Nature Genetics pp 835 - 843

The identification of a gene contributing to the proliferation of fibrous tissue in the liver has been reported in a study in the August issue of Nature Genetics. Chronic liver diseases lead to such liver fibrosis, involving the degradation of normal tissue and replacement with fibrous tissue (scarring), and are the 10th leading cause of mortality in the United States and the 16th globally. Infection with hepatitis C virus (HCV) is one of the frequent causes of chronic liver disease, with approximately 25% of individuals with chronic HCV developing liver fibrosis within 30 years after infection.

Frank Lammert and colleagues first identified the gene (complement factor 5) associated with liver fibrosis in mice, and then confirmed this association in a human population of individuals positive for hepatitis C virus infection. Complement factor 5, which has also been associated with susceptibility to asthma, may contribute to liver fibrogenesis by promoting inflammation or tissue remodeling, although its precise mechanism of action is not yet known. In mice, introducing inhibitors of this protein reduced the extent of liver fibrosis. This suggests potential drug targets reducing, or at least delaying, progression of liver fibrosis in individuals with chronic hepatitis C infection and chronic liver diseases.

Nature Genetics pp 829- 834 and pp 820- 828

In the August issue of Nature Genetics, two research studies present evidence for a new genetic factor underlying two human immunodeficiency syndromes. Common variable immunodeficiency (CVID), the most prevalent primary immunodeficiency, is characterized by various immune-system abnormalities and defective formation of all antibody types. A related syndrome, IgA deficiency (IgAD), is characterized by selective deficiency in IgA (immunoglobulin A) antibodies. IgA protects against infections of the mucous membranes lining the mouth, airways and digestive tract.

Bodo Grimbacher and colleagues report the identification of a gene defective in several families and unrelated individuals with CVID. In an accompanying study, Raif Geha and colleagues report defects in the same gene in individuals with either CVID or IgAD. The gene, encoding the protein TACI, is involved in switching between antibody types in antibody-producing white blood cells.

CVID and IgAD have common and diverse clinical presentations but are particularly characterized by increased risk of infection and autoimmune disorders. A mixture of genetic and environmental factors is thought to influence risk of developing these syndromes but the underlying genetic causes of CVID are largely unknown. CVID and IgAD are often found in the same families, and so a common genetic basis for these syndromes has long been suspected.

Nature Genetics pp 863- 867

A genetic variant associated with susceptibility to obesity and diabetes has been reported in a study in the August issue of Nature Genetics.

Philippe Froguel and colleagues conducted a large-scale study, including several thousand individuals with childhood or adult obesity and type II diabetes, to examine the genetic factors predisposing to disease. They identified a gene associated with increased risk of obesity and diabetes. The gene, ENPP1, is involved with the cellular response to insulin, and may interfere with normal insulin induced signals. Higher expression of this protein, as was found in this study amongst children with obesity or diabetes, may mimic the effects of insulin resistance in the brain, where insulin causes appetite suppression.

The authors suggest that inherited increased expression of this protein may exaggerate insulin resistance and contribute to excessive fat accumulation.