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Early-onset Crohn Disease Is Associated With Male Sex and a Polymorphism in the IL-6 Promoter

Sagiv-Friedgut, Keren*; Karban, Amir; Weiss, Batya; Shaoul, Ron§; Shamir, Raanan; Bujanover, Yoram; Reif, Shimon||; Boaz, Mona#; Shani, Inbar**; Levine, Arie*; Leshinsky-Silver, Esther**

Journal of Pediatric Gastroenterology & Nutrition: January 2010 - Volume 50 - Issue 1 - p 22–26
doi: 10.1097/MPG.0b013e3181b7a6a4
Original Articles: Gastroenterology

Aims: 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.

Patients and 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.

*Pediatric Gastroenterology Unit, Wolfson Medical Center, Holon Sackler School of Medicine, Tel Aviv University, Israel

Gastroenterology Division, Rambam Medical Center, Haifa, Israel

Pediatric Gastroenterology Units of the Safra Children's Hospital, Tel Aviv, Sackler School of Medicine, Tel Aviv University, Israel

§Bnei Zion Medical Center, Haifa, Israel

Meyer Children's Hospital, Haifa, Sackler School of Medicine, Tel Aviv University, Israel

||Dana Children's Hospital, Tel-Aviv, Israel

#Epidemiology Unit, Israel

**Molecular Biology Laboratory, Wolfson Medical Center, Holon, Israel.

Received 4 October, 2008

Accepted 10 July, 2009

Address correspondence and reprint requests to Arie Levine, Pediatric Gastroenterology Unit, Wolfson Medical Center, POB 5, Holon 58100, Israel (e-mail: alevine@wolfson.health.gov.il).

The authors report no conflicts of interest.

© 2010 Lippincott Williams & Wilkins, Inc.