title: Genome wide association study identifies two loci associated with cadmium in erythrocytes among never-smokers.
abstract: Cadmium is a non-essential toxic metal with multiple adverse health effects. Exposure in the general population occurs by smoking and diet. Cadmium in erythrocytes is a valid biomarker of exposure and body burden of cadmium.
  
  
  
  We aimed to identify genetic variants related to concentrations of cadmium in erythrocytes.
  
  
  
  Erythrocyte cadmium was analyzed in 4432 individuals (1728 never smokers) from the Swedish population-based Malmö Diet and Cancer cohort. Genotyping was performed using the Illumina HumanOmniExpressExome Bead chip with genome-wide coverage. Genome wide analyses were performed in the whole sample and in never smokers.
  
  
  
  No single nucleotide polymorphism (SNP) reached a genome-wide significant association with erythrocyte cadmium in the whole sample. However, in never smokers, 14 variants showed genome-wide significant relationships with erythrocyte cadmium after adjusting for age and sex. Thirteen variants were in linkage disequilibrium on chromosome 8q13.3 in the XKR9 and LACTB2 genes. The lead SNP on 8q13.3 was rs12681420 (minor allele G, minor allele frequency [MAF] = 0.46, β: -0.11, P = 3.48 × 10-11), an intron variant within the XKR9 gene. The other significant locus, rs17574271 (minor allele C, MAF = 0.09, β: 0.17, P = 6.18 × 10-9), was an intron variant within the DLGAP1 gene at chromosome 18p11.31.
  
  
  
  This genome-wide study of never smokers from the general population identified two independent regions related to erythrocyte cadmium. The strongest locus covers the XKR9 and LACTB2 genes, which both could have related functions in cadmium absorption and metabolism. Replication studies are needed to confirm the findings and mechanisms should be further investigated.
authors.affiliation: Department of Clinical Sciences in Malmö, CRC, Jan Waldenströms Gata 35, Lund University, Malmö, SE 205 02 Malmö yan.borne@med.lu.se.
authors.forename: Yan
authors.initials: Y
authors.lastname: Borné
authors.affiliation: Department of Clinical Sciences in Malmö, CRC, Jan Waldenströms Gata 35, Lund University, Malmö, SE 205 02 Malmö.
authors.forename: Martin
authors.initials: M
authors.lastname: Söderholm
authors.affiliation: Occupational and Environmental Medicine, Sahlgrenska University Hospital and University of Gothenburg, Po Box 414, SE 405 30.
authors.forename: Lars
authors.initials: L
authors.lastname: Barregard
authors.affiliation: Department of Molecular and Clinical Medicine, Wallenberg Laboratory for Cardiovascular and Metabolic Research, University of Gothenburg, and Sahlgrenska University Hospital, SE 413 45 Gothenburg, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Fagerberg
authors.affiliation: Department of Clinical Sciences in Malmö, CRC, Jan Waldenströms Gata 35, Lund University, Malmö, SE 205 02 Malmö.
authors.forename: Margaretha
authors.initials: M
authors.lastname: Persson
authors.affiliation: Department of Clinical Sciences in Malmö, CRC, Jan Waldenströms Gata 35, Lund University, Malmö, SE 205 02 Malmö.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.affiliation: Department of Physiology, Pathophysiology & Toxicology and ZBAF (Centre for Biomedical Education and Research), Faculty of Health - School of Medicine, Witten/Herdecke University, Stockumer Str 12 (Thyssenhaus), D 58453 Witten, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Thévenod
authors.affiliation: Department of Clinical Sciences in Malmö, CRC, Jan Waldenströms Gata 35, Lund University, Malmö, SE 205 02 Malmö.
authors.forename: Bo
authors.initials: B
authors.lastname: Hedblad
authors.affiliation: Department of Clinical Sciences in Malmö, CRC, Jan Waldenströms Gata 35, Lund University, Malmö, SE 205 02 Malmö.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Engström
mesh_terms: D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins; D002104:Cadmium / Q000097:blood* / Q000633:toxicity; D004912:Erythrocytes / Q000737:chemistry* / Q000378:metabolism; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008565:Membrane Proteins; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000097:blood / Q000235:genetics*; D001618:beta-Lactamases / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C000622702:XKR9 protein, human; D002104:Cadmium; C000607856:LACTB2 protein, human; D001618:beta-Lactamases