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 = 3.20x10(-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 = 1.22x10(-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.