Brooke A. Kennedy
University of Western Ontario
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Brooke A. Kennedy.
WOS | 2013
Christopher T. Johansen; Jian Wang; Matthew B. Lanktree; Henian Cao; Adam D. McIntyre; Matthew R. Ban; Rebecca A. Martins; Brooke A. Kennedy; Reina G. Hassell; Maartje E. Visser; Stephen M. Schwartz; Benjamin F. Voight; Roberto Elosua; Veikko Salomaa; Christopher J. O'Donnell; Geesje M. Dallinga-Thie; Sonia S. Anand; Salim Yusuf; Murray W. Huff; Sekar Kathiresan; Robert A. Hegele
Genome-wide association studies (GWAS) have identified multiple loci associated with plasma lipid concentrations. Common variants at these loci together explain <10% of variation in each lipid trait. Rare variants with large individual effects may also contribute to the heritability of lipid traits; however, the extent to which rare variants affect lipid phenotypes remains to be determined. Here we show an accumulation of rare variants, or a mutation skew, in GWAS-identified genes in individuals with hypertriglyceridemia (HTG). Through GWAS, we identified common variants in APOA5, GCKR, LPL and APOB associated with HTG. Resequencing of these genes revealed a significant burden of 154 rare missense or nonsense variants in 438 individuals with HTG, compared to 53 variants in 327 controls (P = 6.2 × 10−8), corresponding to a carrier frequency of 28.1% of affected individuals and 15.3% of controls (P = 2.6 × 10−5). Considering rare variants in these genes incrementally increased the proportion of genetic variation contributing to HTG.
Human Molecular Genetics | 2008
Jian Wang; Matthew R. Ban; Guangyong Zou; Henian Cao; Tim Lin; Brooke A. Kennedy; Sonia S. Anand; Salim Yusuf; Murray W. Huff; Rebecca L. Pollex; Robert A. Hegele
Recent genome-wide association (GWA) studies have identified new genetic determinants of complex quantitative traits, including plasma triglyceride (TG). We hypothesized that common variants associated with mild TG variation identified in GWA studies would also be associated with severe hypertriglyceridemia (HTG). We studied 132 patients of European ancestry with severe HTG (fasting plasma TG > 10 mmol/l), who had no mutations found by resequencing of candidate genes, and 351 matched normolipidemic controls. We determined genotypes for: GALNT2 rs4846914, TBL2/MLXIPL rs17145738, TRIB1 rs17321515, ANGPTL3 rs12130333, GCKR rs780094, APOA5 rs3135506 (S19W), APOA5 rs662799 (-1131T > C), APOE (isoforms) and LPL rs328 (S447X). We found that: (i) genotypes, including those of APOA5 S19W, APOA5 -1131T > C, APOE, GCKR, TRIB1 and TBL2/MLXIPL, were significantly associated with severe HTG; (ii) odds ratios for these genetic variables were significant in both univariate and multivariate regression analyses, irrespective of the presence or absence of diabetes or obesity; (iii) a significant fraction-about one-quarter-of the explained variation in disease status was associated with these genotypes. Therefore, common SNPs (single nucleotide polymorphisms) that are associated with mild TG variation in GWA studies of normolipidemic subjects are also associated with severe HTG. Our findings are consistent with the emerging model of a complex genetic trait. At the extremes of a quantitative trait, such as severe HTG, are found the cumulative contributions of both multiple rare alleles with large genetic effects and common alleles with small effects.
Arteriosclerosis, Thrombosis, and Vascular Biology | 2007
Jian Wang; Henian Cao; Matthew R. Ban; Brooke A. Kennedy; Siqi Zhu; Sonia S. Anand; Salim Yusuf; Rebecca L. Pollex; Robert A. Hegele
Objective—The genetic determinants of severe hypertriglyceridemia (HTG; MIM 144650) in adults are poorly defined. We therefore resequenced 3 candidate genes, namely LPL, APOC2, and APOA5, to search for accumulation of missense mutations in patients with severe HTG compared with normolipidemic subjects. Methods and Results—We resequenced >2 million base pairs of genomic DNA from 110 nondiabetic patients with severe HTG and determined the prevalence of coding sequence variants compared with 472 age- and sex-matched normolipidemic controls. We found: (1) heterozygous mutations (LPL p.Q-12E >11X, p.D25H, p.W86R, p.G188E, p.I194T and p.P207L; APOC2 p.K19T and IVS2–30G>A) in 10.0% of severe HTG patients compared with 0.2% of controls (carrier odds ratio [OR] 52, 95% confidence interval [CI] 8.6 to 319); and (2) an association of the APOA5 p.S19W missense variant with severe HTG (carrier OR 5.5 95% CI 3.3 to 9.1). Furthermore, either rare mutations or the APOA5 p.S19W variant were found in 41.8% of HTG subjects compared with 8.9% of controls (carrier OR 7.4, 95% CI 4.5 to 12.0). Also, heterozygotes for rare mutations had a significantly reduced plasma triglyceride response to fibrate monotherapy. Conclusions—Both common and rare DNA variants in candidate genes were found in a substantial proportion of severe HTG patients. The findings underscore the value of candidate gene resequencing to understand the genetic contribution in complex lipoprotein and metabolic disorders.
Human Molecular Genetics | 2009
Robert A. Hegele; Matthew R. Ban; Neil Hsueh; Brooke A. Kennedy; Henian Cao; Guangyong Zou; Sonia S. Anand; Salim Yusuf; Murray W. Huff; Jian Wang
Numerous single nucleotide polymorphisms (SNPs) have been found in recent genome wide association studies (GWAS) to be associated with subtle plasma triglyceride (TG) variation in normolipidemic subjects. However, since these GWAS did not specifically evaluate patients with rare disorders of lipoprotein metabolism—‘hyperlipoproteinemia’ (HLP)—it remains largely unresolved whether any of these SNP determinants of modest physiological changes in TG are necessarily also determinants of most HLP phenotypes. To address this question, we evaluated 28 TG-associated SNPs from GWAS in 386 unrelated adult patients with one of five Fredrickson phenotypes (HLP types 2A, 2B, 3, 4 and 5) and 242 matched normolipidemic controls. We found that several SNPs associated with TG in normolipidemic samples, including APOA5 p.S19W and -1131T>C, TRIB1 rs17321515, TBL2 rs17145738, GCKR rs780094, GALNT2 rs4846914 and ANGPTL3 rs12130333, were significantly associated with HLP types 2B, 3, 4 and 5. The findings indicate that: (i) the TG-associated Fredrickson HLP types 2B, 3, 4 and 5 are polygenic traits; (ii) these Fredrickson HLP types share numerous genetic determinants among themselves; and (iii) genetic determinants of modest TG variation in normolipidemic population samples also underlie—to an apparently even greater degree—susceptibility to these rare HLP phenotypes. Thus, the TG-associated Fredrickson HLP types 2B, 3, 4 and 5, although historically considered to be distinct are actually complex traits sharing among them several common genetic determinants seen in GWAS of normolipidemic population samples.
Nature Reviews Cardiology | 2008
Jian Wang; Matthew R. Ban; Brooke A. Kennedy; Sonia S. Anand; Salim Yusuf; Murray W. Huff; Rebecca L. Pollex; Robert A. Hegele
Background Several known candidate gene variants are useful markers for diagnosing hyperlipoproteinemia. In an attempt to identify other useful variants, we evaluated the association of two common APOA5 single-nucleotide polymorphisms across the range of classic hyperlipoproteinemia phenotypes.Methods We assessed plasma lipoprotein profiles and APOA5 S19W and −1131T>C genotypes in 678 adults from a single tertiary referral lipid clinic and in 373 normolipidemic controls matched for age and sex, all of European ancestry.Results We observed significant stepwise relationships between APOA5 minor allele carrier frequencies and plasma triglyceride quartiles. The odds ratios for hyperlipoproteinemia types 2B, 3, 4 and 5 in APOA5 S19W carriers were 3.11 (95% CI 1.63–5.95), 4.76 (2.25–10.1), 2.89 (1.17–7.18) and 6.16 (3.66–10.3), respectively. For APOA5 −1131T>C carriers, the odds ratios for these hyperlipoproteinemia subtypes were 2.23 (95% CI 1.21–4.08), 3.18 (1.55–6.52), 3.95 (1.85–8.45) and 4.24 (2.64–6.81), respectively. The overall odds ratio for the presence of either allele in lipid clinic patients was 2.58 (95% CI 1.89–3.52).Conclusions A high proportion of patients with four classic hyperlipoproteinemia phenotypes are carriers of either the APOA5 S19W or −1131T>C variant or both. These two variants are robust genetic biomarkers of a range of clinical hyperlipoproteinemia phenotypes linked by hypertriglyceridemia.
Arteriosclerosis, Thrombosis, and Vascular Biology | 2011
Christopher T. Johansen; Jian Wang; Matthew B. Lanktree; Adam D. McIntyre; Matthew R. Ban; Rebecca A. Martins; Brooke A. Kennedy; Reina G. Hassell; Maartje E. Visser; Stephen M. Schwartz; Benjamin F. Voight; Roberto Elosua; Veikko Salomaa; Christopher J. O'Donnell; Geesje M. Dallinga-Thie; Sonia S. Anand; Salim Yusuf; Murray W. Huff; Sekar Kathiresan; Henian Cao; Robert A. Hegele
Objective—Earlier studies have suggested that a common genetic architecture underlies the clinically heterogeneous polygenic Fredrickson hyperlipoproteinemia (HLP) phenotypes defined by hypertriglyceridemia (HTG). Here, we comprehensively analyzed 504 HLP-HTG patients and 1213 normotriglyceridemic controls and confirmed that a spectrum of common and rare lipid-associated variants underlies this heterogeneity. Methods and Results—First, we demonstrated that genetic determinants of plasma lipids and lipoproteins, including common variants associated with plasma triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from the Global Lipids Genetics Consortium were associated with multiple HLP-HTG phenotypes. Second, we demonstrated that weighted risk scores composed of common TG-associated variants were distinctly increased across all HLP-HTG phenotypes compared with controls; weighted HDL-C and LDL-C risk scores were also increased, although to a less pronounced degree with some HLP-HTG phenotypes. Interestingly, decomposition of HDL-C and LDL-C risk scores revealed that pleiotropic variants (those jointly associated with TG) accounted for the greatest difference in HDL-C and LDL-C risk scores. The APOE E2/E2 genotype was significantly overrepresented in HLP type 3 versus other phenotypes. Finally, rare variants in 4 genes accumulated equally across HLP-HTG phenotypes. Conclusion—HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants.
Metabolism-clinical and Experimental | 2009
Tisha Joy; Brooke A. Kennedy; Salam A. Al-Attar; Brian K. Rutt; Robert A. Hegele
The objective of the study was to determine correlations between magnetic resonance imaging (MRI) measures of truncal adiposity (trunk fat percentage [TrF %(MRI)], visceral adipose tissue [VAT], and subcutaneous abdominal adipose tissue [SAT]), simple clinical measures (body mass index [BMI], waist circumference [WC], and waist-to-hip ratio [WHR]), and bioelectrical impedance analysis (BIA)-derived measures (total fat percentage [TF %] and TrF %(BIA)) in female patients with familial partial lipodystrophy (FPLD). Our secondary aim was to generate and cross-validate predictive equations for VAT and SAT using these simple clinical and BIA-derived variables. Measures of truncal adiposity were measured using 1.5-T MRI (VAT, SAT, and TrF %(MRI)) and Tanita (Tokyo, Japan) 8-electrode body composition analyzer BC-418 (TrF %(BIA)) in 13 female FPLD patients. Pearson correlation coefficients were determined among the various adiposity parameters (BMI, WC, WHR, SAT, VAT, TrF %(MRI), TrF %(BIA), and TF %). Equations to estimate VAT and SAT were determined among 6 of the 13 FPLD subjects using multilinear regression analysis, and the best equations were then cross-validated in the remaining 7 subjects. Variables entered into the model included age, BMI, WC, WHR, TrF %(BIA), and TF %. The TrF %(MRI) showed moderate correlation (r = 0.647, P = .02) with the TrF %(BIA), but the discrepancy between the 2 variables increased with increasing truncal adiposity. The strongest correlate for TrF %(MRI) was BMI (r = 0.886, P < .0001). Visceral adipose tissue was poorly associated with simple clinical measures of BMI, WC, and WHR, but was inversely correlated with TF %, TrF %(BIA), and SAT. The TF % was the strongest correlate for both SAT and VAT. Thus, the best regression equation for VAT included age, BMI, WC, and TF % (R(2) = 1.0), whereas that for SAT only included TF % (R(2) = 0.75). The corresponding standard error of the estimate for the predictive equations was approximately 0.03 % and 18.5 % of the mean value of VAT and SAT, respectively. In the cross-validation study, differences between predicted and observed values of SAT were larger than those of VAT. We conclude that, among female FPLD patients, (1) no simple clinical anthropometric measure correlates well with VAT, whereas BMI correlates well with SAT; (2) BIA measure of TF % most strongly correlated with both VAT and SAT; and (3) based on the cross-validation study, VAT but not SAT could be more reliably estimated using the regression equations derived.
Circulation-cardiovascular Genetics | 2015
Joseph B. Dubé; Jian Wang; Henian Cao; Adam D. McIntyre; Christopher T. Johansen; Scarlett E. Hopkins; Randa Stringer; Siyavash Hosseinzadeh; Brooke A. Kennedy; Matthew R. Ban; T. Kue Young; Philip W. Connelly; Eric Dewailly; Peter Bjerregaard; Bert B. Boyer; Robert A. Hegele
Background—Inuit are considered to be vulnerable to cardiovascular disease because their lifestyles are becoming more Westernized. During sequence analysis of Inuit individuals at extremes of lipid traits, we identified 2 nonsynonymous variants in low-density lipoprotein receptor (LDLR), namely p.G116S and p.R730W. Methods and Results—Genotyping these variants in 3324 Inuit from Alaska, Canada, and Greenland showed they were common, with allele frequencies 10% to 15%. Only p.G116S was associated with dyslipidemia: the increase in LDL cholesterol was 0.54 mmol/L (20.9 mg/dL) per allele (P=5.6×10−49), which was >3× larger than the largest effect sizes seen with other common variants in other populations. Carriers of p.G116S had a 3.02-fold increased risk of hypercholesterolemia (95% confidence interval, 2.34–3.90; P=1.7×10−17), but did not have classical familial hypercholesterolemia. In vitro, p.G116S showed 60% reduced ligand-binding activity compared with wild-type receptor. In contrast, p.R730W was associated with neither LDL cholesterol level nor altered in vitro activity. Conclusions—LDLR p.G116S is thus unique: a common dysfunctional variant in Inuit whose large effect on LDL cholesterol may have public health implications.Inuit were long-believed to have lower CVD risk than non-indigenous populations.1–3 However, re-evaluation of population studies indicates that ischemic heart disease rates are similar between Inuit and non-Indigenous people.4 Furthermore, ongoing Westernization in many Inuit communities has intensified their exposure to CVD risk factors such as smoking, calorie-dense processed foods, and a more comfortable but also sedentary lifestyle, all of which affect CVD risk and prevalence.4–10 Among classical CVD risk factors, Inuit adults tend to have higher plasma concentrations of LDL cholesterol than non-indigenous populations.11–15 The predominant monogenic cause of elevated LDL cholesterol concentration in most global populations is familial hypercholesterolemia (FH, Online Mendelian Inheritance in Man [OMIM] 143890).16 Heterozygous FH (HeFH) prevalence may be as high as 1:200 in certain European populations, and it is a potent predisposition state for early CVD.11–13 To date, DNA sequencing and biochemical studies have identified >1,600 rare loss-of-function mutations in the gene encoding the LDL receptor (LDLR), which can increase LDL cholesterol levels by 100% or more, and underlie >95% of cases of molecularly diagnosed FH.16 But despite the relatively high levels of LDL cholesterol observed in some Inuit, the role of LDLR gene variation has not been systematically studied.13–15 We thus investigated the LDLR locus in Inuit and tested for association of variants therein with plasma lipids. Through Sanger sequencing and targeted genotyping, we found two new LDLR variants common to five Inuit subgroups from across North America and Greenland: 1) p.G116S was both dysfunctional in vitro and associated with a relatively large increase in plasma LDL cholesterol levels; while 2) p.R730W had minimal dysfunction and impact on the lipid profile.
Journal of investigative medicine high impact case reports | 2018
Uththara Perera; Brooke A. Kennedy; Robert A. Hegele
Background. Multiple symmetric lipomatosis (MSL), also known as Madelung disease, is a rare adult-onset disorder characterized by benign lipomatosis usually localized to the nuchal and upper thoracic region. A subset of these patients has germline variants in mitochondrial DNA. Methods. Three siblings of Northern European descent with MSL were assessed initially and provided whole blood for DNA analysis. Family history revealed several additional affected siblings who were dispersed across Canada. Targeted histories were obtained from 6 additional affected family members by telephone interviews using a standardized questionnaire, and genomic DNA was obtained from saliva. Sequencing of mitochondrial DNA was performed. Genetic analysis. Eight affected individuals who were studied each had the MTTK gene c.8344A>G variant. None of the affected individuals had epilepsy, ataxia, or myopathy. Conclusion. In this extended Canadian family, the rare MTTK c.8344A>G variant was linked with Madelung disease in multiple family members. Knowing the likely basis of MSL in this family may help with diagnosis, genetic counseling, monitoring for associated phenotypes, and potential future targeted interventions.
Circulation-cardiovascular Genetics | 2015
Joseph B. Dubé; Jian Wang; Henian Cao; Adam D. McIntyre; Christopher T. Johansen; Scarlett E. Hopkins; Randa Stringer; Siyavash Hosseinzadeh; Brooke A. Kennedy; Matthew R. Ban; T. Kue Young; Philip W. Connelly; Eric Dewailly; Peter Bjerregaard; Bert B. Boyer; Robert A. Hegele
Background—Inuit are considered to be vulnerable to cardiovascular disease because their lifestyles are becoming more Westernized. During sequence analysis of Inuit individuals at extremes of lipid traits, we identified 2 nonsynonymous variants in low-density lipoprotein receptor (LDLR), namely p.G116S and p.R730W. Methods and Results—Genotyping these variants in 3324 Inuit from Alaska, Canada, and Greenland showed they were common, with allele frequencies 10% to 15%. Only p.G116S was associated with dyslipidemia: the increase in LDL cholesterol was 0.54 mmol/L (20.9 mg/dL) per allele (P=5.6×10−49), which was >3× larger than the largest effect sizes seen with other common variants in other populations. Carriers of p.G116S had a 3.02-fold increased risk of hypercholesterolemia (95% confidence interval, 2.34–3.90; P=1.7×10−17), but did not have classical familial hypercholesterolemia. In vitro, p.G116S showed 60% reduced ligand-binding activity compared with wild-type receptor. In contrast, p.R730W was associated with neither LDL cholesterol level nor altered in vitro activity. Conclusions—LDLR p.G116S is thus unique: a common dysfunctional variant in Inuit whose large effect on LDL cholesterol may have public health implications.Inuit were long-believed to have lower CVD risk than non-indigenous populations.1–3 However, re-evaluation of population studies indicates that ischemic heart disease rates are similar between Inuit and non-Indigenous people.4 Furthermore, ongoing Westernization in many Inuit communities has intensified their exposure to CVD risk factors such as smoking, calorie-dense processed foods, and a more comfortable but also sedentary lifestyle, all of which affect CVD risk and prevalence.4–10 Among classical CVD risk factors, Inuit adults tend to have higher plasma concentrations of LDL cholesterol than non-indigenous populations.11–15 The predominant monogenic cause of elevated LDL cholesterol concentration in most global populations is familial hypercholesterolemia (FH, Online Mendelian Inheritance in Man [OMIM] 143890).16 Heterozygous FH (HeFH) prevalence may be as high as 1:200 in certain European populations, and it is a potent predisposition state for early CVD.11–13 To date, DNA sequencing and biochemical studies have identified >1,600 rare loss-of-function mutations in the gene encoding the LDL receptor (LDLR), which can increase LDL cholesterol levels by 100% or more, and underlie >95% of cases of molecularly diagnosed FH.16 But despite the relatively high levels of LDL cholesterol observed in some Inuit, the role of LDLR gene variation has not been systematically studied.13–15 We thus investigated the LDLR locus in Inuit and tested for association of variants therein with plasma lipids. Through Sanger sequencing and targeted genotyping, we found two new LDLR variants common to five Inuit subgroups from across North America and Greenland: 1) p.G116S was both dysfunctional in vitro and associated with a relatively large increase in plasma LDL cholesterol levels; while 2) p.R730W had minimal dysfunction and impact on the lipid profile.