Genome-wide association study identifies two novel regions at 11p15.5-p13 and 1p31 with major impact on acute-phase serum amyloid A.
Elevated levels of acute-phase serum amyloid A (A-SAA) cause amyloidosis and are a risk factor for atherosclerosis and its clinical complications, type 2 diabetes, as well as various malignancies. To investigate the genetic basis of A-SAA levels, we conducted the first genome-wide association study on baseline A-SAA concentrations in three population-based studies (KORA, TwinsUK, Sorbs) and one prospective case cohort study (LURIC), including a total of 4,212 participants of European descent, and identified two novel genetic susceptibility regions at 11p15.5-p13 and 1p31. The region at 11p15.5-p13 (rs4150642; p = 3.20×10(-111)) contains serum amyloid A1 (SAA1) and the adjacent general transcription factor 2 H1 (GTF2H1), Hermansky-Pudlak Syndrome 5 (HPS5), lactate dehydrogenase A (LDHA), and lactate dehydrogenase C (LDHC). This region explains 10.84% of the total variation of A-SAA levels in our data, which makes up 18.37% of the total estimated heritability. The second region encloses the leptin receptor (LEPR) gene at 1p31 (rs12753193; p = 1.22×10(-11)) and has been found to be associated with CRP and fibrinogen in previous studies. Our findings demonstrate a key role of the 11p15.5-p13 region in the regulation of baseline A-SAA levels and provide confirmative evidence of the importance of the 1p31 region for inflammatory processes and the close interplay between A-SAA, leptin, and other acute-phase proteins.
Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Carola
C
Marzi
Eva
E
Albrecht
Pirro G
PG
Hysi
Vasiliki
V
Lagou
Melanie
M
Waldenberger
Anke
A
Tönjes
Inga
I
Prokopenko
Katharina
K
Heim
Hannah
H
Blackburn
Janina S
JS
Ried
Marcus E
ME
Kleber
Massimo
M
Mangino
Barbara
B
Thorand
Annette
A
Peters
Christopher J
CJ
Hammond
Harald
H
Grallert
Bernhard O
BO
Boehm
Peter
P
Kovacs
Ludwig
L
Geistlinger
Holger
H
Prokisch
Bernhard R
BR
Winkelmann
Tim D
TD
Spector
H-Erich
HE
Wichmann
Michael
M
Stumvoll
Nicole
N
Soranzo
Winfried
W
März
Wolfgang
W
Koenig
Thomas
T
Illig
Christian
C
Gieger
D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D000685:Serum Amyloid A Protein / Q000235:genetics*
C521404:SAA1 protein, human; D000685:Serum Amyloid A Protein