Novel Gene Associated With Variations in A1c Levels

The gene, HK1, encodes the enzyme hexokinase, which carries out the first step in sugar breakdown in the body, but it has never before been linked with diabetes, and the finding "paves the way for further studies" of HK1 in glucose metabolism and diabetes, Dr. Paré said.

Dr. Paré and colleagues undertook a genome-wide association study looking for genetic variants single nucleotide polymorphisms (SNP) associated with glycosylated hemoglobin levels.

The primary population was 14,618 apparently healthy Caucasian women, whose baseline HbA1c was below 7%. Results were replicated in a cohort of 455 non-diabetic Caucasian men and women recruited from the Boston area.

All told, the analysis found variants in four genes that were significantly associated with glycosylated hemoglobin. Three of the genes -- GCK, SLC30A8, and G6PC2 -- had previously been associated with diabetes or blood glucose concentration, the researchers said.

The associations of all four genes with glycosylated hemoglobin were significant at a pre-specified level of P<5x10-8.

The association with HK1 was also significant in the replication cohort, the researchers said, with the bar for significance in that analysis set at P<0.05.

Variation in GCK and G6PC2 is associated with increased blood glucose and was linked with higher glycation in this study, the researchers said. The variant in SLC30A8 has previously been shown to be protective against diabetes and was linked to lower glycation levels.

Because hexokinase is the initial and rate-limiting step in glucose metabolism in red blood cells, it makes sense, the researchers said, that variations in HK1 activity would affect hemoglobin glycation.

But it could also be the case that HK1 variations affect systemic glucose metabolism, "raising the possibility that these variations are associated with the risk of incident diabetes," they said.

However, it "remains an open question" whether gene-based differences in glycosylated hemoglobin are paralleled by glycation in other tissues, they said.
Taken together, the researchers said, the four variants account for only 1.4% of the total variance in glycosylated hemoglobin levels in the population. On the other hand, clinical characteristics -- age, body mass index, and menopause status -- explained about 9.5% of the variance and together the candidate loci and the clinical variables accounted for 10.9% of total variance.

Interestingly, variation in three other genes -- calpain-10, resistin, and adiponectin -- has previously been associated with glycation of hemoglobin, but was not seen in this study.

PLoS Genetics: Paré G, et al "Novel association of HK1 with glycated hemoglobin in a non-diabetic population: a genome-wide evaluation of 14,618 participants in the women's genome health study" PLoS Genet 2008; 4(12): DOI: 10.1371/journal.pgen.1000312.