HDCN Article Review/Hyperlink

Schalin-Jantti C, Nikula-Ijas P, Huan X, Lehto M, Knudsen P, et al.

Polymorphism of the glycogen synthase gene in hypertensive and normotensive subjects

Hypertension (Jan) 27:67-71 1996

This paper examines the association of Xba I polymorphism of the glycogen synthase gene and essential hypertension among 304 nondiabetic subjects (246 normotensives and 58 hypertensives). The A2 allele was found to be twice as frequent in hypertensives as compared to normotensives subjects (28% vs 14%, respectively). The greatest frequency of the A2 allele was observed in hypertensive subjects with a family history of non-insulin dependent diabetes mellitus (NIDDM) (48%) followed by normotensive subjects with a family history of NIDDM (26%). By contrast, hypertensive and normotensive subjects without a family history of NIDDM had low frequencies of the A2 allele (16 and 6%, respectively). Thus, it appears that the association of the A2 allele to a family history of NIDDM is as strong as the association of the A2 allele to hypertension.

Normotensive subjects with the A2 allele exhibited similar glucose tolerance and rates of insulin-stimulated glucose storage as compared to subjects with the A1 allele. In contrast, in hypertensive subjects with the A2 allele glucose tolerance was more impaired than in hypertensive subjects with the A1 allele. Hypertensive subjects with the A2 allele also had lower rates of insulin stimulated glucose storage than hypertensives with the A1 allele.

Comment: This paper reports an impressive association of the A2 allele of the glycogen synthase gene to hypertension, especially for hypertensive subjects with a family history of NIDDM. The authors suggest that a locus in the glycogen synthase gene region on chromosome 19 may serve as a "thrifty gene", increasing susceptibility to insulin resistance when exposed to other environmental or genetic factors. Some issues come to mind:

1) Hypertensive subjects had markedly lower rates of insulin-stimulated glucose storage than normotensive subjects, independent of which glycogen synthase allele was present. This suggests that hypertension per se was associated with impaired insulin-stimulated glucose storage, and that impaired insulin-stimulated glucose storage was not dependent on the presence of the A2 allele The authors do not emphasize (or even run statistics on this finding).

2) There were important differences in the normotensive and hypertensive subjects studied other than blood pressure which could have accounted for the differences between the two populations. The hypertensive subjects were older, had a greater BMI, higher fasting insulin levels and increased levels of cholesterol, HDL and triglycerides as compared to normotensive subjects.

3) The fact that hypertensives with the A2 allele had diminished insulin-stimulated glucose storage, compared to those with the A1 allele (while there was no difference in normotensive subjects) suggests that hypertension, or one of the above mentioned differences could modify the action of the A2 allele of the glycogen synthase gene.

4) Most of the subjects with the A2 allele were heterogenic. It needs to be determined which allele is actually expressed and the relative levels of expression in normotensive and hypertensive subjects. Further, if both alleles are expressed are there differences in the A1:A2 ratio between normotensive and hypertensive subjects?

5) Because of the strong association of the presence of the A2 allele and a family history of NIDDM, it would also be of interest to examine in more detail, glucose tolerance and the rates of insulin-stimulated glucose storage in hypertensive subjects with and without a family history of NIDDM.

This interesting study nevertheless shows that in some hypertensive subjects, there is a greater impairment of insulin-stimulated glucose storage in subjects with the A2 allele than in those with the A1 allele. (Michael LaPointe, Ph.D. and Daniel Batlle, M.D., Northwestern University Medical School, Chicago)