ABCB4 mutations underlie hormonal cholestasis but not pediatric idiopathic gallstones

Table 1 Characteristics of young women with low phospholipid-associated cholelithiasis syndrome and proven ABCB4 mutations

Patient ID	Year of birth	Age at cholecystectomy (yr)	Age at liver biopsy (yr)	Age at pregnancies (yr)	Age (yr), contraceptive, complication
I	1980	20	19, periportal fibrosis	Nulliparous	18 Minisiston, withdrawn for CIC
					22 Mercilon, withdrawn for CIC
II	1978	17	21, periportal fibrosis	Nulliparous	18 Tri-regol, withdrawn for CIC
III	1973	22	22, periportal fibrosis	30, with ICP	20-22 Cilest, withdrawn for CIC
IV	1967	28	31, normal histology	19, without ICP	28 Tri-regol, withdrawn for CIC
					39-now Lunafem, tolerated
V	1973	20	20, periportal fibrosis	23, without ICP	19-?, withdrawn for CIC
				32, without ICP	24-31 Marvelon, tolerated
					32-now Mirena, permanent pruritus, GGT twice normal

Chemical composition of contraceptives: (1) Minisiston (Jenapharm, Jena, Germany): ethinylestradiol 0.030 mg; levonorgestrel 0.125 mg; (2) Mercilon (Organon, Oss, The Netherlands): ethinylestradiol 0.020 mg; desogestrel 0.150 mg; (3) Tri-regol (Chemical Works of Gedeon Richter, Budapest, Hungary): ethinylestradiol 0.030 - 0.040 - 0.030 mg; levonorgestrel 0.050 - 0.075 - 0.125 mg; (4) Cilest (Janssen Pharmaceutica, Beerse, Belgium): ethinylestradiol 0.035 - 0.035 - 0 mg; norgestimate 0.250 - 0.250 - 0 mg; (5) Lunafem (Bayer Schering Pharma, Berlin, Germany): ethinylestradiol 0.020 mg; gestodene 0.075 mg; (6) Marvelon (Organon, Oss, The Netherlands): ethinylestradiol 0.030 mg; desogestrel 0.150 mg; (7) Mirena (Bayer Schering Pharma, Berlin, Germany): levonorgestrel 0.020 mg. Estrogen free intrauterine application. CIC: Contraceptive-induced cholestasis.

Table 2 Known variations in ABCB4, ABCB11 and ABCG8 found in 35 pediatric subjects with idiopathic gallstones

Patient. ID	Variations in the coding sequence of ABCB4						ABCB11 low expression allele	ABCG8 variation
	c.147C>T	c.175C>T	c.459T>C	c.504C>T	c.711A>T	c.1954A>G	c.1331T>C	c.55G>C
	Ser49Ser	Leu59Leu	Phe153Phe	Asn168Asn	Ile237Ile	Arg652Gly	Val444Ala	Asp19His
	rs8187789	rs2302387	rs2230027	rs1202283	rs2109505	rs2230028	rs2287622	rs11887534
1	CC	CC	TT	TT	AA	AA	CC	GG
2	CC	CC	TT	CT	AA	AA	TC	GG
3	CC	CC	TT	CT	AA	AA	TC	GG
4	CC	CC	TT	CT	AT	AG	TC	GG
5	CC	CC	TT	TT	AA	AA	CC	GG
6	CC	CC	TT	CC	AA	AA	TC	GG
7	CC	CC	TT	CT	AA	AA	TC	GG
8	CC	CC	TT	CC	AA	AG	TC	GG
9	CC	CC	TT	TT	AA	AA	TT	GG
10	CC	CC	TT	TT	AA	AA	CC	GG
11	CC	CC	TT	TT	AA	AA	TC	GG
12	CC	CC	TT	TT	AA	AA	CC	GG
13	CC	CC	TT	CT	AA	AA	TC	GG
14	CC	CC	TT	CC	AA	AA	CC	GG
15	CC	CC	TT	TT	AA	AA	TC	GC
16	CC	CC	TT	CC	AA	AA	TC	GC
17	CC	CC	TT	CC	AA	AA	TC	GG
18	CC	CC	TT	TT	AA	AA	TC	GC
19	CC	CC	TT	CT	AA	AA	TC	GC
20	CC	CC	TT	CT	AA	AA	TT	GG
21	CC	CC	TT	TT	AA	AA	TC	GG
22	CC	CC	TT	CT	AA	AA	TT	GG
23	CC	CC	TT	CT	AA	AA	TT	GG
24	CC	CT	TT	CC	AT	AA	CC	GG
25	CC	CC	TT	CC	AA	AA	TC	GG
26	CT	CT	TC	CC	AA	AG	TC	GG
27	CC	CC	TT	TT	AA	AA	TC	GG
28	CC	CC	TT	TT	AA	AA	TT	GG
29	CC	CC	TT	CT	AA	AA	TT	GG
30	CC	CC	TT	TT	AA	AA	CC	GC
31	CC	CC	TT	CT	AA	AA	TT	GC
32	CC	CC	TT	CT	AA	AA	TT	GG
33	CC	CC	TT	TT	AA	AA	TC	GG
34	CC	CC	TT	CC	AA	AA	TT	GG
35	CC	CC	TT	TT	AA	AA	CC	GG
Allelic frequency of variant alleles in patients with gallstones, HapMap populations and Czech population controls
Allele	T	T	C	T	T	G	C	G
Gallstone patients	0.014	0.029	0.014	0.571	0.029	0.043	0.471	0.086
HapMap CEU	0	0.112	01	0.664	0.175	0.075	0.408	0.085
HapMap HCB	0	0.167	01	0.344	0.222	0.023	0.333	0.022
HapMap JPT	0	0.273	01	0.442	0.300	0.023	0.261	0.011
HapMap YRI	0.042	0.525	0.11	0	0.362	0.392	0.425	0.042
Czech controls (n = 150)	n.d.	n.d.	n.d.	n.d.	n.d.	0.090	0.400	0.0672

¹Results from corresponding populations studied in Environmental Genome Project (NIEHS ES15478 project). HapMap population data were not available for this variation;

²Frequency in 285 Czech controls[15]. n.d.: Not done.