title: Contrasting association of a non-synonymous leptin receptor gene polymorphism with Wegener's granulomatosis and Churg-Strauss syndrome.
abstract: OBJECTIVE
  There is evidence that the leptin/ghrelin system is involved in T-cell regulation and plays a role in (auto)immune disorders such as SLE, RA and ANCA-associated vasculitides (AAVs). Here, we evaluate the genetic background of this system in WG.
  
  
  METHODS
  We screened variations in the genes encoding leptin, ghrelin and their receptors, the leptin receptor (LEPR) and the growth hormone secretagogue receptor (GHSR). Three single nucleotide polymorphisms (SNPs) in each gene region were analysed in 460 German WG cases and 878 ethnically matched healthy controls.
  
  
  RESULTS
  A three-SNP haplotype of GHSR was significantly associated with WG [P = 0.0067; corrected P-value (P(c)) = 0.026; odds ratio (OR) = 1.30; 95% CI 1.08, 1.57], as was one non-synonymous SNP in LEPR (Lys656Asn, P = 0.0034; P(c) = 0.013; OR = 0.72; 95% CI 0.58, 0.90). These four SNPs were re-analysed in independent cohorts of 226 German WG cases and 519 controls. While the GHSR association was not confirmed, allele frequencies of the LEPR SNP were virtually identical to those from the initial cohorts. Analysis of this SNP in the combined WG and control panels revealed a significant association of the LEPR 656Lys allele with WG (P = 0.00032; P(c) = 0.0013; OR = 0.72; 95% CI 0.60, 0.86). Remarkably, the Lys656Asn SNP showed contrasting allele distribution in two cohorts of 108 and 88 German cases diagnosed with Churg-Strauss syndrome (CSS, combined P = 0.0067; OR = 1.41; 95% CI 1.10, 1.81), whereas identical allele frequencies were revealed when comparing British WG and microscopic polyangiitis cases.
  
  
  CONCLUSIONS
  While GHSR has to be further evaluated, these data provide profound evidence for an association of the LEPR Lys656Asn SNP with AAV, resulting in opposing effects in WG and CSS.
authors.affiliation: Department of Human Genetics, Ruhr University, Bochum, Germany. stefan.wieczorek@rub.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Wieczorek
authors.forename: Julia U
authors.initials: JU
authors.lastname: Holle
authors.forename: Jan P
authors.initials: JP
authors.lastname: Bremer
authors.forename: David
authors.initials: D
authors.lastname: Wibisono
authors.forename: Frank
authors.initials: F
authors.lastname: Moosig
authors.forename: Harald
authors.initials: H
authors.lastname: Fricke
authors.forename: Gunter
authors.initials: G
authors.lastname: Assmann
authors.forename: Lorraine
authors.initials: L
authors.lastname: Harper
authors.forename: Larissa
authors.initials: L
authors.lastname: Arning
authors.forename: Wolfgang L
authors.initials: WL
authors.lastname: Gross
authors.forename: Joerg T
authors.initials: JT
authors.lastname: Epplen
mesh_terms: D016022:Case-Control Studies; D015267:Churg-Strauss Syndrome / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D054439:Ghrelin / Q000235:genetics; D014890:Granulomatosis with Polyangiitis / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D020738:Leptin / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D054440:Receptors, Ghrelin / Q000235:genetics; D054411:Receptors, Leptin / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D054439:Ghrelin; D020738:Leptin; D054440:Receptors, Ghrelin; D054411:Receptors, Leptin