Differences in genetic background between active smokers, passive smokers, and non-smokers with Crohn's disease.
OBJECTIVE
Smoking behavior and genetic variations are important factors for the development of Crohn's disease (CD), but studies investigating the interaction between smoking and genetic background are scarce. We studied allelic associations of 19 confirmed variants located in 14 CD-associated genes or loci, in CD patients stratified for active smoking at diagnosis and passive smoking in childhood.


METHODS
Genotyping data of 19 CD-associated single-nucleotide polymorphisms (SNPs) were available for 310 CD patients and 976 controls. Data on active smoking at diagnosis and passive smoking in childhood were obtained through a written questionnaire and a review of medical charts.


RESULTS
The loci associated in smoking, but not in non-smoking, CD patients were 5p13.1 (rs17234657), DLG5 (rs2165047), NKX2-3 (rs10883365), and NOD2 (R702W). The loci associated in non-smoking, but not in smoking, CD patients were IL23R (rs7517847), 5p13.1 (rs9292777), IRGM (rs13361189 and rs4958847), IL12B (rs6887695), and CCNY (rs3936503). PTPN2 (rs2542151) was only associated in the smoking CD cohort (P=0.041), and not in the entire cohort (P=0.23) or in the non-smoking CD cohort (P=0.80). In passively smoking CD patients, associations with 13 SNPs in 9 loci were found, including PTPN2. In non-passive smoking CD patients, only associations with NOD2 (1007fsinsC and G908R) were found.


CONCLUSIONS
The difference in associated genes between smoking and non-smoking CD patients implies a complex gene-environment interaction. Therefore, genetic studies of CD should be stratified for smoking behavior, as otherwise moderately associated genes such as PTPN2 can be missed.
van der Heide
Frans
F
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Nolte
Ilja M
IM
Kleibeuker
Jan H
JH
Wijmenga
Cisca
C
Dijkstra
Gerard
G
Weersma
Rinse K
RK
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000483:Alleles; D015331:Cohort Studies; D016001:Confidence Intervals; D003424:Crohn Disease / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D055106:Genome-Wide Association Study; D006801:Humans; D015994:Incidence; D053762:Interleukin-12 Subunit p40 / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011336:Probability; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics*; D012016:Reference Values; D018570:Risk Assessment; D012737:Sex Factors; D012907:Smoking / Q000453:epidemiology / Q000235:genetics*; D018709:Statistics, Nonparametric; D014028:Tobacco Smoke Pollution / Q000706:statistics & numerical data*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
C114461:DLG5 protein, human; C500879:IL12B protein, human; D053762:Interleukin-12 Subunit p40; D008565:Membrane Proteins; D014028:Tobacco Smoke Pollution; D025521:Tumor Suppressor Proteins; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2