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Marzi, Carola; Albrecht, Eva; Hysi, Pirro G.; Lagou, Vasiliki; Waldenberger, Melanie; Toenjes, Anke; Prokopenko, Inga; Heim, Katharina; Blackburn, Hannah; Ried, Janina S.; Kleber, Marcus E.; Mangino, Massimo; Thorand, Barbara; Peters, Annette; Hammond, Christopher J.; Grallert, Harald; Boehm, Bernhard O.; Kovacs, Peter; Geistlinger, Ludwig; Prokisch, Holger; Winkelmann, Bernhard R.; Spector, Tim D.; Wichmann, Heinz-Erich; Stumvoll, Michael; Soranzo, Nicole; Maerz, Winfried; Koenig, Wolfgang; Illig, Thomas; Gieger, Christian (November 2010): Genome-Wide Association Study Identifies Two Novel Regions at 11p15.5-p13 and 1p31 with Major Impact on Acute-Phase Serum Amyloid A.
In: PLOS Genetics 6(11), e1001213
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Abstract

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.