Prevalence of CARD15/NOD2 mutations in Caucasian healthy people.
BACKGROUND
Crohn's disease (CD) has been associated with CARD15/NOD2 mutations in Caucasians. The R702W, G908R, and 1007fs mutations represent 82% of the mutated chromosomes. The relative risk of developing CD in homozygous or compound heterozygous people has been estimated as between 10 and 40 times that of the general population. This high risk may support the opinion that CARD15/NOD2 variants are strong CD risk factors at the individual and population levels.


METHODS
The allele and genotype frequencies were calculated for the R702W, G908R, and 1007fs mutations in 3,575 Caucasian healthy controls recruited by 15 groups distributed on three continents. Geographic homogeneity was tested and the observed proportion of double mutants was compared with the expected value using chi2 tests.


RESULTS
The allele frequencies of the R702W, G908R, and 1007fs mutations were 4.3% (3.6-4.9), 1.2% (0.8-1.6), and 2.3% (1.8-2.8), respectively, with large geographic fluctuations of the G908R, 1007fs, and wild-type alleles (P<0.0001). At the population level, no simple relationship was observed between mutation frequencies and the disease incidences in the studied populations. At the individual level, no significant deficit of double-dose mutation carriers among healthy controls was found, providing strong evidence that the penetrances of the most at-risk genotypes are low.


CONCLUSIONS
Altogether, these data confirm that CARD15/NOD2 acts in interaction with other unknown risk cofactors.
Hugot
Jean-Pierre
JP
INSERM Avenir U763; AP-HP; Université Paris 7, Hôpital Robert Debré, Paris, France.
Zaccaria
Isabelle
I
Cavanaugh
Juleen
J
Yang
Huiying
H
Vermeire
Séverine
S
Lappalainen
Maarit
M
Schreiber
Stefan
S
Annese
Vito
V
Jewell
Derek P
DP
Fowler
Elizabeth V
EV
Brant
Steven R
SR
Silverberg
Mark S
MS
Cho
Judy
J
Rioux
John D
JD
Satsangi
Jack
J
Parkes
Miles
M
D003424:Crohn Disease / Q000235:genetics; D005060:Europe / Q000453:epidemiology; D005787:Gene Frequency; D006801:Humans; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D015995:Prevalence; D012307:Risk Factors; D014481:United States / Q000453:epidemiology; D044465:White People
C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein