In the current issue of PLoS Medicine Andrew Hattersley and colleagues from the Peninsular Medical School, report the findings from a study of 108 individuals from15 families where the mutation was present. Overall more than half of the babies who carried the mutation were defined as macrosomic compared with 13% of those with no mutations.

Macrosomia (birthweight more than 4000g) is associated with complications for both mothers and babies; one cause of macrosomia is diabetes in the mother. The particular type of diabetes investigated in this study is known as maturity-onset diabetes of the young (MODY) genes; two of the genes known to be involved in this disease are HNF4A and HNF1A/TCF1 both of which have a key role in the regulation of the secretion of insulin by the pancreas.

In addition to increased birthweight the researchers also found that low blood-sugar levels at birth were also more common in babies carrying the HNF4A mutation as compared to those who did not. In mice who lacked the equivalent mouse gene (Hnf4a) the researchers were able to show that there was high insulin during development and low blood sugar at birth.

Although this study is in patients with an unusual mutation, these results have wider implications as they establish that HNF4A is important in determining birthweight. However, the mechanism by which the same mutation also causes diabetes (ie with decreased insulin) in later life remains to be determined in view of the increased insulin shown to be present at birth that causes the low glucose. Nonetheless, the authors conclude that ,in addition to maternal factors, paternal factors (including history of diabetes) should be considered when assessing macrosomia risk." A related perspective by Benjamin Glaser from the Hadassah-Hebrew University Medical Center, discusses the paper's implications further

plos

Genes that harbor variants that contribute to both success in quitting smoking and in vulnerability to become dependent on multiple substances include cadherin 13 (a molecule involved in cell adhesion, which governs how cells recognize and connect to their neighbors) and a cyclic G-dependent protein kinase gene, which plays a key role in normal brain development. In addition to genes implicated in intracellular signaling and intercellular interactions, a number of genes involved in other processes have also been identified. While many of the genes identified through this effort make sense because of their role in supporting new neural connections in the brain, more research is now needed to understand the actual mechanisms through which they may increase or reduce the rates of successful quitting.

Dr. Uhl says he and his colleagues have replicated this research in another sample, as he reported at the February 2007 meeting of the Society for Research on Nicotine and Tobacco.

"These findings provide ample justification for continuing the search for even more genetic variants associated with smoking cessation success," says Dr. Volkow. "We soon may be able to make use of this information to match treatments with the smokers most likely to benefit from them."

nida.nih