D&IW

Both houses of Congress have now passed the Genetic Information Nondiscrimination Act, which bars both insurer and employers from using genetic information about an individual to their detriment.

One of the bill's goals is to encourage people to seek genetic testing without fear of findings being used against them in some way in hopes that early identification of at-risk individuals can lead to prevention or early intervention and ultimately, better outcomes for individuals with an increased risk of developing a given disease.

Science, meanwhile, is providing ever more of such basic associations of gene variants to disease risk, and the latest genome-wide association study identifies a gene variant that is linked to high glucose levels.

In the study, published in the May 1 early online edition of Science, researchers reported results of a genome-wide association study conducted to find genes that influence fasting plasma glucose levels within the normal range.

Like many biological systems, blood glucose levels vary along a continuum, and while there is a cutoff point at which glucose levels are deemed high, that cutoff is somewhat arbitrary. Even within the range that is designated normal, higher fasting plasma glucose levels have been linked to an increased risk of diseases, including coronary heart disease and kidney disease.

The researchers first tested nearly 400,000 single-nucleotide polymorphisms for their association with blood sugar levels in 650 individuals whose blood sugar was within the normal range to identify SNPs that were strongly correlated with blood sugar levels. They then retested the SNP with the strongest correlation to blood sugar levels in a second group of more than 9,000 individuals to confirm the association.

The gene identified by the study is the G6PC2 gene, also known as IGRP. The protein product of G6PC2/IGRP blocks the glucose sensor glucokinase, which normally signals to beta cells and increases their secretion of insulin. Decreased secretion of insulin then leads to higher blood sugar levels.

"These sequences explain about 5% of the normal variation in blood glucose levels between otherwise healthy people," co-author Robert Sladek, of McGill University and Génome Québec Innovation Centre (Montreal), said in a statement. "Five percent may not sound huge, but for complex traits, that's rather a lot."

Surprisingly, the gene in question failed to show an association with a higher diabetes risk and though such associations are sometime missed due to the very low "p" values required for statistical significance, that was most definitely not the case here.

The paper reports the "p" value of the association between Type II diabetes and the G6PC2/IGRP gene was 0.6.

The authors note that the lack of a connection runs both ways. The genes most associated with an increased risk for developing Type II diabetes show no association with high fasting plasma glucose levels, "suggesting that the genetic determinants that regulate [fasting plasma glucose] in physiological states may be different from those that increase [Type II diabetes] risk."

They also speculate that the gene variant identified in the new study plays "an important role in the early pathogenesis of this disease without contributing to overall [Type II diabetes] risk."

Another study does report on the genetic underpinnings of diabetes, though it is not Type II diabetes; instead, the authors, who are from Italy, Denmark, and the U.S., investigated neonatal diabetes mellitus. Results of that study, which are published in the May 1, 2008, issue of the Journal of Clinical Investigation, confirm recent similar findings in the Proceedings of the National Academy of Sciences and in Diabetes.

Neonatal diabetes mellitus usually is apparent by the time its sufferers are six months old. Several genes have been linked to this disorder, but in many cases the genetic cause remains unknown. Because there is a mouse model with a mutation in its insulin gene that has neonatal diabetes-like symptoms, the authors sequenced the insulin gene in patients with neonatal diabetes mellitus.

When sequencing the gene, they found seven mutations in the insulin gene in 10 unrelated patients. In eight of those patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time.

The researchers then expressed the mutant insulin genes into cell culture and found that such cells were defective in insulin folding and secretion, and also showed increased expression of some stress proteins and were vulnerable to apoptosis. The authors concluded that "mutations in the insulin gene that promote pro-insulin misfolding" might cause neonatal diabetes.