PLoS Genetics (Nov 2010)

Genome-wide association study identifies two novel regions at 11p15.5-p13 and 1p31 with major impact on acute-phase serum amyloid A.

  • Carola Marzi,
  • Eva Albrecht,
  • Pirro G Hysi,
  • Vasiliki Lagou,
  • Melanie Waldenberger,
  • Anke Tönjes,
  • Inga Prokopenko,
  • Katharina Heim,
  • Hannah Blackburn,
  • Janina S Ried,
  • Marcus E Kleber,
  • Massimo Mangino,
  • Barbara Thorand,
  • Annette Peters,
  • Christopher J Hammond,
  • Harald Grallert,
  • Bernhard O Boehm,
  • Peter Kovacs,
  • Ludwig Geistlinger,
  • Holger Prokisch,
  • Bernhard R Winkelmann,
  • Tim D Spector,
  • H-Erich Wichmann,
  • Michael Stumvoll,
  • Nicole Soranzo,
  • Winfried März,
  • Wolfgang Koenig,
  • Thomas Illig,
  • Christian Gieger

DOI
https://doi.org/10.1371/journal.pgen.1001213
Journal volume & issue
Vol. 6, no. 11
p. e1001213

Abstract

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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.