Gene polymorphisms in primary biliary cirrhosis: association with the disease and hepatic osteopathy

Genetic factors have been implicated in the pathogenesis of osteoporosis, a common disorder in primary biliary cirrhosis (PBC). Estrogen receptor-alpha gene (ER-�), vitamin-D-receptor gene (VDR) and IL-1-receptor-antagonist gene (IL-1RN) are all attractive candidates for osteoporosis susceptibility. Furthermore insulin-like growth factor-I (IGF-I) gene microsatellite repeat polymorphism was found to be associated with osteoporosis in some studies and collagen-I�1 (COLIA1) Sp1 s allele was associated with lower bone mineral density (BMD) in one study in PBC. IGF-I treatment restored osteopenia and reduced fibrogenesis in experimental cirrhosis. In this study we summarize our results on polymorphisms of the above genes and bone disease in Hungarian PBC patients. Patients and methods: 70 female patients with PBC were enrolled (age:57.6yrs, range:37-76yrs, each AMA-M2 positive, stage II-IV). 139 age-matched female subjects served as controls (age: 55.9 yrs, range:43-72 yrs). COLIA1 Sp1 and IGF-I microsatellite polymorphisms were determined by PCR in all patients and controls. VDR BsmI, IL-1RN variable-number tandem repeat (VNTR) and ER-� PvuII and XbaI polymorphisms were detected in 33 patients and controls. BMD was measured by dual energy x-ray absorptiometry (Lunar,Prodigy,USA) in lumbar spine (LS) and femoral neck (FN). Results: There was no difference in IGF-I microsatellite repeat polymorphism (192/192=34.2%, 194/192=28.6%, other=37.2%) and COLIA1 Sp1 polymorphism (SS=72.9%, Ss=22.8% and ss=4.3%) and IL-1 VNTR polymorphism between PBC patients and controls, however, the COLIA1 Sp1 s allele was significantly less frequent in patients with PBC (p=0.038). The genotype frequency of VDR BsmI (BB=57.5%, Bb=33.3%, bb=9.1%, p=0.01) and ER-a PvuII (PP=18.2%, Pp=75.6%, pp=6.2%, p=0.03) and XbaI (XX=9.1%, Xx=90.9%, xx=0%, p=0.0003) of the patients was different from that of the control group, with higher frequency of the BB, Pp and Xx genotypes in PBC. Osteoporosis (t score<-2.5) was detected in 22 patients (31.4%). Osteoporotic patients were elder and had longer disease history (p=0.01 for both). An association was found between the IGF-I genotypes and ODM data, the 192/192 genotype was associated with higher FN Z-score compared to other genotypes (p=0.036). Conclusions: In contrast to previous studies the COLIA1 Sp1 s allele was less frequent in patients with PBC, and its presence was not associated with BMD. We confirmed previous findings on higher frequency of VDR BsmI BB genotype in patients with PBC. The ER-α PvuII and XbaI Pp and Xx genotypes were more frequent in PBC patients, while IL-1RN VNTR and IGF-I microsatellite repeat polymorphism was not different. Since IGF-I polymorphism was associated to BMD, it may be hypothesized that not COLIA1 but IGF-I together with other genetic and environmental factors may be involved in the complex regulation of BMD in PBC.