PMID- 27182959

OWN - NLM
STAT- MEDLINE
DCOM- 20171220
LR - 20181113
IS - 1879-1484 (Electronic)
IS - 0021-9150 (Print)
IS - 0021-9150 (Linking)
VI - 250
DP - 2016 Jul
TI - Targeted exonic sequencing of GWAS loci in the high extremes of the plasma
lipids
distribution.
PG - 63-8
LID - S0021-9150(16)30142-3 [pii]
LID - 10.1016/j.atherosclerosis.2016.04.011 [doi]
AB - OBJECTIVE: Genome-wide association studies (GWAS) for plasma lipid levels
have
mapped numerous genomic loci, with each region often containing many
protein-coding genes. Targeted re-sequencing of exons is a strategy to
pinpoint
causal variants and genes. METHODS: We performed solution-based hybrid
selection
of 9008 exons at 939 genes within 95 GWAS loci for plasma lipid levels and
sequenced using next-generation sequencing technology individuals with
extremely
high as well as low to normal levels of low-density lipoprotein cholesterol
(LDL-C, n = 311; mean low = 71 mg/dl versus high = 241 mg/dl), triglycerides
(TG,
n = 308; mean low = 75 mg/dl versus high = 1938 mg/dl), and high-density
lipoprotein cholesterol (HDL-C, n = 684; mean low = 32 mg/dl versus
high = 102 mg/dl). We identified 15,002 missense, nonsense, or splice site
variants with a frequency <5%. We tested whether coding sequence variants,
individually or aggregated within a gene, were associated with plasma lipid
levels. To replicate findings, we performed sequencing in independent
participants (n = 6424). RESULTS: Across discovery and replication
sequencing, we
found 6 variants with significant associations with plasma lipids. Of these,
one
was a novel association: p.Ser147Asn variant in APOA4 (14.3% frequency, TG
OR = 0.49, P = 7.1 × 10(-4)) with TG. In gene-level association analyses
where
rare variants within each gene are collapsed, APOC3 (P = 2.1 × 10(-5)) and
LDLR
(P = 5.0 × 10(-12)) were associated with plasma lipids. CONCLUSIONS: After
sequencing genes from 95 GWAS loci in participants with extremely high plasma
lipid levels, we identified one new coding variant associated with TG. These
results provide insight regarding design of similar sequencing studies with
respect to sample size, follow-up, and analysis methodology.
CI - Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
FAU - Patel, Aniruddh P
AU - Patel AP
AD - Cardiovascular Research Center and Center for Human Genetic Research,
Massachusetts General Hospital, Boston, MA, USA; Program in Medical and
Population Genetics, Broad Institute, Cambridge, MA, USA; Department of
Medicine,
Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
FAU - Peloso, Gina M
AU - Peloso GM
AD - Cardiovascular Research Center and Center for Human Genetic Research,
Massachusetts General Hospital, Boston, MA, USA; Program in Medical and
Population Genetics, Broad Institute, Cambridge, MA, USA.
FAU - Pirruccello, James P
AU - Pirruccello JP
AD - Cardiovascular Research Center and Center for Human Genetic Research,
Massachusetts General Hospital, Boston, MA, USA; Program in Medical and
Population Genetics, Broad Institute, Cambridge, MA, USA; Department of
Medicine,
Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
FAU - Johansen, Christopher T
AU - Johansen CT
AD - Department of Medicine, Western University, London, Ontario, Canada.
FAU - Dubé, Joseph B
AU - Dubé JB
AD - Department of Medicine, Western University, London, Ontario, Canada.
FAU - Larach, Daniel B
AU - Larach DB
AD - Department of Anesthesiology, University of Michigan Medical School, Ann
Arbor,
MI, USA.
FAU - Ban, Matthew R
AU - Ban MR
AD - Department of Medicine, Western University, London, Ontario, Canada.
FAU - Dallinge-Thie, Geesje M
AU - Dallinge-Thie GM
AD - Department of Vascular Medicine, Academic Medical Center, Amsterdam, The
Netherlands.
FAU - Gupta, Namrata
AU - Gupta N
AD - Program in Medical and Population Genetics, Broad Institute, Cambridge, MA,
USA.
FAU - Boehnke, Michael
AU - Boehnke M
AD - Center for Statistical Genetics, Department of Biostatistics, University of
Michigan, Ann Arbor, MI, USA.
FAU - Abecasis, Gonçalo R
AU - Abecasis GR
AD - Center for Statistical Genetics, Department of Biostatistics, University of
Michigan, Ann Arbor, MI, USA.
FAU - Kastelein, John J P
AU - Kastelein JJ
AD - Department of Vascular Medicine, Academic Medical Center, Amsterdam, The
Netherlands.
FAU - Hovingh, G Kees
AU - Hovingh GK
AD - Department of Vascular Medicine, Academic Medical Center, Amsterdam, The
Netherlands.
FAU - Hegele, Robert A
AU - Hegele RA
AD - Department of Medicine, Western University, London, Ontario, Canada.
FAU - Rader, Daniel J
AU - Rader DJ
AD - Institute for Translational Medicine and Therapeutics, University of
Pennsylvania, Philadelphia, PA, USA.
FAU - Kathiresan, Sekar
AU - Kathiresan S
AD - Cardiovascular Research Center and Center for Human Genetic Research,
Massachusetts General Hospital, Boston, MA, USA; Program in Medical and
 Population Genetics, Broad Institute, Cambridge, MA, USA; Department of
Medicine,
Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Electronic address: Sekar@broadinstitute.org.
LA - eng
GR - R01 HL107816/HL/NHLBI NIH HHS/United States
GR - K01 HL125751/HL/NHLBI NIH HHS/United States
GR - T32 HL007208/HL/NHLBI NIH HHS/United States
GR - U01 DK062370/DK/NIDDK NIH HHS/United States
GR - P30 DK020572/DK/NIDDK NIH HHS/United States
GR - RC1 HL099793/HL/NHLBI NIH HHS/United States
GR - British Heart Foundation/United Kingdom
PT - Journal Article
PT - Research Support, N.I.H., Extramural
PT - Research Support, Non-U.S. Gov't
DEP - 20160423
TA - Atherosclerosis
JT - Atherosclerosis
JID - 0242543
RN - 0 (Cholesterol, HDL)
RN - 0 (Cholesterol, LDL)
RN - 0 (Lipoproteins, HDL)
RN - 0 (Lipoproteins, LDL)
RN - 0 (Triglycerides)
SB - IM
MH - Adult
MH - Aged
MH - Cholesterol, HDL/blood
MH - Cholesterol, LDL/blood
MH - Chromosome Mapping
MH - Cohort Studies
MH - Exons
MH - Female
MH - Genetic Variation
MH - *Genome-Wide Association Study
MH - Humans
MH - Lipoproteins, HDL/blood/*genetics
MH - Lipoproteins, LDL/blood/*genetics
MH - Male
MH - Middle Aged
MH - Phenotype
MH - Quality Control
MH - Sequence Analysis, DNA
MH - Triglycerides/blood/*genetics
PMC - PMC4907838
MID - NIHMS787201
OTO - NOTNLM
OT - *Genetic techniques
OT - *Genomics
OT - *Human genetics
OT - *Lipids
EDAT- 2016/05/18 06:00
MHDA- 2017/12/21 06:00
CRDT- 2016/05/17 06:00
PHST- 2015/09/15 00:00 [received]
PHST- 2016/04/12 00:00 [revised]
PHST- 2016/04/13 00:00 [accepted]
PHST- 2016/05/17 06:00 [entrez]
PHST- 2016/05/18 06:00 [pubmed]
PHST- 2017/12/21 06:00 [medline]
AID - S0021-9150(16)30142-3 [pii]
AID - 10.1016/j.atherosclerosis.2016.04.011 [doi]
PST - ppublish
SO - Atherosclerosis. 2016 Jul;250:63-8. doi:
10.1016/j.atherosclerosis.2016.04.011.
Epub 2016 Apr 23.