Publications by authors named "Stephanie Hesselson"

24 Publications

  • Page 1 of 1

Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation From Genome Sequencing.

Circ Genom Precis Med 2020 12 30;13(6):e003030. Epub 2020 Oct 30.

Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, United Kingdom (A.A.B., T.R.W., S.E.H., D.P., A.A.-H., A.W., D.K., N.J.S., D.A.).

Background: Spontaneous coronary artery dissection (SCAD) occurs when an epicardial coronary artery is narrowed or occluded by an intramural hematoma. SCAD mainly affects women and is associated with pregnancy and systemic arteriopathies, particularly fibromuscular dysplasia. Variants in several genes, such as those causing connective tissue disorders, have been implicated; however, the genetic architecture is poorly understood. Here, we aim to better understand the diagnostic yield of rare variant genetic testing among a cohort of SCAD survivors and to identify genes or gene sets that have a significant enrichment of rare variants.

Methods: We sequenced a cohort of 384 SCAD survivors from the United Kingdom, alongside 13 722 UK Biobank controls and a validation cohort of 92 SCAD survivors. We performed a research diagnostic screen for pathogenic variants and exome-wide and gene-set rare variant collapsing analyses.

Results: The majority of patients within both cohorts are female, 29% of the study cohort and 14% validation cohort have a remote arteriopathy. Four cases across the 2 cohorts had a diagnosed connective tissue disorder. We identified pathogenic or likely pathogenic variants in 7 genes (, , , , , , and ) in 14/384 cases in the study cohort and in 1/92 cases in the validation cohort. In our rare variant collapsing analysis, was the highest-ranked gene, and several functionally plausible genes were enriched for rare variants, although no gene achieved study-wide statistical significance. Gene-set enrichment analysis suggested a role for additional genes involved in renal function.

Conclusions: By studying the largest sequenced cohort of SCAD survivors, we demonstrate that, based on current knowledge, only a small proportion have a pathogenic variant that could explain their disease. Our findings strengthen the overlap between SCAD and renal and connective tissue disorders, and we highlight several new genes for future validation.
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http://dx.doi.org/10.1161/CIRCGEN.120.003030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748045PMC
December 2020

Spontaneous Coronary Artery Dissection and Fibromuscular Dysplasia: Vasculopathies With a Predilection for Women.

Heart Lung Circ 2021 Jan 6;30(1):27-35. Epub 2020 Jul 6.

Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia; St Vincent's Clinical School, St Vincent's Hospital, Sydney, NSW, Australia; Faculty of Medicine, University of NSW, Sydney, NSW, Australia. Electronic address:

The burden of cardiovascular disease in women is being increasingly appreciated. Nevertheless, both clinicians and the general public are largely unaware that cardiovascular disease is the leading cause of death worldwide in women in all countries and that outcomes after a heart attack are worse for women than men. Of note, certain types of cardiovascular disease have a predilection for women, including spontaneous coronary artery dissection (SCAD) and fibromuscular dysplasia (FMD). Although uncommon, SCAD is being increasingly recognised as the cause of an acute coronary syndrome (ACS) and can recur. It is a potentially fatal, under-diagnosed condition that affects relatively young women, who often have few traditional risk factors, and is the commonest cause of a myocardial infarction associated with pregnancy. In contrast, FMD often remains silent but when manifested can also cause major sequelae, including renal infarction, stroke, cervical artery dissection and gut infarction. Here we provide an update on the diagnosis, aetiology and management of these important disorders that overwhelmingly affect women.
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http://dx.doi.org/10.1016/j.hlc.2020.05.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710561PMC
January 2021

Generation of VCCRIi001-A, a human induced pluripotent stem cell line, from a patient with spontaneous coronary artery dissection.

Stem Cell Res 2019 12 8;41:101584. Epub 2019 Oct 8.

Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Kensington, New South Wales 2052, Australia. Electronic address:

Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic form of coronary artery disease of unknown cause that predominantly affects women (>90%; mean age 44-55 years) and can be fatal. The finding of familial clustering, including the concordant involvement of monozygotic twins, and its association with the PHACTR1/EDN1 genetic locus, indicate a genetic predisposition to its pathophysiology. A human induced pluripotent stem cell line (hiPSC) was generated from a patient who had survived an episode of SCAD. This disease-specific hiPSC line will be useful for the study of SCAD after differentiation into blood vessel-forming cells.
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http://dx.doi.org/10.1016/j.scr.2019.101584DOI Listing
December 2019

Deletion distal to the PAX6 coding region reveals a novel basis for familial cosegregation of aniridia and diabetes mellitus.

Diabetes Res Clin Pract 2019 Feb 17;148:64-71. Epub 2018 Dec 17.

Diabetes Centre, St Vincent's Hospital, Sydney, New South Wales, Australia; Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Sydney, Australia; Department of Endocrinology, St Vincent's Hospital, Sydney, Australia.

Aims: Analyze cosegregation of aniridia and diabetes to identify genetic criteria for detection and early treatment of diabetes-susceptible aniridia patients.

Methods: We assessed a two-generation family: three individuals with aniridia, two previously diagnosed as type 2 diabetes. One individual with aniridia, with unknown diabetes status, was evaluated by oral glucose tolerance test. Genetic analysis of aniridia-associated genes was performed on all available family members. Candidate genes were functionally tested by gene silencing in MIN6 pancreatic β-cells.

Results: A 25 year old male with aniridia had a diabetic oral glucose tolerance test despite a normal fasting blood glucose. A 484-630 kb deletion ∼120 kb distal to PAIRED BOX 6 (PAX6) showed dominant cosegregation with aniridia and diabetes in all affected family members. The deleted region contains regulatory elements for PAX6 expression and four additional coding regions. Knockdown of two of the deleted genes (Dnajc24 or Immp1l) with Pax6 impaired glucose-stimulated insulin secretion.

Conclusions: We demonstrate dominant cosegregation of diabetes and aniridia with a deletion distal to PAX6, which is clinically distinct from the mild glucose intolerance previously reported with PAX6 coding mutations. Asymptomatic aniridia individuals appear at risk of diabetes (and its complications) and could benefit from earlier diagnosis and treatment.
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http://dx.doi.org/10.1016/j.diabres.2018.12.002DOI Listing
February 2019

Circulating n-3 fatty acids and trans-fatty acids, PLA2G2A gene variation and sudden cardiac arrest.

J Nutr Sci 2016 1;5:e12. Epub 2016 Mar 1.

New York Academy of Medicine , New York, NY , USA.

Whether genetic factors influence the associations of fatty acids with the risk of sudden cardiac arrest (SCA) is largely unknown. To investigate possible gene-fatty acid interactions on SCA risk, we used a case-only approach and measured fatty acids in erythrocyte samples from 1869 SCA cases in a population-based repository with genetic data. We selected 191 SNP in ENCODE-identified regulatory regions of fifty-five candidate genes in fatty acid metabolic pathways. Using linear regression and additive genetic models, we investigated the association of the selected SNP with erythrocyte levels of fatty acids, including DHA, EPA and trans-fatty acids among the SCA cases. The assumption of no association in non-cases was supported by analysis of publicly available datasets containing over 8000 samples. None of the SNP-fatty acid associations tested among the cases reached statistical significance after correction for multiple comparisons. One SNP, rs4654990 near PLA2G2A, with an allele frequency of 0·33, was nominally associated with lower levels of DHA and EPA and higher levels of trans-fatty acids. The strongest association was with DHA levels (exponentiated coefficient for one unit (1 % of total fatty acids), 0·90, 95 % CI 0·85, 0·97; P = 0·003), indicating that for subjects with a coded allele, the OR of SCA associated with one unit higher DHA is about 90 % what it is for subjects with one fewer coded allele. These findings suggest that the associations of circulating n-3 and trans-fatty acids with SCA risk may be more pronounced in carriers of the rs4654990 G allele.
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http://dx.doi.org/10.1017/jns.2016.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791519PMC
June 2016

In the Wrong Place with the Wrong SNP: The Association Between Stressful Neighborhoods and Cardiac Arrest Within Beta-2-adrenergic Receptor Variants.

Epidemiology 2016 09;27(5):656-62

From the aDepartment of Epidemiology, Columbia University, New York, NY; bCardiovascular Health Research Unit, University of Washington, Seattle, WA; cSeattle Children's Research Institute, Seattle, WA; dIDEAS Center, VA Salt Lake City Health Care System, Salt Lake City, UT; eNew York Academy of Medicine, New York, NY; fDepartment of Biostatistics, University of Washington, Seattle, WA; gCardiovascular Research Institute, University of California, San Francisco, CA; and hGarvan Institute of Medical Research, Sydney, Australia.

Background: Sudden cardiac arrest has been linked independently both to stressful neighborhood conditions and to polymorphisms in the ADRB2 gene. The ADRB2 gene mediates sympathetic activation in response to stress. Therefore, if neighborhood conditions cause cardiac arrest through the stress pathway, the ADRB2 variant may modify the association between neighborhood conditions, such as socioeconomic deprivation and incidence of cardiac arrest.

Methods: The Cardiac Arrest Blood Study Repository is a population-based repository of specimens and other data from adult cardiac arrest patients residing in King County, Washington. Cases (n = 1,539) were 25- to 100-year-old individuals of European descent who experienced out-of-hospital cardiac arrest from 1988 to 2004. Interactions between neighborhood conditions and the ADRB2 genotype on cardiac arrest risk were assessed in a case-only study design. Gene-environment independence was assessed in blood samples obtained from King County residents initially contacted by random-digit dialing.

Results: Fewer than 4% of study subjects resided in socioeconomically deprived neighborhoods. Nonetheless, the case-only analysis indicated the presence of supramultiplicative interaction of socioeconomic deprivation and the homozygous Gln27Glu variant (case-only odds ratio: 1.8 [95% confidence interval: 1.0, 2.9]). Interactions between population density and the homozygous Gln27Glu variant were weaker (case-only odds ratio: 1.2 [95% confidence interval: 0.97, 1.5]).

Conclusions: Findings support a supramultiplicative interaction between the Gln27Glu ADRB2 variant and socioeconomic deprivation among individuals of European descent. This result is consistent with the hypothesis that the elevation in cardiac arrest risk associated with socioeconomic deprivation operates through the stress pathway.
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http://dx.doi.org/10.1097/EDE.0000000000000503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505271PMC
September 2016

Genotyping Informatics and Quality Control for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort.

Genetics 2015 Aug 19;200(4):1051-60. Epub 2015 Jun 19.

Kaiser Permanente Northern California Division of Research, Oakland, California 94612.

The Kaiser Permanente (KP) Research Program on Genes, Environment and Health (RPGEH), in collaboration with the University of California-San Francisco, undertook genome-wide genotyping of >100,000 subjects that constitute the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. The project, which generated >70 billion genotypes, represents the first large-scale use of the Affymetrix Axiom Genotyping Solution. Because genotyping took place over a short 14-month period, creating a near-real-time analysis pipeline for experimental assay quality control and final optimized analyses was critical. Because of the multi-ethnic nature of the cohort, four different ethnic-specific arrays were employed to enhance genome-wide coverage. All assays were performed on DNA extracted from saliva samples. To improve sample call rates and significantly increase genotype concordance, we partitioned the cohort into disjoint packages of plates with similar assay contexts. Using strict QC criteria, the overall genotyping success rate was 103,067 of 109,837 samples assayed (93.8%), with a range of 92.1-95.4% for the four different arrays. Similarly, the SNP genotyping success rate ranged from 98.1 to 99.4% across the four arrays, the variation depending mostly on how many SNPs were included as single copy vs. double copy on a particular array. The high quality and large scale of genotype data created on this cohort, in conjunction with comprehensive longitudinal data from the KP electronic health records of participants, will enable a broad range of highly powered genome-wide association studies on a diversity of traits and conditions.
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http://dx.doi.org/10.1534/genetics.115.178905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574249PMC
August 2015

Automated Assay of Telomere Length Measurement and Informatics for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort.

Genetics 2015 Aug 19;200(4):1061-72. Epub 2015 Jun 19.

Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2517

The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort includes DNA specimens extracted from saliva samples of 110,266 individuals. Because of its relationship to aging, telomere length measurement was considered an important biomarker to develop on these subjects. To assay relative telomere length (TL) on this large cohort over a short time period, we created a novel high throughput robotic system for TL analysis and informatics. Samples were run in triplicate, along with control samples, in a randomized design. As part of quality control, we determined the within-sample variability and employed thresholds for the elimination of outlying measurements. Of 106,902 samples assayed, 105,539 (98.7%) passed all quality control (QC) measures. As expected, TL in general showed a decline with age and a sex difference. While telomeres showed a negative correlation with age up to 75 years, in those older than 75 years, age positively correlated with longer telomeres, indicative of an association of longer telomeres with more years of survival in those older than 75. Furthermore, while females in general had longer telomeres than males, this difference was significant only for those older than age 50. An additional novel finding was that the variance of TL between individuals increased with age. This study establishes reliable assay and analysis methodologies for measurement of TL in large, population-based human studies. The GERA cohort represents the largest currently available such resource, linked to comprehensive electronic health and genotype data for analysis.
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http://dx.doi.org/10.1534/genetics.115.178624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574243PMC
August 2015

Characterizing Race/Ethnicity and Genetic Ancestry for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort.

Genetics 2015 Aug 19;200(4):1285-95. Epub 2015 Jun 19.

Institute for Human Genetics, University of California, San Francisco, California 94143-0794 Department of Epidemiology and Biostatistics, University of California, San Francisco, California 94158-2549 Kaiser Permanente Northern California Division of Research, Oakland, California 94612-2304

Using genome-wide genotypes, we characterized the genetic structure of 103,006 participants in the Kaiser Permanente Northern California multi-ethnic Genetic Epidemiology Research on Adult Health and Aging Cohort and analyzed the relationship to self-reported race/ethnicity. Participants endorsed any of 23 race/ethnicity/nationality categories, which were collapsed into seven major race/ethnicity groups. By self-report the cohort is 80.8% white and 19.2% minority; 93.8% endorsed a single race/ethnicity group, while 6.2% endorsed two or more. Principal component (PC) and admixture analyses were generally consistent with prior studies. Approximately 17% of subjects had genetic ancestry from more than one continent, and 12% were genetically admixed, considering only nonadjacent geographical origins. Self-reported whites were spread on a continuum along the first two PCs, indicating extensive mixing among European nationalities. Self-identified East Asian nationalities correlated with genetic clustering, consistent with extensive endogamy. Individuals of mixed East Asian-European genetic ancestry were easily identified; we also observed a modest amount of European genetic ancestry in individuals self-identified as Filipinos. Self-reported African Americans and Latinos showed extensive European and African genetic ancestry, and Native American genetic ancestry for the latter. Among 3741 genetically identified parent-child pairs, 93% were concordant for self-reported race/ethnicity; among 2018 genetically identified full-sib pairs, 96% were concordant; the lower rate for parent-child pairs was largely due to intermarriage. The parent-child pairs revealed a trend toward increasing exogamy over time; the presence in the cohort of individuals endorsing multiple race/ethnicity categories creates interesting challenges and future opportunities for genetic epidemiologic studies.
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http://dx.doi.org/10.1534/genetics.115.178616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574246PMC
August 2015

A common SCN5A variant is associated with PR interval and atrial fibrillation among African Americans.

J Cardiovasc Electrophysiol 2014 Nov 25;25(11):1150-7. Epub 2014 Aug 25.

Department of Medicine, Division of Cardiology, Section of Electrophysiology, Northwestern University, Chicago, Illinois, USA.

Objective: We examined the association of rs7626962 (S1103Y) or rs7629265, a variant in high linkage disequilibrium with S1103Y (r(2) = 0.87 - 1), with sudden cardiac death (SCD) and atrial fibrillation (AF) among African Americans.

Background: The SCN5A missense variant S1103Y has been associated with SCD among African Americans in small case-control studies, but larger population-based studies are needed to validate these findings. The association of this variant with AF has not been fully explored.

Methods: Using genotyping data on over 7,000 African Americans from 5 cohorts (Atherosclerosis Risk in Communities [ARIC], Cleveland Family Study [CFS], Jackson Heart Study [JHS], Multi-Ethnic Study of Atherosclerosis [MESA], Cardiovascular Health Study [CHS]), we examined the association of rs7629265 with electrocardiographic PR, QRS, and QT intervals, and with incident AF and SCD. We examined association of S1103Y (rs7626962) with SCD using a population-based case-control study of SCD Cardiac Arrest Blood Study (CABS).

Results: Meta-analyses across 5 cohorts demonstrated that rs7629265 was significantly associated with PR duration (β = -4.1 milliseconds; P = 2.2×10(-6) ), but not significantly associated with QRS or QT intervals. In meta-analyses of prospectively followed ARIC and CHS participants (n = 3,656), rs7629265 was associated with increased AF risk (n = 299 AF cases; HR = 1.74, P = 1.9 × 10(-4) ). By contrast, rs7629265 was not significantly associated with SCD risk in ARIC (n = 83 SCD cases; P = 0.30) or CHS (n = 54 SCD cases; P = 0.47). Similarly, S1103Y was not significantly associated with SCD risk in CABS (n = 225 SCD cases; P = 0.29).

Conclusion: The common SCN5A variant, rs7629265, is associated with increased AF risk and shorter PR interval among African Americans. In contrast to prior reports, we found no evidence of association of rs7629265 or rs7626962 (S1103Y) with SCD risk in the general population.
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http://dx.doi.org/10.1111/jce.12483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454499PMC
November 2014

Maternal genetic variation accounts in part for the associations of maternal size during pregnancy with offspring cardiometabolic risk in adulthood.

PLoS One 2014 26;9(3):e91835. Epub 2014 Mar 26.

Braun School of Public Health, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.

Background: Maternal pre-pregnancy body-mass index (ppBMI) and gestational weight gain (GWG) are associated with cardiometabolic risk (CMR) traits in the offspring. The extent to which maternal genetic variation accounts for these associations is unknown.

Methods/results: In 1249 mother-offspring pairs recruited from the Jerusalem Perinatal Study, we used archival data to characterize ppBMI and GWG and follow-up data from offspring to assess CMR, including body mass index (BMI), waist circumference, glucose, insulin, blood pressure, and lipid levels, at an average age of 32. Maternal genetic risk scores (GRS) were created using a subset of SNPs most predictive of ppBMI, GWG, and each CMR trait, selected among 1384 single-nucleotide polymorphisms (SNPs) characterizing variation in 170 candidate genes potentially related to fetal development and/or metabolic risk. We fit linear regression models to examine the associations of ppBMI and GWG with CMR traits with and without adjustment for GRS. Compared to unadjusted models, the coefficient for the association of a one-standard-deviation (SD) difference in GWG and offspring BMI decreased by 41% (95%CI -81%, -11%) from 0.847 to 0.503 and the coefficient for a 1SD difference in GWG and WC decreased by 63% (95%CI -318%, -11%) from 1.196 to 0.443. For other traits, there were no statistically significant changes in the coefficients for GWG with adjustment for GRS. None of the associations of ppBMI with CMR traits were significantly altered by adjustment for GRS.

Conclusions: Maternal genetic variation may account in part for associations of GWG with offspring BMI and WC in young adults.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0091835PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966761PMC
December 2015

Common variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest.

Heart Rhythm 2014 Mar 10;11(3):471-7. Epub 2014 Jan 10.

Cardiovascular Genetics Center, Institut Investigació Biomèdica de Girona IDIBGI-Universitat de Girona, Girona, Spain.

Background: There is limited information on genetic factors associated with sudden cardiac arrest (SCA).

Objective: To assess the association of common variation in genes in fatty acid pathways with SCA risk.

Methods: We selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n = 2160) were from a repository of SCA in the greater Seattle area. Controls (n = 2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed permutation-based p-min tests to account for multiple comparisons within each gene. The SNP associations with a corrected P value of <.05 were then examined in a meta-analysis of these SNP associations in 9 replication studies totaling 2129 SCA cases and 23,833 noncases.

Results: Eight SNPs in or near 8 genes were associated with SCA risk in the discovery study, one of which was nominally significant in the replication phase (rs7737692, minor allele frequency 36%, near the LPCAT1 gene). For each copy of the minor allele, rs7737692 was associated with 13% lower SCA risk (95% confidence interval -21% to -5%) in the discovery phase and 9% lower SCA risk (95% confidence interval -16% to -1%) in the replication phase.

Conclusions: While none of the associations reached significance with Bonferroni correction, a common genetic variant near LPCAT1, a gene involved in the remodeling of phospholipids, was nominally associated with incident SCA risk. Further study is needed to validate this observation.
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http://dx.doi.org/10.1016/j.hrthm.2014.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966996PMC
March 2014

Associations of maternal pre-pregnancy and gestational body size with offspring longitudinal change in BMI.

Obesity (Silver Spring) 2014 Apr 5;22(4):1165-71. Epub 2013 Dec 5.

Braun School of Public Health, The Hebrew University-Hadassah Medical Center, Jerusalem, Israel.

Objectives: Studies demonstrate associations between changes in obesity-related phenotypes and cardiovascular risk. Although maternal pre-pregnancy BMI (mppBMI) and gestational weight gain (GWG) may be associated with adult offspring adiposity, no study has examined associations with obesity changes. Associations of mppBMI and GWG with longitudinal change in offspring's BMI (ΔBMI) were examined, and whether associations are explained by offspring genetics was assessed.

Methods: A birth cohort of 1400 adults, with data at birth, age 17 and 32 years was used. After genotyping offspring, genetic scores, predictive of exposures and outcome were created, and linear regression models with and without scores were fit to examine the associations of mppBMI and GWG with ΔBMI.

Results: A one SD change in mppBMI and GWG was associated with a 0.83 and a 0.75 kg/m² increase in ΔBMI, respectively. The association between mppBMI and offspring ΔBMI was slightly attenuated (12%) with the addition of genetic scores. In the GWG model, a significant substantial 28.2% decrease in the coefficient was observed.

Conclusions: This study points to an association between maternal excess weight in pregnancy and offspring BMI change from adolescence to adulthood. Genetic factors may account, in part, for GWG/ΔBMI association. These findings broaden observations that maternal obesity-related phenotypes have long-term consequences for offspring health.
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http://dx.doi.org/10.1002/oby.20643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968220PMC
April 2014

Common variation in fatty acid genes and resuscitation from sudden cardiac arrest.

Circ Cardiovasc Genet 2012 Aug 1;5(4):422-9. Epub 2012 Jun 1.

Department of Medicine, University of Washington CHRU, 1730 Minor Ave, Seattle, WA 98101, USA.

Background: Fatty acids provide energy and structural substrates for the heart and brain and may influence resuscitation from sudden cardiac arrest (SCA). We investigated whether genetic variation in fatty acid metabolism pathways was associated with SCA survival.

Methods And Results: Subjects (mean age, 67 years; 80% male, white) were out-of-hospital SCA patients found in ventricular fibrillation in King County, WA. We compared subjects who survived to hospital admission (n=664) with those who did not (n=689), and subjects who survived to hospital discharge (n=334) with those who did not (n=1019). Associations between survival and genetic variants were assessed using logistic regression adjusting for age, sex, location, time to arrival of paramedics, whether the event was witnessed, and receipt of bystander cardiopulmonary resuscitation. Within-gene permutation tests were used to correct for multiple comparisons. Variants in 5 genes were significantly associated with SCA survival. After correction for multiple comparisons, single-nucleotide polymorphisms in ACSL1 and ACSL3 were significantly associated with survival to hospital admission. Single-nucleotide polymorphisms in ACSL3, AGPAT3, MLYCD, and SLC27A6 were significantly associated with survival to hospital discharge.

Conclusions: Our findings indicate that variants in genes important in fatty acid metabolism are associated with SCA survival in this population.
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http://dx.doi.org/10.1161/CIRCGENETICS.111.961912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422654PMC
August 2012

Design and coverage of high throughput genotyping arrays optimized for individuals of East Asian, African American, and Latino race/ethnicity using imputation and a novel hybrid SNP selection algorithm.

Genomics 2011 Dec 28;98(6):422-30. Epub 2011 Aug 28.

Institute for Human Genetics, University of California, San Francisco, CA 94143-0794, USA.

Four custom Axiom genotyping arrays were designed for a genome-wide association (GWA) study of 100,000 participants from the Kaiser Permanente Research Program on Genes, Environment and Health. The array optimized for individuals of European race/ethnicity was previously described. Here we detail the development of three additional microarrays optimized for individuals of East Asian, African American, and Latino race/ethnicity. For these arrays, we decreased redundancy of high-performing SNPs to increase SNP capacity. The East Asian array was designed using greedy pairwise SNP selection. However, removing SNPs from the target set based on imputation coverage is more efficient than pairwise tagging. Therefore, we developed a novel hybrid SNP selection method for the African American and Latino arrays utilizing rounds of greedy pairwise SNP selection, followed by removal from the target set of SNPs covered by imputation. The arrays provide excellent genome-wide coverage and are valuable additions for large-scale GWA studies.
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http://dx.doi.org/10.1016/j.ygeno.2011.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3502750PMC
December 2011

Next generation genome-wide association tool: design and coverage of a high-throughput European-optimized SNP array.

Genomics 2011 Aug 30;98(2):79-89. Epub 2011 Apr 30.

Institute for Human Genetics, University of California, San Francisco 94143-0794, CA, USA.

The success of genome-wide association studies has paralleled the development of efficient genotyping technologies. We describe the development of a next-generation microarray based on the new highly-efficient Affymetrix Axiom genotyping technology that we are using to genotype individuals of European ancestry from the Kaiser Permanente Research Program on Genes, Environment and Health (RPGEH). The array contains 674,517 SNPs, and provides excellent genome-wide as well as gene-based and candidate-SNP coverage. Coverage was calculated using an approach based on imputation and cross validation. Preliminary results for the first 80,301 saliva-derived DNA samples from the RPGEH demonstrate very high quality genotypes, with sample success rates above 94% and over 98% of successful samples having SNP call rates exceeding 98%. At steady state, we have produced 462 million genotypes per week for each Axiom system. The new array provides a valuable addition to the repertoire of tools for large scale genome-wide association studies.
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http://dx.doi.org/10.1016/j.ygeno.2011.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146553PMC
August 2011

Common variants in P2RY11 are associated with narcolepsy.

Nat Genet 2011 Jan 19;43(1):66-71. Epub 2010 Dec 19.

Center for Sleep Sciences and Department of Psychiatry, Stanford University School of Medicine, Palo Alto, California, USA.

Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y₁₁ gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10⁻¹⁰, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.
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http://dx.doi.org/10.1038/ng.734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3019286PMC
January 2011

Identification and characterization of novel polymorphisms in the basal promoter of the human transporter, MATE1.

Pharmacogenet Genomics 2009 Oct;19(10):770-80

Department of Pharmacology, Ewha Womans University, Seoul, Korea.

Objectives: Human multidrug and toxin extrusion member 1, MATE1 (SLC47A1), plays an important role in the renal and biliary excretion of endogenous and exogenous organic cations including many therapeutic drugs. In this study, we characterized the transcriptional effects of five polymorphic variants and six common haplotypes in the basal promoter region of MATE1 that were identified in 272 DNA samples from ethnically diverse US populations.

Methods: We measured luciferase activities of the six common promoter haplotypes of MATE1 using in-vitro and in-vivo reporter assays.

Results: Haplotypes that contain the most common variant (mean allele frequency in four ethnic groups: 0.322), g.-66T>C, showed a significant decrease in reporter activities compared to the reference. Two transcription factors, activating protein-1 (AP-1) and activating protein-2 repressor (AP-2rep), were predicted to bind to the promoter in the region of g.-66T>C. Results from electrophoretic mobility shift assays showed that the g.-66T allele, exhibited greater binding to AP-1 than the g.-66C allele. AP-2rep inhibited the binding of AP-1 to the MATE1 basal promoter region, and the effect was considerably greater for the g.-66T>C. These data suggest that the reduced transcriptional activity of g.-66T>C results from a reduction in the binding potency of the transcriptional activator, AP-1, and an enhanced binding potency of the repressor, AP-2rep to the MATE1 basal promoter region. Consistent with the reporter assays, MATE1 mRNA expression levels were significantly lower in kidney samples from individuals who were homozygous or heterozygous for g.-66T>C in comparison with samples from individuals who were homozygous for the g.-66T allele.

Conclusion: Our study suggests that the rate of transcription of MATE1 is regulated by AP-1 and AP-2rep and that a common promoter variant, g.-66T>C may affect the expression level of MATE1 in human kidney, and ultimately result in variation in drug disposition and response.
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http://dx.doi.org/10.1097/FPC.0b013e328330eecaDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2976711PMC
October 2009

Genetic variation in the proximal promoter of ABC and SLC superfamilies: liver and kidney specific expression and promoter activity predict variation.

PLoS One 2009 Sep 9;4(9):e6942. Epub 2009 Sep 9.

Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, United States of America.

Membrane transporters play crucial roles in the cellular uptake and efflux of an array of small molecules including nutrients, environmental toxins, and many clinically used drugs. We hypothesized that common genetic variation in the proximal promoter regions of transporter genes contribute to observed variation in drug response. A total of 579 polymorphisms were identified in the proximal promoters (-250 to +50 bp) and flanking 5' sequence of 107 transporters in the ATP Binding Cassette (ABC) and Solute Carrier (SLC) superfamilies in 272 DNA samples from ethnically diverse populations. Many transporter promoters contained multiple common polymorphisms. Using a sliding window analysis, we observed that, on average, nucleotide diversity (pi) was lowest at approximately 300 bp upstream of the transcription start site, suggesting that this region may harbor important functional elements. The proximal promoters of transporters that were highly expressed in the liver had greater nucleotide diversity than those that were highly expressed in the kidney consistent with greater negative selective pressure on the promoters of kidney transporters. Twenty-one promoters were evaluated for activity using reporter assays. Greater nucleotide diversity was observed in promoters with strong activity compared to promoters with weak activity, suggesting that weak promoters are under more negative selective pressure than promoters with high activity. Collectively, these results suggest that the proximal promoter region of membrane transporters is rich in variation and that variants in these regions may play a role in interindividual variation in drug disposition and response.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0006942PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735003PMC
September 2009

Narcolepsy is strongly associated with the T-cell receptor alpha locus.

Nat Genet 2009 Jun 3;41(6):708-11. Epub 2009 May 3.

Center for Sleep Sciences, Stanford University School of Medicine, Palo Alto, California, USA.

Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs and mice, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the [email protected] (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P < 10(-21), 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the [email protected] locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders; thus, narcolepsy will provide new insights on how HLA-TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders.
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http://dx.doi.org/10.1038/ng.372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803042PMC
June 2009

Genetic variants in multidrug and toxic compound extrusion-1, hMATE1, alter transport function.

Pharmacogenomics J 2009 Apr 27;9(2):127-36. Epub 2009 Jan 27.

Division of Clinical Pharmacology and Experimental Therapeutics, Department of Biopharmaceutical Sciences, University of California at San Francisco, San Francisco, CA 94158, USA.

hMATE1 (human multidrug and toxin compound extrusion-1; encoded by SLC47A1) is thought to have an important function in the renal and hepatic elimination of drugs, endogenous compounds and environmental toxins. The goals of this study were to identify genetic variants of hMATE1 and to determine their effects on hMATE1 transport function. We identified four synonymous and six nonsynonymous, coding region variants in DNA samples from 272 individuals (68 Caucasians, 68 African Americans, 68 Asian Americans and 68 Mexican Americans). The overall prevalence of hMATE1 nonsynonymous variants was relatively low with three singleton variants and three variants having allele frequencies > or =2% in a specific ethnic group. The nonsynonymous hMATE1 variants were constructed and stably transfected into HEK-293 cells. Uptake studies using four known hMATE1 substrates (paraquat, metformin, tetraethylammonium and oxaliplatin) were performed in cells transfected with hMATE1 reference or variants. We found that two singleton variants, G64D and V480M, produced a complete loss of function for all four tested substrates whereas three polymorphic variants (allele frequencies > or =2%), L125F, V338I and C497S, significantly altered the transport function in a substrate-dependent manner. Confocal microscopy studies were consistent with functional studies suggesting that the altered function of the variants was due to altered localization to the plasma membrane. These data suggest that nonsynonymous variants in hMATE1 may alter drug disposition and ultimately affect clinical drug response.
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http://dx.doi.org/10.1038/tpj.2008.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949062PMC
April 2009

Functional genetic variation in the basal promoter of the organic cation/carnitine transporters OCTN1 (SLC22A4) and OCTN2 (SLC22A5).

J Pharmacol Exp Ther 2009 Apr 13;329(1):262-71. Epub 2009 Jan 13.

Department of Biopharmaceutical Sciences, University of California, San Francisco, San Francisco, CA 94158-2911, USA.

The organic cation/ergothioneine transporter OCTN1 (SLC22A4) and the high-affinity carnitine transporter OCTN2 (SLC22A5), play an important role in the disposition of xenobiotics and endogenous compounds. Here, we analyzed the sequence of the proximal promoter regions of OCTN1 and OCTN2 in four ethnic groups and determined the effects of the identified genetic variants on transcriptional activities and mRNA expression. Six variants were found in the proximal promoter of OCTN1, one of which showed high allele frequency ranging from 13 to 34% in samples from individuals with ancestries in Africa, Europe, China, and Mexico. OCTN1 haplotypes had similar activities as the reference in luciferase reporter assays. For OCTN2, three of the seven variants identified in the proximal promoter showed allele frequencies greater than 29.5% in all populations, with the exception of -207C>G (rs2631367) that was monomorphic in Asian Americans. OCTN2 haplotypes containing -207G, present in all populations, were associated with a gain of function in luciferase reporter assays. Consistent with reporter assays, OCTN2 mRNA expression levels in lymphoblastoid cell lines (LCLs) from gene expression analysis were greater in samples carrying a marker for -207G. This SNP seems to contribute to racial differences in OCTN2 mRNA expression levels in LCLs. Our study with healthy subjects (n = 16) homozygous for either -207C or -207G, showed no appreciable effect of this SNP on carnitine disposition. However, there were significant effects of gender on carnitine plasma levels (p < 0.01). Further in vivo studies of OCTN2 promoter variants on carnitine disposition and variation in drug response are warranted.
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http://dx.doi.org/10.1124/jpet.108.146449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670604PMC
April 2009

Identification and characterization of proximal promoter polymorphisms in the human concentrative nucleoside transporter 2 (SLC28A2).

J Pharmacol Exp Ther 2009 Mar 19;328(3):699-707. Epub 2008 Dec 19.

Department of Biopharmaceutical Sciences, University of California, 1550 4th Street, RH584, Box 2911, San Francisco, CA 94158-2911, USA.

The human concentrative nucleoside transporter 2 (CNT2) plays an important role in the absorption, disposition, and biological effects of endogenous nucleosides and nucleoside analog drugs. We identified genetic variation in the basal promoter region of CNT2 and characterized the function of the variants. We screened DNA from an ethnically diverse population and identified five basal promoter variants in CNT2. Three major haplotypes in the CNT2 basal promoter region were identified and were found at different allele frequencies in various ethnic groups. The common promoter variants and haplotypes were constructed and characterized for their promoter activity using luciferase reporter assays. One polymorphic variant, rs2413775 (-146T>A), with an allele frequency >20% in all populations, showed a gain of function in luciferase activity. Furthermore, in vivo mouse promoter assays of these nucleotide variants using the hydrodynamic tail vein injection, leading to their expression in the liver, demonstrated similar results. Transcription factor binding site (TFBS) analysis indicated this variant alters a hepatic nuclear factor (HNF) 1 TFBS. Electrophoretic mobility shift assay demonstrated stronger binding of HNF1alpha and weaker binding of HNF1beta to the -146T and -146A regions, whereas the single nucleotide polymorphism (SNP), -146A, exhibited enhanced binding to both HNF1alpha and HNF1beta, consistent with its greater activity in reporter assays. The data collectively suggest that the common variant, -146T>A, in the proximal promoter of CNT2 may result in an enhanced transcription rate of the gene and, thus, expression levels of CNT2. This SNP may play a role in variation in the pharmacokinetics and pharmacological effects of nucleoside analogs.
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http://dx.doi.org/10.1124/jpet.108.147207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682268PMC
March 2009

Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk.

Proc Natl Acad Sci U S A 2007 Apr 2;104(15):6299-304. Epub 2007 Apr 2.

McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, Madison, WI 53706, USA.

Breast cancer risk is a polygenic trait. To identify breast cancer modifier alleles that have a high population frequency and low penetrance we used a comparative genomics approach. Quantitative trait loci (QTL) were initially identified by linkage analysis in a rat mammary carcinogenesis model followed by verification in congenic rats carrying the specific QTL allele under study. The Mcs5a locus was identified by fine-mapping Mcs5 in a congenic model. Here we characterize the Mcs5a locus, which when homozygous for the Wky allele, reduces mammary cancer risk by 50%. The Mcs5a locus is a compound QTL with at least two noncoding interacting elements: Mcs5a1 and Mcs5a2. The resistance phenotype is only observed in rats carrying at least one copy of the Wky allele of each element on the same chromosome. Mcs5a1 is located within the ubiquitin ligase Fbxo10, whereas Mcs5a2 includes the 5' portion of Frmpd1. Resistant congenic rats show a down-regulation of Fbxo10 in the thymus and an up-regulation of Frmpd1 in the spleen. The association of the Mcs5a1 and Mcs5a2 human orthologs with breast cancer was tested in two population-based breast cancer case-control studies (approximately 12,000 women). The minor alleles of rs6476643 (MCS5A1) and rs2182317 (MCS5A2) were independently associated with breast cancer risk. The minor allele of rs6476643 increases risk, whereas the rs2182317 minor allele decreases risk. Both alleles have a high population frequency and a low penetrance toward breast cancer risk.
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http://dx.doi.org/10.1073/pnas.0701687104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1847458PMC
April 2007
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