Patients with drug-induced hepatocellular jaundice have 11.7% chance of progressing to death or transplantation. Amoxicillin-clavulanate stands out as the most common drug related to DILI.
Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.
Background & Aims
Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction.
Methods
We performed a genome-wide association study using 822,927 single-nucleotide polymorphism (SNP) markers from 201 White European and US cases of AC-DILI and 532 population controls, matched for genetic background.
Results
AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with a human leukocyte antigen (HLA) class II SNP (rs9274407, P=4.8×10−14), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10−4). An independent association was observed in the class I region (rs2523822, P=1.8×10−10), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=0.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10−6) and HLA-DQB1*0602 (P=5×10−10), and their interaction (P=0.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of auto-immunerelated genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10−4).
Conclusions
Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI, but have limited utility as predictive or diagnostic biomarkers because of the low positive-predictive values.
Increased age and female sex are suggested risk factors for drug-induced hepatotoxicity (DILI). We studied the influence of these variables on the propensity to develop DILI, as well as its clinical expression and outcome. All cases of DILI submitted to the Spanish Registry between April 1994 and August 2007 were analyzed. Six hundred three DILI cases (310 men; mean age, 54 years) showed a similar sex distribution, reaching two peaks in the 40-to 49-year-old and 60-to 69-year-old age groups. No cases were recorded in the 20-to 29-year-old group. Patients aged >60 years accounted for 46% of the cases, with a male predominance (158 males, 118 females; P ؍ 0.009), as opposed to younger patients. Older age was independently associated with cholestatic type of injury (odds ratio for an age interval for 1 year: 1.024 [95% confidence interval: 1.010-1.038]; male/female ratio, 1:2; P ؍ 0.001) and younger age with hepatocellular damage (odds ratio: 0.983 [95% confidence interval: 0.972-0.994]; female/male ratio, 1:2; P ؍ 0.002). In the mixed group, no age effect was evident. Outcome with fulminant liver failure/liver transplantation was more frequently encountered in women (P < 0.01). Conclusion: Neither older age nor female sex are predisposing factors to overall DILI. However, older age is a determinant for cholestatic damage with a male predominance, whereas younger age is associated with cytolytic damage and a female overrepresentation. Women distinctly exhibit the worst outcome. Knowledge of these phenotypic associations could guide differential diagnosis and attribution of causality in
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