|
|
| PMID |
|
|
| TITLE |
|
| The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis. |
|
| ABSTRACT |
|
| BACKGROUND |
NlmCategory: BACKGROUND |
| The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. |
| METHODS AND FINDINGS |
NlmCategory: RESULTS |
| We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p < 0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p < 0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). |
| CONCLUSIONS |
NlmCategory: CONCLUSIONS |
| We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes. |
|
| DATE PUBLISHED |
|
|
| HISTORY |
|
| PUBSTATUS |
PUBSTATUSDATE |
| ppublish |
2013/06 |
| received |
2012/12/03 |
| accepted |
2013/05/14 |
| epublish |
2013/06/25 |
| entrez |
2013/07/05 06:00 |
| pubmed |
2013/07/05 06:00 |
| medline |
2014/03/22 06:00 |
|
| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Fall T |
|
Fall |
Tove |
T |
|
Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden. |
| Hägg S |
|
Hägg |
Sara |
S |
|
|
| Mägi R |
|
Mägi |
Reedik |
R |
|
|
| Ploner A |
|
Ploner |
Alexander |
A |
|
|
| Fischer K |
|
Fischer |
Krista |
K |
|
|
| Horikoshi M |
|
Horikoshi |
Momoko |
M |
|
|
| Sarin AP |
|
Sarin |
Antti-Pekka |
AP |
|
|
| Thorleifsson G |
|
Thorleifsson |
Gudmar |
G |
|
|
| Ladenvall C |
|
Ladenvall |
Claes |
C |
|
|
| Kals M |
|
Kals |
Mart |
M |
|
|
| Kuningas M |
|
Kuningas |
Maris |
M |
|
|
| Draisma HH |
|
Draisma |
Harmen H M |
HH |
|
|
| Ried JS |
|
Ried |
Janina S |
JS |
|
|
| van Zuydam NR |
|
van Zuydam |
Natalie R |
NR |
|
|
| Huikari V |
|
Huikari |
Ville |
V |
|
|
| Mangino M |
|
Mangino |
Massimo |
M |
|
|
| Sonestedt E |
|
Sonestedt |
Emily |
E |
|
|
| Benyamin B |
|
Benyamin |
Beben |
B |
|
|
| Nelson CP |
|
Nelson |
Christopher P |
CP |
|
|
| Rivera NV |
|
Rivera |
Natalia V |
NV |
|
|
| Kristiansson K |
|
Kristiansson |
Kati |
K |
|
|
| Shen HY |
|
Shen |
Huei-Yi |
HY |
|
|
| Havulinna AS |
|
Havulinna |
Aki S |
AS |
|
|
| Dehghan A |
|
Dehghan |
Abbas |
A |
|
|
| Donnelly LA |
|
Donnelly |
Louise A |
LA |
|
|
| Kaakinen M |
|
Kaakinen |
Marika |
M |
|
|
| Nuotio ML |
|
Nuotio |
Marja-Liisa |
ML |
|
|
| Robertson N |
|
Robertson |
Neil |
N |
|
|
| de Bruijn RF |
|
de Bruijn |
Renée F A G |
RF |
|
|
| Ikram MA |
|
Ikram |
M Arfan |
MA |
|
|
| Amin N |
|
Amin |
Najaf |
N |
|
|
| Balmforth AJ |
|
Balmforth |
Anthony J |
AJ |
|
|
| Braund PS |
|
Braund |
Peter S |
PS |
|
|
| Doney AS |
|
Doney |
Alexander S F |
AS |
|
|
| Döring A |
|
Döring |
Angela |
A |
|
|
| Elliott P |
|
Elliott |
Paul |
P |
|
|
| Esko T |
|
Esko |
Tõnu |
T |
|
|
| Franco OH |
|
Franco |
Oscar H |
OH |
|
|
| Gretarsdottir S |
|
Gretarsdottir |
Solveig |
S |
|
|
| Hartikainen AL |
|
Hartikainen |
Anna-Liisa |
AL |
|
|
| Heikkilä K |
|
Heikkilä |
Kauko |
K |
|
|
| Herzig KH |
|
Herzig |
Karl-Heinz |
KH |
|
|
| Holm H |
|
Holm |
Hilma |
H |
|
|
| Hottenga JJ |
|
Hottenga |
Jouke Jan |
JJ |
|
|
| Hyppönen E |
|
Hyppönen |
Elina |
E |
|
|
| Illig T |
|
Illig |
Thomas |
T |
|
|
| Isaacs A |
|
Isaacs |
Aaron |
A |
|
|
| Isomaa B |
|
Isomaa |
Bo |
B |
|
|
| Karssen LC |
|
Karssen |
Lennart C |
LC |
|
|
| Kettunen J |
|
Kettunen |
Johannes |
J |
|
|
| Koenig W |
|
Koenig |
Wolfgang |
W |
|
|
| Kuulasmaa K |
|
Kuulasmaa |
Kari |
K |
|
|
| Laatikainen T |
|
Laatikainen |
Tiina |
T |
|
|
| Laitinen J |
|
Laitinen |
Jaana |
J |
|
|
| Lindgren C |
|
Lindgren |
Cecilia |
C |
|
|
| Lyssenko V |
|
Lyssenko |
Valeriya |
V |
|
|
| Läärä E |
|
Läärä |
Esa |
E |
|
|
| Rayner NW |
|
Rayner |
Nigel W |
NW |
|
|
| Männistö S |
|
Männistö |
Satu |
S |
|
|
| Pouta A |
|
Pouta |
Anneli |
A |
|
|
| Rathmann W |
|
Rathmann |
Wolfgang |
W |
|
|
| Rivadeneira F |
|
Rivadeneira |
Fernando |
F |
|
|
| Ruokonen A |
|
Ruokonen |
Aimo |
A |
|
|
| Savolainen MJ |
|
Savolainen |
Markku J |
MJ |
|
|
| Sijbrands EJ |
|
Sijbrands |
Eric J G |
EJ |
|
|
| Small KS |
|
Small |
Kerrin S |
KS |
|
|
| Smit JH |
|
Smit |
Jan H |
JH |
|
|
| Steinthorsdottir V |
|
Steinthorsdottir |
Valgerdur |
V |
|
|
| Syvänen AC |
|
Syvänen |
Ann-Christine |
AC |
|
|
| Taanila A |
|
Taanila |
Anja |
A |
|
|
| Tobin MD |
|
Tobin |
Martin D |
MD |
|
|
| Uitterlinden AG |
|
Uitterlinden |
Andre G |
AG |
|
|
| Willems SM |
|
Willems |
Sara M |
SM |
|
|
| Willemsen G |
|
Willemsen |
Gonneke |
G |
|
|
| Witteman J |
|
Witteman |
Jacqueline |
J |
|
|
| Perola M |
|
Perola |
Markus |
M |
|
|
| Evans A |
|
Evans |
Alun |
A |
|
|
| Ferrières J |
|
Ferrières |
Jean |
J |
|
|
| Virtamo J |
|
Virtamo |
Jarmo |
J |
|
|
| Kee F |
|
Kee |
Frank |
F |
|
|
| Tregouet DA |
|
Tregouet |
David-Alexandre |
DA |
|
|
| Arveiler D |
|
Arveiler |
Dominique |
D |
|
|
| Amouyel P |
|
Amouyel |
Philippe |
P |
|
|
| Ferrario MM |
|
Ferrario |
Marco M |
MM |
|
|
| Brambilla P |
|
Brambilla |
Paolo |
P |
|
|
| Hall AS |
|
Hall |
Alistair S |
AS |
|
|
| Heath AC |
|
Heath |
Andrew C |
AC |
|
|
| Madden PA |
|
Madden |
Pamela A F |
PA |
|
|
| Martin NG |
|
Martin |
Nicholas G |
NG |
|
|
| Montgomery GW |
|
Montgomery |
Grant W |
GW |
|
|
| Whitfield JB |
|
Whitfield |
John B |
JB |
|
|
| Jula A |
|
Jula |
Antti |
A |
|
|
| Knekt P |
|
Knekt |
Paul |
P |
|
|
| Oostra B |
|
Oostra |
Ben |
B |
|
|
| van Duijn CM |
|
van Duijn |
Cornelia M |
CM |
|
|
| Penninx BW |
|
Penninx |
Brenda W J H |
BW |
|
|
| Smith GD |
|
Smith |
George Davey |
GD |
|
|
| Kaprio J |
|
Kaprio |
Jaakko |
J |
|
|
| Samani NJ |
|
Samani |
Nilesh J |
NJ |
|
|
| Gieger C |
|
Gieger |
Christian |
C |
|
|
| Peters A |
|
Peters |
Annette |
A |
|
|
| Wichmann HE |
|
Wichmann |
H Erich |
HE |
|
|
| Boomsma DI |
|
Boomsma |
Dorret I |
DI |
|
|
| de Geus EJ |
|
de Geus |
Eco J C |
EJ |
|
|
| Tuomi T |
|
Tuomi |
TiinaMaija |
T |
|
|
| Power C |
|
Power |
Chris |
C |
|
|
| Hammond CJ |
|
Hammond |
Christopher J |
CJ |
|
|
| Spector TD |
|
Spector |
Tim D |
TD |
|
|
| Lind L |
|
Lind |
Lars |
L |
|
|
| Orho-Melander M |
|
Orho-Melander |
Marju |
M |
|
|
| Palmer CN |
|
Palmer |
Colin Neil Alexander |
CN |
|
|
| Morris AD |
|
Morris |
Andrew D |
AD |
|
|
| Groop L |
|
Groop |
Leif |
L |
|
|
| Järvelin MR |
|
Järvelin |
Marjo-Riitta |
MR |
|
|
| Salomaa V |
|
Salomaa |
Veikko |
V |
|
|
| Vartiainen E |
|
Vartiainen |
Erkki |
E |
|
|
| Hofman A |
|
Hofman |
Albert |
A |
|
|
| Ripatti S |
|
Ripatti |
Samuli |
S |
|
|
| Metspalu A |
|
Metspalu |
Andres |
A |
|
|
| Thorsteinsdottir U |
|
Thorsteinsdottir |
Unnur |
U |
|
|
| Stefansson K |
|
Stefansson |
Kari |
K |
|
|
| Pedersen NL |
|
Pedersen |
Nancy L |
NL |
|
|
| McCarthy MI |
|
McCarthy |
Mark I |
MI |
|
|
| Ingelsson E |
|
Ingelsson |
Erik |
E |
|
|
| Prokopenko I |
|
Prokopenko |
Inga |
I |
|
|
|
European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium |
|
|
|
|
|
|
| INVESTIGATORS |
|
|
| JOURNAL |
|
| VOLUME: 10 |
| ISSUE: 6 |
| TITLE: PLoS medicine |
| ISOABBREVIATION: PLoS Med. |
| YEAR: 2013 |
| MONTH: |
| DAY: |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1549-1676 |
| ISSNTYPE: Electronic |
|
| MEDLINE JOURNAL |
|
| MEDLINETA: PLoS Med |
| COUNTRY: United States |
| ISSNLINKING: 1549-1277 |
| NLMUNIQUEID: 101231360 |
|
| PUBLICATION TYPE |
|
| PUBLICATIONTYPE TEXT |
| Journal Article |
| Research Support, N.I.H., Extramural |
| Research Support, Non-U.S. Gov't |
| Research Support, U.S. Gov't, P.H.S. |
|
| COMMENTS AND CORRECTIONS |
|
| REFTYPE |
REFSOURCE |
REFPMID |
NOTE |
| Cites |
Eur Heart J. 2010 Mar;31(6):642-8 |
20176800 |
|
| Cites |
J Clin Endocrinol Metab. 2010 Jan;95(1):93-9 |
19906786 |
|
| Cites |
Nat Genet. 2010 Nov;42(11):937-48 |
20935630 |
|
| Cites |
Nat Genet. 2010 Dec;42(12):1086-92 |
21076408 |
|
| Cites |
Methods Mol Biol. 2011;713:153-66 |
21153618 |
|
| Cites |
Circulation. 2011 Feb 1;123(4):e18-e209 |
21160056 |
|
| Cites |
Int J Obes (Lond). 2011 Feb;35(2):300-8 |
20714329 |
|
| Cites |
Nature. 2011 May 26;473(7348):528-31 |
21532591 |
|
| Cites |
Am J Epidemiol. 2011 Jun 15;173(12):1392-403 |
21555716 |
|
| Cites |
J Nutrigenet Nutrigenomics. 2011;4(4):222-38 |
22056736 |
|
| Cites |
Diabetologia. 2012 Apr;55(4):981-95 |
22109280 |
|
| Cites |
Diabetologia. 2012 Apr;55(4):873-6 |
22297584 |
|
| Cites |
PLoS Med. 2012;9(5):e1001212 |
22563304 |
|
| Cites |
Stat Methods Med Res. 2012 Jun;21(3):223-42 |
21216802 |
|
| Cites |
Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1784-9 |
10677535 |
|
| Cites |
J Intern Med. 2001 Mar;249(3):253-61 |
11285045 |
|
| Cites |
N Engl J Med. 2001 May 3;344(18):1343-50 |
11333990 |
|
| Cites |
N Engl J Med. 2002 Feb 7;346(6):393-403 |
11832527 |
|
| Cites |
N Engl J Med. 2002 Aug 1;347(5):305-13 |
12151467 |
|
| Cites |
Int J Epidemiol. 2003 Feb;32(1):1-22 |
12689998 |
|
| Cites |
N Engl J Med. 1990 Mar 29;322(13):882-9 |
2314422 |
|
| Cites |
JAMA. 1991 Jul 10;266(2):231-6 |
1829117 |
|
| Cites |
Diabetes Care. 1997 Apr;20(4):537-44 |
9096977 |
|
| Cites |
Int J Obes Relat Metab Disord. 1999 Jan;23(1):67-74 |
10094579 |
|
| Cites |
JAMA. 2005 Jul 20;294(3):334-41 |
16030278 |
|
| Cites |
Circulation. 2005 Oct 25;112(17):2735-52 |
16157765 |
|
| Cites |
Science. 2007 May 11;316(5826):889-94 |
17434869 |
|
| Cites |
Stat Methods Med Res. 2007 Aug;16(4):309-30 |
17715159 |
|
| Cites |
PLoS Med. 2007 Dec;4(12):e352 |
18076282 |
|
| Cites |
Diabetes. 2008 May;57(5):1419-26 |
18346983 |
|
| Cites |
Lancet. 2008 May 24;371(9626):1783-9 |
18502303 |
|
| Cites |
PLoS Med. 2008 Aug 26;5(8):e177 |
18752343 |
|
| Cites |
Eur Heart J. 2008 Oct;29(20):2552-60 |
18550552 |
|
| Cites |
N Engl J Med. 2008 Dec 11;359(24):2558-66 |
19073975 |
|
| Cites |
Nat Genet. 2009 Jan;41(1):25-34 |
19079261 |
|
| Cites |
Lancet. 2009 Mar 28;373(9669):1083-96 |
19299006 |
|
| Cites |
PLoS One. 2009;4(5):e5656 |
19479072 |
|
| Cites |
Hypertension. 2009 Jul;54(1):84-90 |
19470880 |
|
| Cites |
BMJ. 2009;339:b5043 |
20028778 |
|
| Cites |
BMC Bioinformatics. 2010;11:288 |
20509871 |
|
|
| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| 01GS0834 |
PHS HHS |
United States |
| 050-060-810 |
PHS HHS |
United States |
| 090532 |
Wellcome Trust |
United Kingdom |
| 10-000-1002 |
PHS HHS |
United States |
| 104781 |
PHS HHS |
United States |
| 11-0312 |
PHS HHS |
United States |
| 120315 |
PHS HHS |
United States |
| 129418 |
PHS HHS |
United States |
| 129494 |
PHS HHS |
United States |
| 129680 |
PHS HHS |
United States |
| 139635 |
PHS HHS |
United States |
| 141054 |
PHS HHS |
United States |
| 17155/2004 |
PHS HHS |
United States |
| 1RC2 MH089995-01 |
NIMH NIH HHS |
United States |
| 1RC2MH089951-01 |
NIMH NIH HHS |
United States |
| 1RL1MH083268-01 |
NIMH NIH HHS |
United States |
| 201413 |
PHS HHS |
United States |
| 213506 |
PHS HHS |
United States |
| 230374 |
PHS HHS |
United States |
| 241944 |
Medical Research Council |
United Kingdom |
| 31160008 |
PHS HHS |
United States |
| 31737/1997 |
PHS HHS |
United States |
| 339462 |
Medical Research Council |
United Kingdom |
| 389875 |
Medical Research Council |
United Kingdom |
| 389891 |
Medical Research Council |
United Kingdom |
| 389892 |
Medical Research Council |
United Kingdom |
| 389927 |
Medical Research Council |
United Kingdom |
| 389938 |
Medical Research Council |
United Kingdom |
| 400-05-717 |
PHS HHS |
United States |
| 41795/1993 |
PHS HHS |
United States |
| 442915 |
Medical Research Council |
United Kingdom |
| 442981 |
Medical Research Council |
United Kingdom |
| 480-04-004 |
PHS HHS |
United States |
| 496739 |
Medical Research Council |
United Kingdom |
| 552485 |
Medical Research Council |
United Kingdom |
| 552498 |
Medical Research Council |
United Kingdom |
| 56-464-14192 |
PHS HHS |
United States |
| 5R01HL087679-02 |
NHLBI NIH HHS |
United States |
| 5R01MH63706 |
NIMH NIH HHS |
United States |
| 904-61-090 |
PHS HHS |
United States |
| 904-61-193 |
PHS HHS |
United States |
| 911-03-012 |
PHS HHS |
United States |
| 911-09-032 |
PHS HHS |
United States |
| 918-76-619 |
PHS HHS |
United States |
| 9783/1986 |
PHS HHS |
United States |
| 985-10-002 |
PHS HHS |
United States |
| A7960034 |
PHS HHS |
United States |
| A79801419 |
PHS HHS |
United States |
| A79906588 |
PHS HHS |
United States |
| AA07535 |
NIAAA NIH HHS |
United States |
| AA10248 |
NIAAA NIH HHS |
United States |
| AA11998 |
NIAAA NIH HHS |
United States |
| AA13320 |
NIAAA NIH HHS |
United States |
| AA13321 |
NIAAA NIH HHS |
United States |
| AA13326 |
NIAAA NIH HHS |
United States |
| AA14041 |
NIAAA NIH HHS |
United States |
| AA15416 |
NIAAA NIH HHS |
United States |
| AA17688 |
NIAAA NIH HHS |
United States |
| AG028555 |
NIA NIH HHS |
United States |
| AG04563 |
NIA NIH HHS |
United States |
| AG08724 |
NIA NIH HHS |
United States |
| AG08861 |
NIA NIH HHS |
United States |
| AG10175 |
NIA NIH HHS |
United States |
| CEED3 223211 |
PHS HHS |
United States |
| CT-2006-019473 |
CIT NIH HHS |
United States |
| CT-2006-037593 |
CIT NIH HHS |
United States |
| DA12854 |
NIDA NIH HHS |
United States |
| DK U01-066134 |
NIDDK NIH HHS |
United States |
| DP0212016 |
NCCDPHP CDC HHS |
United States |
| DP0343921 |
NCCDPHP CDC HHS |
United States |
| DP0770096 |
NCCDPHP CDC HHS |
United States |
| ETF9353 |
PHS HHS |
United States |
| EU/QLRT-2001-01254 |
PHS HHS |
United States |
| EU/WLRT-2001-01254 |
PHS HHS |
United States |
| FP6 STRP 018947 |
OFP OPHS HHS |
United States |
| FP7-HEALTH-F4-2007 |
OFP OPHS HHS |
United States |
| FP7/2007-2013 |
OFP OPHS HHS |
United States |
| G0500539 |
Medical Research Council |
United Kingdom |
| G0600705 |
Medical Research Council |
United Kingdom |
| G0801056 |
Medical Research Council |
United Kingdom |
| G0902313 |
Medical Research Council |
United Kingdom |
| GR072960 |
Wellcome Trust |
United Kingdom |
| I 480-05-003 |
PHS HHS |
United States |
| K05 AA017688 |
NIAAA NIH HHS |
United States |
| MH66206 |
NIMH NIH HHS |
United States |
| N01-CN-45165 |
NCI NIH HHS |
United States |
| N01-RC-37004 |
CCR NIH HHS |
United States |
| N01-RC-45035 |
CCR NIH HHS |
United States |
| PG/09/023/26806 |
British Heart Foundation |
United Kingdom |
| QLG1-CT-2000-0164 |
CIT NIH HHS |
United States |
| QLG2-CT-2002-01254 |
CIT NIH HHS |
United States |
| R01 MH059160 |
NIMH NIH HHS |
United States |
| R01D0042157-01A |
PHS HHS |
United States |
| R01EY018246-01-1 |
NEI NIH HHS |
United States |
| R01HL089650-02 |
NHLBI NIH HHS |
United States |
| SF0180142S08 |
SBRP NIH HHS |
United States |
| SRF/01/010 |
Department of Health |
United Kingdom |
| U24 MH068457-06 |
NIMH NIH HHS |
United States |
|
Biotechnology and Biological Sciences Research Council |
United Kingdom |
|
British Heart Foundation |
United Kingdom |
|
| GENERAL NOTE |
|
|
| KEYWORDS |
|
|
| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Adiposity |
genetics |
| Body Mass Index |
genetics |
| Cardiovascular Diseases |
metabolism |
| Case-Control Studies |
metabolism |
| Confounding Factors (Epidemiology) |
metabolism |
| Genetic Association Studies |
metabolism |
| Humans |
metabolism |
| Mendelian Randomization Analysis |
metabolism |
| Meta-Analysis as Topic |
metabolism |
| Polymorphism, Single Nucleotide |
genetics |
| Proteins |
genetics |
| Quantitative Trait, Heritable |
genetics |
|
| SUPPLEMENTARY MESH |
|
|
| GENE SYMBOLS |
|
|
| CHEMICALS |
|
| REGISTRYNUMBER |
NAMEOFSUBSTANCE |
| 0 |
FTO protein, human |
| 0 |
Proteins |
|
| OTHER ID's |
|
| OTHERID |
SOURCE |
| PMC3692470 |
NLM |
|
|
