title: A genome-wide association study identifies rs2000999 as a strong genetic determinant of circulating haptoglobin levels.
abstract: Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far.We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (P(overall) = 8.1 × 10(-59)), explaining 45.4% of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (β = 0.23 ± 0.08, P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (P(total cholesterol) = 0.002 and P(LDL) = 0.0008).Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact.
authors.affiliation: Centre National de la Recherche Scientifique (CNRS) 8199 - Institute of Biology, Pasteur Institute, Lille 2 University, Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Ndeye Coumba
authors.initials: NC
authors.lastname: Ndiaye
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
authors.forename: Nabila
authors.initials: N
authors.lastname: Bouatia-Naji
authors.forename: Aurélie
authors.initials: A
authors.lastname: Dechaume
authors.forename: Gérard
authors.initials: G
authors.lastname: Siest
authors.forename: Bernard
authors.initials: B
authors.lastname: Herbeth
authors.forename: Mario
authors.initials: M
authors.lastname: Falchi
authors.forename: Leonardo
authors.initials: L
authors.lastname: Bottolo
authors.forename: Rosa-Maria
authors.initials: RM
authors.lastname: Guéant-Rodriguez
authors.forename: Cécile
authors.initials: C
authors.lastname: Lecoeur
authors.forename: Michel R
authors.initials: MR
authors.lastname: Langlois
authors.forename: Yann
authors.initials: Y
authors.lastname: Labrune
authors.forename: Aimo
authors.initials: A
authors.lastname: Ruokonen
authors.forename: Said
authors.initials: S
authors.lastname: El Shamieh
authors.forename: Maria G
authors.initials: MG
authors.lastname: Stathopoulou
authors.forename: Anita
authors.initials: A
authors.lastname: Morandi
authors.forename: Claudio
authors.initials: C
authors.lastname: Maffeis
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Joris R
authors.initials: JR
authors.lastname: Delanghe
authors.forename: Peter
authors.initials: P
authors.lastname: Jacobson
authors.forename: Lars
authors.initials: L
authors.lastname: Sjöström
authors.forename: Lena M S
authors.initials: LM
authors.lastname: Carlsson
authors.forename: Andrew
authors.initials: A
authors.lastname: Walley
authors.forename: Paul
authors.initials: P
authors.lastname: Elliott
authors.forename: Marjo-Riita
authors.initials: MR
authors.lastname: Jarvelin
authors.forename: George V
authors.initials: GV
authors.lastname: Dedoussis
authors.forename: Sophie
authors.initials: S
authors.lastname: Visvikis-Siest
mesh_terms: D000328:Adult; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics; D002648:Child; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006242:Haptoglobins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D006242:Haptoglobins