Genetic variant c.711A>T in the hepatobiliary phospholipid transporter ABCB4 is associated with significant liver fibrosis.

Liver fibrosis is the common consequence of chronic liver diseases (CLD). Recently liver stiffness measurements (LSM) ≥ 9.1 kPa, as determined by transient elastography (TE), were demonstrated to predict significant fibrosis (stages ≥ F2) in a population-based setting. The PNPLA3 (adiponutrin) p.I148M polymorphism enhances the risk of liver injury. The aim of our study was to investigate the association between the procholestatic ABCB4 polymorphism c.711A>T and LSM ≥ 9.1 kPa in humans as well as the interaction between ABCB4 and PNPLA3 in a mouse model of chronic cholestasis. Prospectively, we recruited 712 patients with CLD (278 women, age 50 ± 13 years) with available TE results; liver biopsy results were available in 165 individuals. The ABCB4 c.711 genotype was determined by PCR-based assays. PNPLA3 expression and liver injury were studied in Abcb4-/- mice and wild-type controls. Overall, median LSM in our cohort was 6.7 kPa, and 226 individuals had LSM ≥ 9.1 kPa. Carriers of the ABCB4 variant c.711A presented more frequently with LSM ≥ 9.1 kPa (OR = 1.33, P = 0.020) and FIB-4 score ≥ 2.67 (OR = 1.38, P = 0.040). The presence of the risk allele was associated (P = 0.002) with FIB-4. In a multivariate model, the ABCB4 variant (OR = 1.43, P = 0.047) as well as BMI (P = 0.043, OR = 1.04) and age (OR = 1.02, P < 0.010) were independent risk factors for fibrosis stage ≥ F2. Abcb4 deficiency in mice led to enhanced liver injury, coupled with a decrease (P = 0.020) of hepatic PNPLA3 expression. To conclude, the procholestatic variant ABCB4 c.711A>T might represent a new genetic risk factor for clinically significant liver fibrosis. Lower expression of PNPLA3 in fibrotic Abcb4-/- livers points to the interaction between phospholipid metabolism and PNPLA3 in progressive liver injury.

The common adiponutrin variant p.I148M does not confer gallstone risk but affects fasting glucose and triglyceride levels.

Recently the common adiponutrin (PNPLA3) polymorphism p.I148M has been identified as a genetic determinant of severe forms of non-alcoholic fatty liver disease and alcoholic liver disease. Additionally, insulin resistance - linked to the development of non-alcoholic steatohepatitis - increases the risk of developing gallstones. Here we assessed whether the PNPLA3 p.I148M (c.444 C-G) polymorphism affects glucose and lipid levels and increases gallstone risk. We analysed 229 individuals with gallstones from 108 families (age 24-80 years, BMI 17-55 kg/m(2)) and 258 gallstone-free controls (age 20-70 years, BMI 14-43 kg/m(2)). Fasting glucose, triglyceride and cholesterol serum levels were determined. The p.I148M polymorphism was genotyped using a PCR-based assay with 5'-nuclease and fluorescence detection. Case-control association tests and nonparametric linkage (NPL) analysis in sib-pairs were performed. Individuals carrying the [GG] genotype had significantly (P<0.0001) higher median fasting glucose levels as compared to [GC] and [CC] carriers. After adjustment for multiple testing, we detected a trend for an association between triglyceride levels and variant adiponutrin in gallstone patients (P=0.032), and gallstone cases carrying the genotype [CC] presented with significantly higher triglyceride levels than the corresponding controls (P<0.003). No significant effects on cholesterol metabolism were detected. Neither genotype distributions nor NPL scores provided evidence for association or linkage between the PNPLA3 variant and gallstones. In conclusion, homozygous carriers of the PNPLA3 risk allele display higher fasting glucose. Although this adiponutrin variant may affect triglyceride homeostasis, it does not increase the risk of cholelithiasis.

Lymphoid pneumonitis as an immune reconstitution inflammatory syndrome in a patient with CD4 cell recovery after HAART initiation.

In the era of highly active antiretroviral therapy (HAART), immune reconstitution inflammatory syndrome (IRIS) has come to present a significant clinical challenge. Following the recovery of memory T cells, latent infections may lead to clinical and laboratory deterioration despite immunological and virological reconvalescence. However, many other forms of complications after induction of HAART, which are not entirely understood, must be included in the entity of IRIS. Here we report a case of a patient complaining of respiratory distress and fever 10 days after initiating HAART. Radiologically and clinically, his findings mimicked Pneumocystis jiroveci pneumonia. However, no infectious agent could be detected, and bronchoalveolary lavage showed a high cell count (90% lymphocytes and 4% eosinophils) consistent with interstitial pneumonitis. He improved dramatically after treatment with oral steroids.

Linkage disequilibrium mapping at DAT1, DRD5 and DBH narrows the search for ADHD susceptibility alleles at these loci.

Abnormalities in dopaminergic neurotransmission are now accepted as factors in predisposing to ADHD. Evidence of associations between dopamine transporter gene polymorphism and ADHD was first reported by Cook et al. We confirmed the DAT1 association and also identified two additional susceptibility loci at the DRD5 and DBH. Notably, none of the associated variants at these three genes are known to be expressed. Other variants within or closely mapped to the associated alleles are likely to be relevant. In this investigation, we analyse additional markers creating a high-density map across and flanking these genes, and measure intermarker linkage disequilibrium (LD). None of the newly examined markers were more strongly associated with ADHD. At DAT1, the pattern of intermarker LD and haplotype association with the phenotype between exon 9 and the 3' of the gene suggests that the functional variant at DAT1 may be located to this region. For DRD5, three markers, covering a region of approximately 68 kb including the single DRD5 exon are all associated with disease, and thus do not provide localizing information. However, the data for DBH point to a region close to the centre of the gene. Correlation between D' and physical distance was observed between markers at DAT1 and DRD5 for distances less than 50 kb. This was not the case for DBH, where LD breakdown was observed between the intron 5 and intron 9 polymorphisms although they are only 9 kb apart. Further genetic analysis is unlikely to refine the location of susceptibility variants and functional assessment of variants within associated regions is required.