A common variant in the hepatobiliary phospholipid transporter ABCB4 modulates liver injury in PBC but not in PSC: prospective analysis in 867 patients

Clinical characteristics of the study cohorts

Table 1A, B summarize the clinical characteristics of study cohorts. In total 867 Polish patients (456 with PBC and 411 with PSC, 551 women, age range 17–87 years) were included in the study. Among them, 331 were recruited at the Pomeranian Medical University in Szczecin (Table 1A) and 536 at the Medical University in Warsaw (Table 1B). In the Szczecin cohort, 196 patients had PBC (174 women, age range 23–87 years) and 135 had PSC (39 women, age range 17–69 years). The PBC group was characterized by a higher number of cirrhotic patients compared to PSC patients (41%/35%, respectively). As demonstrated in Table 1A, in the cohort from Szczecin, patients with PBC were older, had significantly higher BMI but lower serum hemoglobin, platelet count and alanine aminotransferase (ALT) as compared to patients with PSC. In the Warsaw cohort, 260 patients had PBC (241 women, age range 29–86 years) and 276 patients had PSC (97 women, age range 22–81 years). Compared to patients with PSC, PBC patients were older, of higher BMI and had significantly lower serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), hemoglobin and platelet counts (Table 1B). The control cohort from Szczecin consisted of 150 healthy blood donors (127 women), the control cohort from Warsaw comprised 318 patients without acute or chronic liver disease (290 women).

Table 1 Clinical and laboratory characteristic of PBC and PSC cohorts recruited in (A) Szczecin, (B) WarsawThe ABCB4 c.711A > T is associated with liver injury in patients with PBC

The ABCB4 c.711A > T (rs2109505) polymorphism was successfully genotyped in all patients and controls. The exact distribution of genotypes in patients with PBC, PSC and in controls is presented in Table 2. The ABCB4 c.711A > T risk allele was carried by a total of 833 (96.1%) patients that were included in the analysis (PSC = 95.8%, PBC = 96.3%). We did not detect any deviation from the HWE in any of the PBC or PSC cohorts (P > 0.05). There was no difference of genotype distribution between study patients and controls in either group (all P > 0.05 by Armitage’s trend test). We also did not detect differences in the distribution of this variant between patients from Szczecin and Warsaw (P > 0.05).

Table 2 Distribution of the ABCB4 c.711A > T genotypes in patients with PBC, PSC and in controls

Subsequently, we compared the distribution of ABCB4 variant in patients with and without liver cirrhosis separately for the PBC and PSC (Table 3). This analysis demonstrated that in both cohorts of PBC patients, carriers of the risk variant had increased odds of developing liver cirrhosis risk (Szczecin: OR = 1.84, P = 0.025; Warsaw: OR = 1.53, P = 0.039 by Armitage`s trend test). In contrast, the risk-associated allele did not increase the risk of cirrhosis in PSC patients (Table 3, all P > 0.05). As shown in Fig. 1, the ABCB4 c.711A > T polymorphism modulated serum AST (P = 0.018, Fig. 1A), ALP (P < 0.001, Fig. 1B), GGT (P = 0.003, Fig. 1C) in the PBC patients from Szczecin and serum ALP (P = 0.021, Fig. 2A) and GGT (P = 0.045, Fig. 2B) in the PBC patients from Warsaw.

Table 3 Distribution of the ABCB4 c.711A > T genotypes in patients with and without cirrhosisFig. 1figure 1

Serum AST (A), ALP (B) and GGT (C) in relation to the presence of the ABCB4c.711A > T variant in patients with PBC from Szczecin

Fig. 2figure 2

Serum ALP (A) and GGT (B) in relation to the presence of the ABCB4 c.711A > T variant in patients with PBC from Warsaw

We performed logistic regression analyses to investigate additional non-genetic factors for cirrhosis in our patients with PBC. As shown in Table 4A, univariate regression analysis in patients from Szczecin demonstrated significant associations of cirrhosis with both ABCB4 c.711A > T and patients' gender. Multivariate analysis demonstrated that both the ABCB4 c.711A > T polymorphism and patients' gender represent two independent determinants of cirrhosis in our cohort (Table 4A). In the Warsaw PBC cohort, univariate and multivariate regression analysis showed significant associations of ABCB4 c.711A > T, as well as patients` age and gender with cirrhosis (all P < 0.05, Table 4B).

Table 4 Risk factors for developing liver cirrhosis in patients with PBC (A) Szczecin, (B) Warsaw

For 148 patients of the Szczecin PBC cohort, clinical data were collected at two time points with a mean follow-up of 8 ± 4 years. We detected significant improvements in laboratory findings (AST, ALT, ALP and GGT) during the follow-up (Table 5A), which was not affected by the ABCB4 c.711A > T genotype (P > 0.05). On the other hand, a total of 22 patients in this cohort developed cirrhosis, and this risk was significantly modulated by the ABCB4 c.711A > T risk variant (OR = 5.65, P = 0.040 by Armitage's trend test, Fig. 3).

Table 5 Clinical and laboratory characteristic of (A) 148 patients with PBC at two time points (follow-up: 8 ± 4 years)—Szczecin cohort, (B) 214 patients with PBC at two time points (follow-up: 4 ± 2 years)—Warsaw cohortFig. 3figure 3

Frequencies of the ABCB4 c.711A > T genotypes in patients with PBC from Szczecin who did and did not develop de novo cirrhosis during the follow-up period. The ABCB4 c.711A > T risk allele was significantly more frequent in patients who developed cirrhosis

In a total of 214 PBC patients recruited in Warsaw, clinical data were collected at two time points with a mean follow-up 4 ± 2 years. During follow-up, we observed significant improvements in laboratory findings (AST, ALT, ALP and GGT, Table 5B), and 46 patients developed cirrhosis. However, in this cohort the presence of ABCB4 c.711A > T did not modulate the risk of cirrhosis during follow-up (P > 0.05).

In contrast to the PBC patients, ABCB4 c.711A > T did not modulate liver injury in patients with PSC (all P > 0.05). The risk of transplantation was not increased by the presence of ABCB4 c.711A > T in either PSC or PBC patients (all P > 0.05). In the PSC cohort from Warsaw, recurrence of PSC after transplantation was detected in 24 patients. The ABCB4 c.711A > T risk allele was not associated with PSC recurrence (P > 0.05). Although data presented recently in the literature [18] describe effects of the ABCB4 genetic variants on patients' wellbeing, we did not detect any significant association between the ABCB4 polymorphism and HRQoL in either PBC or PSC patients (Additional file 1:  S1 Table ).

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