like 4 (ANGPTL4), a secreted glycoprotein, is thought to be involved in angiogenesis and required for proper postnatal blood vessel partitioning. We investigated whether common single nucleotide polymorphisms (SNPs) in ANGPTL4 were associated with risk of BAVM or ICH.
Methods and Results
We conducted a case-control study of 216 Caucasian BAVM cases and 246 healthy controls, and a secondary case-only analysis, comparing 83 ruptured (ICH) with 133 unruptured BAVM cases at presentation. Four tagSNPs in ANGPTL4 captured variation over a 10-kb region (rs2278236, rs1044250, rs11672433, and rs1808536) and were tested for association with BAVM or ICH. The minor allele (A) of rs11672433 (exon 6, Pro389Pro) was associated with an increased risk of BAVM (p = 0.006), which persisted after adjusting for multiple comparisons (p = 0.03). After adjustments for age and sex, carriers of the minor allele (A) remained at higher risk for BAVM compared to noncarriers (odds ratio, OR = 1.56; 95% confidence interval, CI = 1.01–2.41; p = 0.046) and risk of BAVM was increased with increasing copy of the minor A allele (OR = 1.49, 95% CI = 1.03–2.15; ptrend = 0.03). Five common haplotypes (frequency >1%) were inferred; overall haplotype distribution differed between BAVM cases and controls (χ2 = 12.2, d.f. = 4, p = 0.02). Neither SNPs (p > 0.05) nor haplotype distribution (χ2 = 1.1, d.f. = 4, p = 0.89) were associated with risk of ICH among BAVM cases.
A synonymous SNP in ANGPTL4 and haplotypes carrying it are associated with risk of BAVM but not with ICH presentation in BAVM cases.
PMCID: PMC3030504  PMID: 21212665
Arteriovenous malformations; Cerebrovascular disorders; Epidemiology; Genetics; Intracranial hemorrhage
15.  Single Nucleotide Polymorphisms in the Beta-adrenergic Receptor Genes are Associated with Lung Allograft Utilization 
Pulmonary edema and associated impaired oxygenation are a major reason for rejection of donor lung allografts offered for transplantation. Clearance of pulmonary edema can be up-regulated by stimulation of ϐ adrenergic receptors (ϐAR). Single nucleotide polymorphisms (SNPs) in ϐAR genes have functional effects in vitro and in vivo. We hypothesized that SNPs in ϐAR genes would be associated with rates of utilization of donor lung allografts offered for transplantation.
951 organ donors were genotyped for 4 amino-acid coding SNPs in the ϐAR genes. Lung allograft utilization was compared among donors stratified by genotypes.
Utilization of donor lung allografts was 55% vs. 35% (p = 0.02) among donors with GG vs. AA/AG genotypes of the Ser49Gly SNP, 39% vs. 32% (p = 0.04) with GG vs. AA/AG genotype of Gly16Arg SNP and 37% vs. 32% (p = 0.1) with CC vs. GC/GG genotype of the Arg389Gly SNP. In combined analysis, donors carrying 0–1 associated genotypes had a utilization rate of 33%, whereas donors carrying two or three associated genotypes had utilization rate of 44% and 58% respectively (p=0.008). There was a stepwise decrease in chest radiograph infiltrates and increase in the PaO2/FiO2 with increasing number of these associated genotypes.
Genetic variants in the ϐAR genes among organ donors are associated with higher rates of lung allograft utilization. The increased utilization may be related to increased clearance of pulmonary edema and improved oxygenation in donors with favorable genotypes and suggests ϐAR agonists may have a role in donor management.
PMCID: PMC3019270  PMID: 20869266
16.  Brain Arteriovenous Malformation Pathogenesis: A Response-to-Injury Paradigm 
Brain arteriovenous malformations (AVMs) are a rare but important cause of intracranial hemorrhage (ICH) in young adults. In this paper, we review both human and animal studies of brain AVM, focusing on the: (1) natural history of AVM hemorrhage; (2) genetic and expression studies of AVM susceptibility and hemorrhage; and (3) strategies for development of a brain AVM model in adult mice. These data target various mechanisms which must act in concert to regulate normal angiogenic response to injury. Based on the various lines of evidence reviewed in this paper, we propose a “response-to-injury” model of brain AVM pathogenesis.
PMCID: PMC3187860  PMID: 21725736
Brain arteriovenous malformations; Intracranial hemorrhage; Gene expression; Genetics; Angiogenesis; Inflammation; Animal models
17.  Differences in presentation and progression between severe FIC1 and BSEP deficiencies 
Journal of hepatology  2010;53(1):170-178.
Background & Aims
Progressive familial intrahepatic cholestasis (PFIC) with normal serum levels of gamma-glutamyltranspeptidase can result from mutations in ATP8B1 (encoding familial intrahepatic cholestasis 1 [FIC1]) or ABCB11 (encoding bile salt export pump [BSEP]). We evaluated clinical and laboratory features of disease in patients diagnosed with PFIC, who carried mutations in ATP8B1 (FIC1 deficiency) or ABCB11 (BSEP deficiency). Our goal was to identify features that distinguish presentation and course of these 2 disorders, thus facilitating diagnosis and elucidating the differing consequences of ATP8B1 and ABCB11 mutations.
A retrospective multi-center study was conducted, using questionnaires and chart review. Available clinical and biochemical data from 145 PFIC patients with mutations in either ATP8B1 (61 “FIC1 patients”) or ABCB11 (84 “BSEP patients”) were evaluated.
At presentation, serum aminotransferase and bile salt levels were higher in BSEP patients; serum alkaline phosphatase values were higher, and serum albumin values were lower, in FIC1 patients. Elevated white blood cell counts, and giant or multinucleate cells at liver biopsy, were more common in BSEP patients. BSEP patients more often had gallstones and portal hypertension. Diarrhea, pancreatic disease, rickets, pneumonia, abnormal sweat tests, hearing impairment, and poor growth were more common in FIC1 patients. Among BSEP patients, the course of disease was less rapidly progressive in patients bearing the D482G mutation.
Severe forms of FIC1 and BSEP deficiency differed. BSEP patients manifested more severe hepatobiliary disease, while FIC1 patients showed greater evidence of extrahepatic disease.
PMCID: PMC3042805  PMID: 20447715
cholestasis; genetics; transport protein; pediatrics; P-type ATPase; ATP binding cassette protein; ATP8B1; FIC1; ABCB11; BSEP
18.  GWAS for discovery and replication of genetic loci associated with sudden cardiac arrest in patients with coronary artery disease 
Epidemiologic evidence suggests a heritable component to risk for sudden cardiac arrest independent of risk for myocardial infarction. Recent candidate gene association studies for community sudden cardiac arrests have focused on a limited number of biological pathways and yielded conflicting results. We sought to identify novel gene associations for sudden cardiac arrest in patients with coronary artery disease by performing a genome-wide association study.
Tagging SNPs (n = 338,328) spanning the genome were typed in a case-control study comparing 89 patients with coronary artery disease and sudden cardiac arrest due to ventricular tachycardia or ventricular fibrillation to 520 healthy controls.
Fourteen SNPs including 7 SNPs among 7 genes (ACYP2, AP1G2, ESR1, DGES2, GRIA1, KCTD1, ZNF385B) were associated with sudden cardiac arrest (all p < 1.30 × 10-7), following Bonferroni correction and adjustment for population substructure, age, and sex; genetic variation in ESR1 (p = 2.62 × 10-8; Odds Ratio [OR] = 1.43, 95% confidence interval [CI]:1.277, 1.596) has previously been established as a risk factor for cardiovascular disease. In tandem, the role of 9 genes for monogenic long QT syndrome (LQT1-9) was assessed, yielding evidence of association with CACNA1C (LQT8; p = 3.09 × 10-4; OR = 1.18, 95% CI:1.079, 1.290). We also assessed 4 recently published gene associations for sudden cardiac arrest, validating NOS1AP (p = 4.50 × 10-2, OR = 1.15, 95% CI:1.003, 1.326), CSMD2 (p = 6.6 × 10-3, OR = 2.27, 95% CI:1.681, 2.859), and AGTR1 (p = 3.00 × 10-3, OR = 1.13, 95% CI:1.042, 1.215).
We demonstrate 11 gene associations for sudden cardiac arrest due to ventricular tachycardia/ventricular fibrillation in patients with coronary artery disease. Validation studies in independent cohorts and functional studies are required to confirm these associations.
PMCID: PMC3141757  PMID: 21658281
19.  Association of TGFBR2 Polymorphism with Risk of Sudden Cardiac Arrest in Patients with Coronary Artery Disease 
Transforming growth factor β (TGFβ) signaling has been shown to promote myocardial fibrosis and remodeling with coronary artery disease (CAD), and previous studies demonstrate a major role for fibrosis in the initiation of malignant ventricular arrhythmias (VA) and sudden cardiac arrest (SCA). Common single nucleotide polymorphisms (SNPs) in TGFß pathway genes may be associated with SCA.
We examined the association of common SNPs among 12 candidate genes in the TGFß pathway with the risk of SCA.
SNPs (n=617) were genotyped in a case-control study comparing 89 patients with CAD and SCA due to VA to 520 healthy controls.
Nineteen SNPs among 5 genes (TGFB2, TGFBR2, SMAD1, SMAD3, SMAD6) were associated with SCA after adjustment for age and sex. After permutation analysis to account for multiple testing, a single SNP in TGFBR2 (rs9838682) was associated with SCA (OR = 1.66, 95% CI = 1.08-2.54, p=0.02).
We demonstrate an association between a common TGFBR2 polymorphism and risk of SCA due to VA in the setting of CAD. If validated, these findings support the role of genetic variation in TGFß signaling in SCA susceptibility.
PMCID: PMC2789271  PMID: 19959123
Sudden cardiac arrest; ventricular tachycardia; ventricular fibrillation; coronary artery disease; transforming growth factor ß; genetics
20.  Is Altered Expression of Hepatic Insulin-Related Genes in Growth Hormone Receptor Knockout Mice Due to GH Resistance or a Difference in Biological Life Spans? 
Growth hormone receptor knockout (GHRKO) mice live about 40%–55% longer than their normal (N) littermates. Previous studies of 21-month-old GHRKO and N mice showed major alterations of the hepatic expression of genes involved in insulin signaling. Differences detected at this age may have been caused by the knockout of the growth hormone receptor (GHR) or by differences in biological age between GHRKO and N mice. To address this question, we compared GHRKO and N mice at ages corresponding to the same percentage of median life span to see if the differences of gene expression persisted. Comparison of GHRKO and N mice at ∼50% of biological life span showed significant differences in hepatic expression of all 14 analyzed genes. We conclude that these changes are due to disruption of GHR gene and the consequent suppression of growth hormone signaling rather than to differences in “biological age” between mutant and normal animals sampled at the same chronological age.
PMCID: PMC2759569  PMID: 19706698
Aging; GHRKO; Insulin
21.  EPH Receptor B4 (EPHB4) Gene Polymorphisms and Risk of Intracranial Hemorrhage in Patients with Brain Arteriovenous Malformations 
Brain arteriovenous malformations (BAVM) are a tangle of abnormal vessels directly shunting blood from the arterial to venous circulation and an important cause of intracranial hemorrhage (ICH). EphB4 is involved in arterial-venous determination during embryogenesis; altered signaling could lead to vascular instability resulting in ICH. We investigated the association of single-nucleotide polymorphisms (SNPs) and haplotypes in EPHB4 with risk of ICH at clinical presentation in BAVM patients.
Methods and Results
Eight haplotype-tagging SNPs spanning ∼29 kb were tested for association with ICH presentation in 146 Caucasian BAVM patients (phase I: 56 ICH, 90 non-ICH) using allelic, haplotypic, and principal components analysis. Associated SNPs were then genotyped in 102 additional cases (phase II: 37 ICH, 65 non-ICH) and data combined for multivariable logistic regression. Minor alleles of 2 SNPs were associated with reduced risk of ICH presentation (rs314313 C, P=0.005; rs314308 T, P=0.0004). Overall, haplotypes were also significantly associated with ICH presentation (χ2=17.24, 6 df, P=0.008); 2 haplotypes containing the rs314308 T allele (GCCTGGGT, P=0.003; GTCTGGGC, P=0.036) were associated with reduced risk. In principal components analysis, 2 components explained 91% of the variance, and complemented haplotype results by implicating 4 SNPs at the 5′ end, including rs314308 and rs314313. These 2 SNPs were replicated in the phase II cohort, and combined data resulted in greater significance (rs314313, P=0.0007; rs314308, P=0.00008). SNP association with ICH presentation persisted after adjusting for age, sex, BAVM size, and deep venous drainage.
EPHB4 polymorphisms are associated with risk of ICH presentation in BAVM patients, warranting further study.
PMCID: PMC2939745  PMID: 20031623
cerebrovascular disorders; genetics; hemorrhage; receptors; risk factors
22.  A Common Variant in the Telomerase RNA Component Is Associated with Short Telomere Length 
PLoS ONE  2010;5(9):e13048.
Telomeres shorten as cells divide. This shortening is compensated by the enzyme telomerase. We evaluated the effect of common variants in the telomerase RNA component (TERC) gene on telomere length (TL) in the population-based Health Aging and Body Composition (Health ABC) Study and in two replication samples (the TwinsUK Study and the Amish Family Osteoporosis Study, AFOS).
Five variants were identified in the TERC region by sequence analysis and only one SNP was common (rs2293607, G/A). The frequency of the G allele was 0.26 and 0.07 in white and black, respectively. Testing for association between TL and rs2293607 was performed using linear regression models or variance component analysis conditioning on relatedness among subjects.
The adjusted mean TL was significantly shorter in 665 white carriers of the G allele compared to 887 non-carriers from the Health ABC Study (4.69±0.05 kbp vs. 4.86±0.04 kbp, measured by quantitative PCR, p = 0.005). This association was replicated in another white sample from the TwinsUK Study (6.90±0.03 kbp in 301 carriers compared to 7.06±0.03 kbp in 395 non-carriers, measured by Southern blots, p = 0.009). A similar pattern of association was observed in whites from the family-based AFOS and blacks from the Health ABC cohort, although not statistically significant, possibly due to the lower allele frequency in these populations. Combined analysis using 2,953 white subjects from 3 studies showed a significant association between TL and rs2293607 (β = −0.19±0.04 kbp, p = 0.001).
Our study shows a significant association between a common variant in TERC and TL in humans, suggesting that TERC may play a role in telomere homeostasis.
PMCID: PMC2946401  PMID: 20885959
Experimental gerontology  2009;44(5):350-355.
Interleukin-6 (IL-6) is an inflammatory cytokine that influences the development of inflammatory and aging-related disorders and ultimately longevity. In order to study the influence of variants in genes that regulate inflammatory response on IL-6 levels and longevity, we screened a panel of 477 tag SNPs across 87 candidate genes in >5,000 older participants from the population-based Cardiovascular Health Study (CHS). Baseline plasma IL-6 concentration was first confirmed as a strong predictor of all-cause mortality. Functional alleles of the IL6R and PARP1 genes were significantly associated with 15%-20% higher baseline IL-6 concentration per copy among CHS European-American (EA) participants (all p<10−4). In a case/control analysis nested within this EA cohort, the minor allele of PARP1 rs1805415 was nominally associated with decreased longevity (p=0.001), but there was no evidence of association between IL6R genotype and longevity. The PARP1 rs1805415 – longevity association was subsequently replicated in one of two independent case/control studies. In a pooled analysis of all 3 studies, the “risk” of longevity associated with the minor allele of PARP1 rs1805415 was 0.79 (95%CI 0.62 – 1.02; p=0.07). These findings warrant further study of the potential role of PARP1 genotype in inflammatory and aging-related phenotypes.
PMCID: PMC2791897  PMID: 19249341
Inflammation; IL-6; PARP1; Longevity; Genetic Epidemiology
24.  Brain arteriovenous malformation biology relevant to hemorrhage and implication for therapeutic development 
Stroke; a journal of cerebral circulation  2008;40(3 Suppl):S95-S97.
Brain arteriovenous malformations (AVM) cause intracranial hemorrhage (ICH). Molecular characterization of lesional tissue implicates angiogenic (VEGF, ANG-2, MMP-9) and inflammatory (cytokines and chemokines) pathways, but the pathogenesis remain obscure and medical therapy is lacking. Macrophage and neutrophil invasion has also been observed in the absence of prior ICH. Single nucleotide polymorphisms (SNPs) in interleukin-1β (IL-1β) and activin receptor-like kinase-1 (ALK-1) are associated with AVM susceptibility, and SNPs in IL-1β, IL-6, TNF-α and APOE are associated with AVM rupture. These observations suggest that even without a complete understanding of the determinants of AVM development, the recent discoveries of downstream derangements in vascular function and integrity may offer potential targets for therapy development. Further, biomarkers can be established for assessing ICH risk. Finally, these data will aid in development of model systems for mechanistic testing, by development of surrogate phenotypes (microvascular dysplasia) and/or models recapitulating the clinical syndrome of recurrent spontaneous ICH.
PMCID: PMC2677752  PMID: 19064791
angiogenesis; inflammation; vascular malformations
25.  Strain Background Modifies Phenotypes in the ATP8B1-Deficient Mouse 
PLoS ONE  2010;5(2):e8984.
Mutations in ATP8B1 (FIC1) underlie cases of cholestatic disease, ranging from chronic and progressive (progressive familial intrahepatic cholestasis) to intermittent (benign recurrent intrahepatic cholestasis). The ATP8B1-deficient mouse serves as an animal model of human ATP8B1 deficiency.
Methodology/Principal Findings
We investigated the effect of genetic background on phenotypes of ATP8B1-deficient and wild-type mice, using C57Bl/6 (B6), 129, and (B6-129) F1 strain backgrounds. B6 background resulted in greater abnormalities in ATP8B1-deficient mice than did 129 and/or F1 background. ATP8B1-deficient pups of B6 background gained less weight. In adult ATP8B1-deficient mice at baseline, those of B6 background had lower serum cholesterol levels, higher serum alkaline phosphatase levels, and larger livers. After challenge with cholate-supplemented diet, these mice exhibited higher serum alkaline phosphatase and bilirubin levels, greater weight loss and larger livers. ATP8B1-deficient phenotypes in mice of F1 and 129 backgrounds are usually similar, suggesting that susceptibility to manifestations of ATP8B1 deficiency may be recessive. We also detected differences in hepatobiliary phenotypes between wild-type mice of differing strains.
Our results indicate that the ATP8B1-deficient mouse in a B6 background may be a better model of human ATP8B1 deficiency and highlight the importance of informed background strain selection for mouse models of liver disease.
PMCID: PMC2813882  PMID: 20126555

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