Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease.
OBJECTIVE
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 (r(2) > 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).


CONCLUSIONS
Our study suggests a potential role of the CLOCK polymorphisms and their haplotypes in susceptibility to NAFLD and disease severity.
Sookoian
Silvia
S
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
Castaño
Gustavo
G
Gemma
Carolina
C
Gianotti
Tomas-Fernández
TF
Pirola
Carlos-Jose
CJ
D001706:Biopsy; D056926:CLOCK Proteins; D016022:Case-Control Studies; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012720:Severity of Illness Index; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
D015534:Trans-Activators; D056926:CLOCK Proteins; C538943:CLOCK protein, human
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