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World J Gastroenterol. Aug 21, 2007; 13(31): 4242-4248
Published online Aug 21, 2007. doi: 10.3748/wjg.v13.i31.4242
Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease
Silvia Sookoian, Gustavo Castaño, Carolina Gemma, Tomas Fernández Gianotti, Carlos Jose Pirola
Silvia Sookoian, Carolina Gemma, Tomas Fernández Gianotti, Carlos Jose Pirola, Instituto de Investigaciones Medicas, A. Lanari. Universidad de Buenos Aires, CONICET, Combatiente de Malvinas 3150, 1427- Ciudad Autonoma de Buenos Aires, Argentina
Silvia Sookoian, Gustavo Castaño, Consejo de Investigación, GCBA, Buenos Aires, Argentina
Author contributions: All authors contributed equally to the work.
Supported by Grant B119 (Universidad de Buenos Aires), PICT 25920 (Agencia Nacional de Promoción Científica y Tecnológica) and PIP 5195 (Consejo Nacional de Investigaciones Científicas y Técnicas). SS, CG and CJP belong to Consejo Nacional de Investigaciones Científicas y Técnicas
Correspondence to: Silvia Sookoian, MD, PhD, Instituto de Investigaciones Medicas, A. Lanari. Universidad de Buenos Aires, CONICET, Combatiente de Malvinas 3150, 1427- Ciudad Autonoma de Buenos Aires, Argentina. ssookoian@intramed.net
Telephone: +54-11-45148701-167 Fax: +54-11-45238947
Received: March 26, 2007
Revised: April 23, 2007
Accepted: April 27, 2007
Published online: August 21, 2007
Abstract

AIM: To investigate the role of gene variants and derived haplotypes of the CLOCK transcription factor in nonalcoholic fatty liver disease (NAFLD) and their relation with the disease severity.

METHODS: A total of 136 patients with NAFLD and 64 healthy individuals were studied. Liver biopsy was performed in 91 patients. Six tag SNPs showing a minor allele frequency > 10% (rs1554483 C/G; rs11932595 A/G; rs4580704 C/G; rs6843722 A/C; rs6850524 C/G and rs4864548 A/G) encompassing 117 kb of chromosome 4 and representing 115 polymorphic sites (r2 > 0.8) were genotyped.

RESULTS: rs11932595 and rs6843722 showed significant associations with NAFLD (empiric P = 0.0449 and 0.023, respectively). A significant association was also observed between clinical or histologic spectrum of NAFLD and rs1554483 (empiric P = 0.0399), rs6843722 (empiric P = 0.0229) and rs6850524 (empiric P = 0.00899) and between fibrosis score and rs1554483 (empiric P = 0.02697), rs6843722 (empiric P = 0.01898) and rs4864548 (empiric P = 0.02697). Test of haplotypic association showed that CLOCK gene variant haplotypes frequencies in NAFLD individuals significantly differed from those in controls (empiric P = 0.0097).

CONCLUSION: Our study suggests a potential role of the CLOCK polymorphisms and their haplotypes in susceptibility to NAFLD and disease severity.

Keywords: Circadian rhythm; Circadian locomoter output cycles protein kaput; Gene variants; Haplotypes; Fatty liver; Liver disease; Obesity; Nonalcoholic steatohepatitis