Identification of a shared genetic susceptibility locus for coronary heart disease and periodontitis.
Recent studies indicate a mutual epidemiological relationship between coronary heart disease (CHD) and periodontitis. Both diseases are associated with similar risk factors and are characterized by a chronic inflammatory process. In a candidate-gene association study, we identify an association of a genetic susceptibility locus shared by both diseases. We confirm the known association of two neighboring linkage disequilibrium regions on human chromosome 9p21.3 with CHD and show the additional strong association of these loci with the risk of aggressive periodontitis. For the lead SNP of the main associated linkage disequilibrium region, rs1333048, the odds ratio of the autosomal-recessive mode of inheritance is 1.99 (95% confidence interval 1.33-2.94; P = 6.9 x 10(-4)) for generalized aggressive periodontitis, and 1.72 (1.06-2.76; P = 2.6 x 10(-2)) for localized aggressive periodontitis. The two associated linkage disequilibrium regions map to the sequence of the large antisense noncoding RNA ANRIL, which partly overlaps regulatory and coding sequences of CDKN2A/CDKN2B. A closely located diabetes-associated variant was independent of the CHD and periodontitis risk haplotypes. Our study demonstrates that CHD and periodontitis are genetically related by at least one susceptibility locus, which is possibly involved in ANRIL activity and independent of diabetes associated risk variants within this region. Elucidation of the interplay of ANRIL transcript variants and their involvement in increased susceptibility to the interactive diseases CHD and periodontitis promises new insight into the underlying shared pathogenic mechanisms of these complex common diseases.
Schaefer
Arne S
AS
Institute for Clinical Molecular Biology, University Medical Center Schleswig-Holstein, Kiel, Germany. a.schaefer@ikmb.uni-kiel.de
Richter
Gesa M
GM
Groessner-Schreiber
Birte
B
Noack
Barbara
B
Nothnagel
Michael
M
El Mokhtari
Nour-Eddine
NE
Loos
Bruno G
BG
Jepsen
Søren
S
Schreiber
Stefan
S
D000328:Adult; D000368:Aged; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D003327:Coronary Disease / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010518:Periodontitis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016372:RNA, Antisense / Q000235:genetics*
C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016372:RNA, Antisense