TY - JOUR
T1 - A genome-wide association study identifies nucleotide variants at SIGLEC5 and DEFA1A3 as risk loci for periodontitis
AU - Munz, M.
AU - Willenborg, C.
AU - Richter, G.M.
AU - Jockel-Schneider, Y.
AU - Graetz, C.
AU - Staufenbiel, I.
AU - Wellmann, J.
AU - Berger, K.
AU - Krone, B.
AU - Hoffmann, P.
AU - van der Velde, N.
AU - Uitterlinden, A.G.
AU - de Groot, L.C.P.G.M.
AU - Sawalha, A.H.
AU - Direskeneli, H.
AU - Saruhan-Direskeneli, G.
AU - Guzeldemir-Akcakanat, E.
AU - Keceli, H.G.
AU - Laudes, M.
AU - Noack, B.
AU - Teumer, A.
AU - Holtfreter, B.
AU - Kocher, T.
AU - Eickholz, P.
AU - Meyle, J.
AU - Doerfer, C.
AU - Bruckmann, C.
AU - Lieb, W.
AU - Franke, A.
AU - Schreiber, S.
AU - Nohutcu, R.M.
AU - Erdmann, J.
AU - Loos, B.G.
AU - Jepsen, S.
AU - Dommisch, H.
AU - Schaefer, A.S.
N1 - Correction published in: Human Molecular Genetics, Volume 27, Issue 5, 1 March 2018, Pages 941–942,.
PY - 2017/7
Y1 - 2017/7
N2 - Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. The disease is characterized by destruction of the alveolar bone due to an aberrant host inflammatory response to a dysbiotic oral microbiome. Previous genome-wide association studies (GWAS) have reported several suggestive susceptibility loci. Here, we conducted a GWAS using a German and Dutch case-control sample of aggressive periodontitis (AgP, 896 cases, 7,104 controls), a rare but highly severe and early-onset form of periodontitis, validated the associations in a German sample of severe forms of the more moderate phenotype chronic periodontitis (CP) (993 cases, 1,419 controls). Positive findings were replicated in a Turkish sample of AgP (223 cases, 564 controls). A locus at SIGLEC5 (sialic acid binding Ig-like lectin 5) and a chromosomal region downstream of the DEFA1A3 locus (defensin alpha 1-3) showed association with both disease phenotypes and were associated with periodontitis at a genome-wide significance level in the pooled samples, with P = 1.09E-08 (rs4284742,-G; OR = 1.34, 95% CI = 1.21-1.48) and P = 5.48E-10 (rs2738058,-T; OR = 1.28, 95% CI = 1.18-1.38), respectively. SIGLEC5 is expressed in various myeloid immune cells and classified as an inhibitory receptor with the potential to mediate tyrosine phosphatases SHP-1/-2 dependent signaling. Alpha defensins are antimicrobial peptides with expression in neutrophils and mucosal surfaces and a role in phagocyte-mediated host defense. This study identifies the first shared genetic risk loci of AgP and CP with genome-wide significance and highlights the role of innate and adaptive immunity in the etiology of periodontitis.
AB - Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. The disease is characterized by destruction of the alveolar bone due to an aberrant host inflammatory response to a dysbiotic oral microbiome. Previous genome-wide association studies (GWAS) have reported several suggestive susceptibility loci. Here, we conducted a GWAS using a German and Dutch case-control sample of aggressive periodontitis (AgP, 896 cases, 7,104 controls), a rare but highly severe and early-onset form of periodontitis, validated the associations in a German sample of severe forms of the more moderate phenotype chronic periodontitis (CP) (993 cases, 1,419 controls). Positive findings were replicated in a Turkish sample of AgP (223 cases, 564 controls). A locus at SIGLEC5 (sialic acid binding Ig-like lectin 5) and a chromosomal region downstream of the DEFA1A3 locus (defensin alpha 1-3) showed association with both disease phenotypes and were associated with periodontitis at a genome-wide significance level in the pooled samples, with P = 1.09E-08 (rs4284742,-G; OR = 1.34, 95% CI = 1.21-1.48) and P = 5.48E-10 (rs2738058,-T; OR = 1.28, 95% CI = 1.18-1.38), respectively. SIGLEC5 is expressed in various myeloid immune cells and classified as an inhibitory receptor with the potential to mediate tyrosine phosphatases SHP-1/-2 dependent signaling. Alpha defensins are antimicrobial peptides with expression in neutrophils and mucosal surfaces and a role in phagocyte-mediated host defense. This study identifies the first shared genetic risk loci of AgP and CP with genome-wide significance and highlights the role of innate and adaptive immunity in the etiology of periodontitis.
U2 - 10.1093/hmg/ddx151
DO - 10.1093/hmg/ddx151
M3 - Article
C2 - 28449029
SN - 0964-6906
VL - 26
SP - 2577
EP - 2588
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 13
ER -
