Comparison between siblings and twins supports a role for modifier genes in ADPKD.
BACKGROUND
Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by intrafamilial variability in renal disease progression, which could result from a combination of environmental and genetic factors. Although a role for modifier genes has been evidenced in mouse models, direct evidence in ADPKD patients is lacking. The analysis of variability in affected siblings and monozygotic (MZ) twins would help evaluate the relative contribution of environment and genetic factors on renal disease progression in ADPKD.


METHODS
The difference in the age at end-stage renal disease (ESRD) and the intraclass correlation coefficient (ICC) were quantified in a large series of ADPKD siblings from western Europe and compared with the values obtained in a series of MZ ADPKD twins from the same geographic area.


RESULTS
Fifty-six sibships (including 129 patients) and nine pairs of MZ twins were included. The difference in the age at ESRD was significantly higher in siblings (6.9 +/- 6.0 years, range 2 months to 23 years) than in MZ twins (2.1 +/- 1.9 years, range 1 month to 6 years; P = 0.02). Furthermore, the intraclass correlation coefficient was significantly lower in siblings than in MZ twins (0.49 vs. 0.92, respectively; P = 0.003). The intrafamilial difference in the age at ESRD was not influenced by gender.


CONCLUSIONS
These data substantiate the existence of a large intrafamilial variability in renal disease progression in ADPKD siblings. The fact that the variability in siblings is in a significant excess of that found in MZ twins strongly suggests that modifier genes account for a significant part of this variability.
Persu
Alexandre
A
Division of Nephrology, Université Catholique de Louvain Medical School, Brussels, Belgium.
Duyme
Michel
M
Pirson
Yves
Y
Lens
Xosé M
XM
Messiaen
Thierry
T
Breuning
Martijn H
MH
Chauveau
Dominique
D
Levy
Micheline
M
Grünfeld
Jean-Pierre
JP
Devuyst
Olivier
O
D000328:Adult; D000367:Age Factors; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000503:physiopathology*; D012737:Sex Factors; D035781:Siblings; D014430:Twins, Monozygotic