Investigation of the Lith6 candidate genes APOBEC1 and PPARG in human gallstone disease.
BACKGROUND
Genetic susceptibility contributes to the aetiology of gallbladder diseases as shown by multiple epidemiological studies. A major gallstone susceptibility locus (Lith6) was identified in 2003 by quantitative trait locus mapping in mice. Two attractive positional and functional candidate genes in apolipoprotein B mRNA-editing protein (APOBEC1) and peroxisome proliferator-activated receptor gamma (PPARG) are located in this interval.


OBJECTIVE
To investigate APOBEC1 and PPARG as candidate genes for common symptomatic gallstone disease in humans.


METHODS
Eight hundred and ten patients who underwent cholecystectomy for symptomatic gallstone disease (median age of onset 50) were compared with 718 sex-matched control individuals. An independent additional sample included 368 gallstone patients and 368 controls. Control individuals were sonographically free of gallstones. Haplotype tagging and all known coding single nucleotide polymorphisms were genotyped for PPARG (N=32) and APOBEC1 (N=11).


RESULTS
The investigated high-risk patient sample provides a power of greater than 80% for the detection of odds ratios down to 1.45. No evidence of association of the two genes in the single-point tagging markers, coding variants and in the sliding window haplotype analysis was detected (all nominal single point P-values >0.04). A logistic regression analysis including age, sex and BMI as covariates was also negative (nominal P-values > or =0.08).


CONCLUSIONS
In the investigated German samples, no evidence of association of APOBEC1 and PPARG with gallstone susceptibility was detected. Systematic fine mapping of the complete Lith6 region is required to identify the causative genetic variants for gallstone in mice and humans.
Schafmayer
Clemens
C
Department of General Surgery and Thoracic Surgery, Christian-Albrechts-University Kiel, Kiel, Germany.
Völzke
Henry
H
Buch
Stephan
S
Egberts
Jan
J
Spille
Annika
A
von Eberstein
Huberta
H
Franke
Andre
A
Seeger
Markus
M
Hinz
Sebastian
S
Elsharawy
Abdou
A
Rosskopf
Dieter
D
Brosch
Mario
M
Krawczak
Michael
M
Foelsch
Ulrich R
UR
Schafmayer
Anton
A
Lammert
Frank
F
Schreiber
Stefan
S
Faendrich
Fred
F
Hampe
Jochen
J
Tepel
Juergen
J
D000071479:APOBEC-1 Deaminase; D000818:Animals; D016022:Case-Control Studies; D003564:Cytidine Deaminase / Q000235:genetics*; D042882:Gallstones / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005858:Germany; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D051379:Mice; D016017:Odds Ratio; D047495:PPAR gamma / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D018570:Risk Assessment; D012307:Risk Factors
D047495:PPAR gamma; D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase