title: Putting pleiotropy and selection into context defines a new paradigm for interpreting genetic data.
abstract: BACKGROUND
  Natural selection shapes many human genes, including some related to complex diseases. Understanding how selection affects genes, especially pleiotropic ones, may be important in evaluating disease associations and the role played by environmental variation. This may be of particular interest for genes with antagonistic roles that cause divergent patterns of selection. The lectin-like low-density lipoprotein 1 receptor, encoded by OLR1, is exemplary. It has antagonistic functions in the cardiovascular and immune systems because the same protein domain binds oxidized low-density lipoprotein and bacterial cell wall proteins, the former contributing to atherosclerosis and the latter presumably protecting from infection. We studied patterns of selection in this gene, in humans and nonhuman primates, to determine whether variable selection can lead to conflicting results in cardiovascular disease association studies.
  
  
  RESULTS
  We analyzed sequences from 11 nonhuman primate species, as well as single-nucleotide polymorphisms and sequence data from multiple human populations. Results indicate that the derived allele is favored across primate lineages (probably because of recent positive selection). However, both the derived and ancestral alleles were maintained in human populations, especially European ones (possibly because of balancing selection derived from dual roles of LOX-1). Balancing selection likely reflects response to diverse environmental pressures among humans.
  
  
  CONCLUSIONS
  These data indicate that differential selection patterns, within and between species, in OLR1 render association studies difficult to replicate even if the gene is etiologically connected to cardiovascular disease. Selection analyses can identify genes exhibiting gene-environment interactions critical for unraveling disease association.
authors.affiliation: Division of Cardiovascular Medicine, Section of Cardiovascular Disease Prevention, Vanderbilt University Medical Center, Nashville, TN 37232, USA. irene.m.predazzi@vanderbilt.edu
authors.forename: Irene M
authors.initials: IM
authors.lastname: Predazzi
authors.forename: Antonis
authors.initials: A
authors.lastname: Rokas
authors.forename: Amos
authors.initials: A
authors.lastname: Deinard
authors.forename: Nathalie
authors.initials: N
authors.lastname: Schnetz-Boutaud
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Williams
authors.forename: William S
authors.initials: WS
authors.lastname: Bush
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tacconelli
authors.forename: Klaus
authors.initials: K
authors.lastname: Friedrich
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sirugo
authors.forename: Scott M
authors.initials: SM
authors.lastname: Williams
mesh_terms: D000483:Alleles; D000818:Animals; D057225:Data Mining; D019143:Evolution, Molecular; D058685:Genetic Pleiotropy; D005828:Genetics, Population; D006801:Humans; D007438:Introns; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D011323:Primates / Q000145:classification / Q000235:genetics*; D051127:Scavenger Receptors, Class E / Q000235:genetics; D012641:Selection, Genetic
chemical_list: D051127:Scavenger Receptors, Class E
keywords: LOX-1 receptor; Pleitropic gene; evolution; genetics; immune system; lipoproteins