Published Online
on September 27, 2004

A more recent version of this article appeared on November 1, 2004

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Submitted on July 1, 2004
Revised on July 21, 2004

Interaction Between an 11HSD1 Gene Variant and Birth Era Modifies the Risk of Hypertension in Pima Indians

Paul W. Franks^*; William C. Knowler; Saras Nair; Juraj Koska; Yong-Ho Lee; Robert S. Lindsay; Brian R. Walker; Helen C. Looker; Paska A. Permana; P. Antonio Tataranni; and Robert L. Hanson

From the Phoenix Epidemiology and Clinical Research Branch (P.W.F., W.C.K., S.N., J.K., Y.-H.L., H.C.L., P.A.T., R.L.H.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Ariz; the Division of Cardiovascular and Medical Sciences (R.S.L.), Gardiner Institute, Western Infirmary, University of Glasgow, Glasgow, Scotland; the Endocrinology Unit (B.R.W.), University of Edinburgh, Western General Hospital, Edinburgh, Scotland; and the Carl T. Hayden VA Medical Center (P.A.P.), Phoenix, Ariz.

^* To whom correspondence should be addressed. E-mail: pfranks{at}niddk.nih.gov.

Abstract--11-Hydroxysteroid dehydrogenase type 1 (11HSD1) is a candidate gene for hypertension, diabetes, and obesity through altered glucocorticoid production. This study explored the association of 11HSD1 gene variants with diabetes, hypertension, and obesity in a longitudinal population study of American Indians (N=918; exams=5508). In multivariate mixed models assuming an additive effect of genotype, a 5' upstream variant (rs846910) was associated with blood pressure (diastolic blood pressure =1.58 mm Hg per copy of the A allele, P=0.0008; systolic blood pressure =2.28 mm Hg per copy of the A allele, P=0.004; mean arterial blood pressure =1.83 mm Hg per copy of the A allele, P=0.0006) and hypertension (odds ratio=1.27 per copy of the A allele, P=0.02). However, birth date modified these associations (test for interaction: diastolic blood pressure P=0.16; systolic blood pressure P=0.007; mean arterial blood pressure P=0.01), such that the magnitude and direction of association between genotype and blood pressure changed with time. Finally, in models controlling for potential confounding by population stratification, we observed evidence of within-family effects for blood pressure (diastolic blood pressure =1.77 mm Hg per copy of the A allele, P=0.004; systolic blood pressure =2.04 mm Hg per copy of the A allele, P=0.07; mean arterial blood pressure =1.85 mm Hg per copy of the A allele, P=0.01) and for hypertension (odds ratio=1.26 per copy of the A allele; P=0.08). No association was observed for obesity. Associations with diabetes were similar in magnitude as reported previously but were not statistically significant. These data demonstrate association between genetic variability at 11HSD1 with hypertension, but these effects are modified by environmental factors.

Key words: genetics • epidemiology • blood pressure • nutrition • gene expression

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