Transcript PowerPoint - 埼玉医科大学総合医療センター 内分泌・糖尿病内科

Journal Club
Ogden CL, Carroll MD, Kit BK, Flegal KM.
Prevalence of childhood and adult obesity in the United States, 2011-2012.
JAMA. 2014 Feb 26;311(8):806-14. doi: 10.1001/jama.2014.732.
Beuschlein F1, Fassnacht M, Assié G, Calebiro D, Stratakis CA, Osswald A,
Ronchi CL, Wieland T, Sbiera S, Faucz FR, Schaak K, Schmittfull A,
Schwarzmayr T, Barreau O, Vezzosi D, Rizk-Rabin M, Zabel U, Szarek E, Salpea
P, Forlino A, Vetro A, Zuffardi O, Kisker C, Diener S, Meitinger T, Lohse MJ,
Reincke M, Bertherat J, Strom TM, Allolio B.
Constitutive Activation of PKA Catalytic Subunit in Adrenal Cushing's Syndrome.
N Engl J Med. 2014 Feb 26. [Epub ahead of print]
2014年3月06日 8:30-8:55
８階 医局
埼玉医科大学 総合医療センター 内分泌・糖尿病内科
Department of Endocrinology and Diabetes,
Saitama Medical Center, Saitama Medical University
松田 昌文
Matsuda, Masafumi
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文部科学省 学校保健統計調査
平成24年 国民健康・栄養調査結果の概要
米国で1998年に幼稚園に入園し
た7738人のデータを対象に、小
児期（5-14歳）の肥満発生率を
前向きコホート研究で調査。5万
396人年の追跡の結果、肥満の年
間発生率は幼稚園児の5.4％から
5-8年生では1.7％へ低下した。
過体重の5歳児が肥満になる確率
は正常体重児の4倍だった（9年
間累積発生率31.8％対7.9％）。
Figure 1. Prevalence and Incidence of Obesity between Kindergarten and Eighth Grade.
Shown are the age-specific prevalence of overweight and obesity (left graph on each panel) and annual incidence
of obesity according to the weight status at baseline (right graph on each panel) among boys (Panel A) and girls
(Panel B). The black vertical lines and I bars represent 95% confidence intervals.
N Engl J Med 2014;370:403-11.
Cynthia L. Ogden, PhD1; Margaret D. Carroll, MSPH1; Brian K. Kit, MD, MPH1,2;
Katherine M. Flegal, PhD1
1National
Center for Health Statistics, Centers for Disease Control and Prevention,
Hyattsville, Maryland
2United States Public Health Service, Rockville, Maryland
JAMA. 2014;311(8):806-814. doi:10.1001/jama.2014.732.
Importance More than one-third of adults
and 17% of youth in the United States are
obese, although the prevalence remained
stable between 2003-2004 and 2009-2010.
Objective To provide the most recent
national estimates of childhood obesity,
analyze trends in childhood obesity
between 2003 and 2012, and provide
detailed obesity trend analyses among
adults.
Design, Setting, and Participants Weight and height or
recumbent length were measured in 9120 participants in the
2011-2012 nationally representative National Health and
Nutrition Examination Survey.
Main Outcomes and Measures In infants and toddlers from
birth to 2 years, high weight for recumbent length was
defined as weight for length at or above the 95th percentile
of the sex-specific Centers for Disease Control and
Prevention (CDC) growth charts. In children and adolescents
aged 2 to 19 years, obesity was defined as a body mass
index (BMI) at or above the 95th percentile of the sexspecific CDC BMI-for-age growth charts. In adults, obesity
was defined as a BMI greater than or equal to 30. Analyses
of trends in high weight for recumbent length or obesity
prevalence were conducted overall and separately by age
across 5 periods (2003-2004, 2005-2006, 2007-2008, 20092010, and 2011-2012).
Abbreviations: CDC, Centers for Disease Control and Prevention; WHO, World Health Organization.
A Data from the National Health and Nutrition Examination Survey; estimatesare weighted.
b Includes race/Hispanic origin groups not shown separately.
c Relative standard error >30% (but <40%).
d No. of cases <10.
Abbreviations: BMI, body mass index, calculated as weight in kilograms divided by height in meters squared; CDC, Centers for Disease Control and
Prevention.
a Data from the National Health and Nutrition Examination Survey; estimates are weighted.
b Includes race/Hispanic origin groups not shown separately.
c No. of cases <10.
Abbreviations: BMI, body mass index, calculated as weight in kilograms divided by height in meters squared; CDC, Centers for Disease Control and
Prevention.
a Data from the National Health and Nutrition Examination Survey; estimates are weighted.
b Includes race/Hispanic origin groups not shown separately.
c No. of cases <10.
Abbreviation: BMI, body mass index, calculated as weight in kilograms divided by height in meters squared.
a Data from the National Health and Nutrition Examination Survey; estimates are weighted.
b Age adjusted by the direct method to the 2000 Census population, using the age groups 20-39, 40-50, and 60 years and older.
c Includes race/Hispanic origin groups not shown separately.
d No. of cases <10.
e Relative standard error >30% but <40%.
Abbreviation: BMI, body mass index, calculated as weight in kilograms divided by height in meters squared.
a Data from the National Health and Nutrition Examination Survey; estimates are weighted.
b Age adjusted by the direct method to the 2000 Census population, using the age groups 20-39, 40-50, and 60 years and older.
c Includes race/Hispanic origin groups not shown separately.
d No. of cases <10.
e Relative standard error >30% but <40%.
Abbreviation: BMI, body mass index, calculated as weight in kilograms divided by height in meters squared.
a Data from the National Health and Nutrition Examination Survey; estimates are weighted.
b Age adjusted by the direct method to the 2000 Census population, using the age groups 20-39, 40-50, and 60 years and older.
c Includes race/Hispanic origin groups not shown separately.
d No. of cases <10.
e Relative standard error >30% but <40%.
Abbreviation: BMI, body mass index, calculated as weight in kilograms divided by height in meters squared.
a Data from the National Health and Nutrition Examination Survey; estimates are weighted.
b Age adjusted by the direct method to the 2000 Census population, using the age groups 20-39, 40-50, and 60 years and older.
c Includes race/Hispanic origin groups not shown separately.
d No. of cases <10.
e Relative standard error >30% but <40%.
Results In 2011-2012, 8.1% (95% CI, 5.8%-11.1%) of
infants and toddlers had high weight for recumbent
length, and 16.9% (95% CI, 14.9%-19.2%) of 2- to 19year-olds and 34.9% (95% CI, 32.0%-37.9%) of adults
(age-adjusted) aged 20 years or older were obese.
Overall, there was no significant change from 2003-2004
through 2011-2012 in high weight for recumbent length
among infants and toddlers, obesity in 2- to 19-yearolds, or obesity in adults. Tests for an interaction
between survey period and age found an interaction in
children (P = .03) and women (P = .02). There was a
significant decrease in obesity among 2- to 5-year-old
children (from 13.9% to 8.4%; P = .03) and a significant
increase in obesity among women aged 60 years and
older (from 31.5% to 38.1%; P = .006).
Conclusions and Relevance Overall,
there have been no significant changes in
obesity prevalence in youth or adults
between 2003-2004 and 2011-2012.
Obesity prevalence remains high and thus it
is important to continue surveillance.
Message
2011-12年の米国国民健康栄養調査を基に、参加
者9120人の肥満傾向を分析。肥満有病率は乳幼
児8.1％、2-19歳16.9％、成人34.9％だった。
2003-04年から2011-12年の全般的有病率に有意
な変化はなかったが、2-5歳で有意に低下し（P
＝0.03）、60歳以上の女性で有意に上昇した（P
＝0.006）。
Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München (F.B., M.F., A.O., S.S., K.S., M.R.), Institute of Human Genetics,
Technische Universität München (T.M., T.M.S.), and Deutsches Zentrum für Herz-Kreislauf-Forschung partner site, Munich Heart Alliance (T.M.,
T.M.S.), Munich, the Department of Medicine I, Endocrine and Diabetes Unit, University Hospital (M.F., S.S., B.A.), Comprehensive Heart Failure
Center (M.F., M.J.L., B.A.), Institute of Pharmacology and Toxicology (D.C., U.Z., M.J.L.), Rudolf Virchow Center and Deutsche
Forschungsgemeinschaft Research Center for Experimental Biomedicine (D.C., C.K., M.J.L.), and Comprehensive Cancer Center Mainfranken
(C.L.R.), University of Würzburg, Würzburg, and the Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg (T.W., A.S., T.S., S.D.,
T.M., T.M.S.) — all in Germany; INSERM Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin,
Faculté de Médecine Paris Descartes, Université Paris Descartes, Sorbonne Paris Cité (G.A., O.B., D.V., M.R.-R., J.B.), and the Department of
Endocrinology, Referral Center for Rare Adrenal Diseases, Assistance Publique–Hôpitaux de Paris, Hôpital Cochin (G.A., O.B., J.B.), Paris; Section on
Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development,
National Institutes of Health, Bethesda, MD (C.A.S., F.R.F., E.S., P.S.); and Dipartimento di Medicina Molecolare, University of Pavia (A.F., O.Z.), and
Biotechnology Research Laboratory, Foundation Istituto di Ricovoro e Cura a Carattere Scientifico, Policlinico San Matteo (A.V.), Pavia, Italy.
Background
Corticotropin-independent Cushing's
syndrome is caused by tumors or
hyperplasia of the adrenal cortex. The
molecular pathogenesis of cortisolproducing adrenal adenomas is not well
understood.
Methods
We performed exome sequencing of tumortissue specimens from 10 patients with
cortisol-producing adrenal adenomas and
evaluated recurrent mutations in candidate
genes in an additional 171 patients with
adrenocortical tumors. We also performed
genomewide copy-number analysis in 35
patients with cortisol-secreting bilateral
adrenal hyperplasias. We studied the
effects of these genetic defects both
clinically and in vitro.
Study Patients and DNA Extraction
Patients were recruited at three centers that participate in the European
Network for the Study of Adrenal Tumors and at the U.S. National
Institutes of Health.
The diagnosis of corticotropin-independent Cushing's syndrome was
based on a combination of biochemical hallmarks of hypercortisolism —
elevated urinary excretion of free cortisol, increased late-night salivary
or serum cortisol levels, suppressed plasma corticotropin levels (<10 pg
per milliliter [<2.2 pmol per liter]), and nonsuppressible serum cortisol
levels (>5 μg per deciliter [>138 nmol per liter]) after the administration
of 1 mg of dexamethasone — as well as on the presence of catabolic
signs of hypercortisolism. Patients were classified as having overt
Cushing's syndrome if they had at least three abnormal biochemical test
results or if they had typical catabolic features (i.e., muscle weakness,
skin fragility, and osteoporosis) plus at least two abnormal biochemical
test results. Patients were considered to have endocrine-inactive
adrenal lesions if they had normal biochemical test results and no
catabolic signs. All patients who had no catabolic signs but had at least
one abnormal result in the abovementioned tests were classified as
having subclinical Cushing's syndrome.
Figure 1.
Identification of
Somatic PRKACA
Mutation and
Germline Genetic
Duplications.
Panel A shows a
sequence
chromatogram of
normal adrenal tissue,
and Panel B a
chromatogram of a
cortisol-producing
adrenal adenoma. A
somatic mutation in
PRKACA (c.617A→C)
was identified in the
cortisol-producing
adenoma, resulting in
a Leu206Arg
substitution that is not
present in the adjacent
normal tissue. Panel C
shows an ideogram of
chromosome 19 (top)
with the genes
included in the p13.2–
p13.12 band
(GRCh37/h19). The
black blocks (bottom)
represent the size and
position of the
duplications. The gray
blocks represent the
genes included only in
the shared region of
duplication. The red
block represents
Figure 2. Functional Characterization of PRKACA Variants.
Panel A shows the structure derived from the protein kinase A (PKA) tetramer, with the nonmutant
catalytic subunit (Cα) depicted in green and the regulatory subunit (RIIβ) depicted in red. A zoomed
view into the region of Leu206 in the Cα subunit is shown. Leu206 is depicted as a space-filling
representation; the two residues in close proximity (Val115 and Tyr228) and additional residues
from the inhibitory site (Arg111–Ser114, marked with an asterisk) of the regulatory subunit are
depicted as sticks.
Panel B shows the same region of the PKA tetramer, with Leu206 in the Cα subunit replaced by
Arg206, also depicted as a space-filling representation.
Figure 2. Functional Characterization of
PRKACA Variants.
Panel C shows PKA activity of nonmutant and
mutant PKA Cα subunits transfected in human
embryonic kidney 293 cells, as determined by
means of fluorescence resonance energy transfer
(FRET) assay with a PKA reporter (for details, see
Fig. S4 in the Supplementary Appendix). The
results indicate that the mutant variants are
constitutively active. Asterisks indicate P<0.05 for
the comparison with Cαnonmutant + RIIβ. AKAR4NES denotes a protein activity reporter 4 with a
nuclear export signal.
Panel D shows that high constitutive PKA activity
was maintained when either mutant was
cotransfected with an equal amount of nonmutant
Cα subunit. Asterisks indicate P<0.05 for the
comparison with Cαnonmutant + RIIβ. The data in
Panels C and D were compared by means of a
two-way analysis of variance followed by
Bonferroni's test. Panel E shows the quantification
of enzymatic PKA activity; COS-7 cells were
transfected with Cα (nonmutant or mutant) and
RIIβ, with or without the addition of cyclic AMP
(cAMP). Asterisks indicate P<0.05 for the
comparison between samples with and those
without the addition of cAMP. The hatch mark
indicates P<0.05 for the comparison between
samples transfected with nonmutant Cα subunit
and those transfected with mutant Cα subunit
without the addition of cAMP. In Panels C, D, and
E, the I bars represent the standard error.
Figure 2. Functional Characterization of PRKACA Variants.
Results
Exome sequencing revealed somatic mutations in PRKACA,
which encodes the catalytic subunit of cyclic AMP–dependent
protein kinase (protein kinase A [PKA]), in 8 of 10 adenomas
(c.617A→C in 7 and c.595_596insCAC in 1). Overall, PRKACA
somatic mutations were identified in 22 of 59 unilateral adenomas
(37%) from patients with overt Cushing's syndrome; these
mutations were not detectable in 40 patients with subclinical
hypercortisolism or in 82 patients with other adrenal tumors.
Among 35 patients with cortisol-producing hyperplasias, 5
(including 2 first-degree relatives) carried a germline copy-number
gain (duplication) of the genomic region on chromosome 19 that
includes PRKACA. In vitro studies showed impaired inhibition of
both PKA catalytic subunit mutants by the PKA regulatory subunit,
whereas cells from patients with germline chromosomal gains
showed increased protein levels of the PKA catalytic subunit; in
both instances, basal PKA activity was increased.
Conclusions
Genetic alterations of the catalytic subunit of PKA
were found to be associated with human disease.
Germline duplications of this gene resulted in
bilateral adrenal hyperplasias, whereas somatic
PRKACA mutations resulted in unilateral cortisolproducing adrenal adenomas.
(Funded by the European Commission Seventh
Framework Program and others.)
Message
コルチコトロピン非依存性クッシング症候
群の原因となる副腎腺腫・過形成に関与す
る遺伝子変化を、エクソーム配列解析、全
ゲノムコピー数解析などで検討。プロテイ
ンキナーゼA（PKA）の触媒サブユニットを
コードするPRKACAの生殖細胞系列の重複で
両側性副腎過形成、体細胞変異で片側生の
副腎コルチゾール産生腺腫が発症すると示
された。