Genetic variants associated with rheumatoid arthritis

Genetic variants in a region on chromosome 6 are associated with risk of rheumatoid arthritis, report two studies online this week in Nature Genetics. Rheumatoid arthritis is the most common inflammatory arthritis, affecting up to 1% of the adult population, and these variants join a very short list of confirmed genetic factors that affect susceptibility to the disease.

Robert Plenge and colleagues carried out a genome-wide association study of individuals with rheumatoid arthritis, identifying a variant on chromosome 6, which was very close to a different variant on chromosome 6 identified in previous studies. They show that these variants probably independently contribute to risk of the disease.

In a separate study, Jane Worthington and colleagues attempted to replicate all variants identified in a recent comprehensive report, and found that the one on chromosome 6 was unequivocally replicated. Although these variants are not located in a gene, the authors suggest that a gene some distance from them (TNFAIP3) is a plausible candidate to explain the effects of these markers, given its involvement in inflammatory processes.

Genetic mutation in familial aortic aneurysm

Mutations in a gene expressed in smooth muscle cells account for about 14% of cases of hereditary thoracic aortic aneurysm, reports a paper published online this week in Nature Genetics. A thoracic aortic aneurysm is a widening of the wall of the aorta -- the body's largest artery -- and can lead to heart attack and stroke.

About one in five of all individuals affected by thoracic aortic aneurysms and dissections (TAAD) have a family history of the disorder, suggesting a genetic predisposition. Only two genes have been implicated in familial cases of TAAD so far, and they account for only about 5% of such cases. Dianna Milewicz and colleagues mapped the gene causing a novel form of TAAD in a large family, and identified mutations in ACTA2, encoding smooth muscle alpha-actin. Mutations in ACTA2 were also identified in individuals in 14 additional families affected by TAAD. Smooth muscle alpha-actin is the most abundant protein found in smooth muscle cells, which are required for contraction of the aorta and other blood vessels in the regulation of blood pressure and flow. One of the other proteins associated with TAAD, MYH11, interacts with ACTA2 in regulating smooth muscle cell contraction, and the authors suggest that this process must be critical in maintaining the structural integrity of the aorta. It is not known whether mutations in ACTA2 are involved in non-familial cases of TAAD.

Gene prevents sudden death in mice after infection

Mice that lack a particular gene die suddenly and without overt signs of illness in response to an infection that is usually harmless, according to a study to be published online this week in Nature Genetics. This work may lead to new insights into the origins of sudden death in humans, although such a link has not yet been made.

Bruce Beutler and colleagues treated mice with a chemical mutagen -- an agent that changes genetic information; and examined the third-generation offspring of the mutant mice for susceptibility to cytomegalovirus (CMV). This virus, at the dose delivered, is normally harmless. The progeny of four of the original mutants, however, died suddenly between 36 hours and 3 days after inoculation. One of these lines has a large deletion in Kcnj8, a gene encoding a component of a potassium channel expressed in smooth muscle and endothelial cells of the coronary artery (two of the other lines carry different mutations in Kcnj8).

The protein that interacts with Kcnj8 has a counterpart in the fruit fly, and the authors show that it similarly protects flies against sudden death after challenge with flock house virus (FHV). The authors propose that this potassium channel is required for the coronary arteries to survive the systemic metabolic stress and arterial constriction that accompanies the innate immune response to viruses such as CMV and FHV.

Mutation identified in neurodegenerative disorder

Individuals with a neurodegenerative disease called spinocerebellar ataxia 11 (SCA11) have mutations in a gene called TTBK2, according to a study to be published online this week in Nature Genetics. TTBK2, which encodes the protein tau tubulin kinase 2, functions in a pathway that has also been implicated in Alzheimer's disease.

Henry Houlden and colleagues studied two families with SCA11, which is one of a group of similar spinocerebellar ataxias, and is characterized by poor coordination, abnormal eye movement, and impairment of speech and swallowing. The authors identified mutations in TTBK2 in affected individuals from a family in Devon, England, some of whose members have had the disease going back eight generations. They also report TTBK2 mutations in affected individuals from a Pakistani family.

Tau tubulin kinase 2 is an enzyme that adds phosphate groups to a protein called tau, whose accumulation in phosphorylated form has been associated with the progression of Alzheimer's disease and other neurodegenerative disorders. Another member of this protein family, TTBK1, has been shown to phosphorylate tau proteins at sites that are identical to those observed in Alzheimer's disease. The study by Houlden and colleagues is the first report of a genetic defect in a tau kinase in any neurodegenerative disease, and suggests that further study of SCA11 may shed light on the molecular basis of other so-called 'tauopathies'.