Early-onset Crohn disease is associated with male sex and a polymorphism in the IL-6 promoter.
OBJECTIVE
Pediatric onset of Crohn disease (CD) is characterized by male sex predominance while adult-onset disease demonstrates female sex predominance. It has been postulated that this phenomenon may be genetically determined or due to an effect of estrogen on age of onset. Interleukin (IL)-6 modulates the TH17 pathway, and the IL-6 promoter is modulated by estrogen, possibly linking genetically determined inflammation and the presence of estrogen. The aim of our study was to investigate whether differences in IL-6 promoter genotype could explain male sex in earlier disease onset.


METHODS
We genotyped 333 patients with CD and 100 controls, 162 pediatric-onset patients (age of onset 18 years and younger) for the IL-6-174 polymorphic site. Genotype, sex, and age of onset were compared.


RESULTS
Males with IL-6-174GG genotype (the wild-type allele) had an increased risk for a younger age of onset compared to males with IL-6-174GC or CC genotype (G --> C genotype), hazard ratio (HR) 1.49, P = 0.02, 95% confidence interval (CI) 1.07-2.09. Females with GG genotype were not found to have an increased risk for a younger age of onset compared with females with G --> C genotype, HR 1.01, P = 0.96, 95% CI 0.72-1.41.


CONCLUSIONS
Males with IL-6-174GG genotype are prone to develop CD at a younger age than males with the IL-6-174G --> C genotype. Our study suggests that age of onset may be modified by the IL-6-174GG genotype and this modification is sex dependent. This may be due to increased transcription of IL-6, an effect that may be repressed by estrogen in females.
Sagiv-Friedgut
Keren
K
Pediatric Gastroenterology Unit, Wolfson Medical Center, Holon Sackler School of Medicine, Tel Aviv University, Israel.
Karban
Amir
A
Weiss
Batya
B
Shaoul
Ron
R
Shamir
Raanan
R
Bujanover
Yoram
Y
Reif
Shimon
S
Boaz
Mona
M
Shani
Inbar
I
Levine
Arie
A
Leshinsky-Silver
Esther
E
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D002648:Child; D003424:Crohn Disease / Q000235:genetics*; D004967:Estrogens; D005260:Female; D005838:Genotype; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D055815:Young Adult
D004967:Estrogens; D015850:Interleukin-6