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Interaction Between Birthweight and Polymorphism in the Calcium-Sensing Receptor Gene in Determination of Adult Bone Mass: The Hertfordshire Cohort Study
MIRJAM A. LIPS, HOLLY E. SYDDALL, TOM R. GAUNT, SANTIAGO RODRIGUEZ, IAN N.M. DAY, CYRUS COOPER, ELAINE M. DENNISON, and the Southampton Genetic Epidemiology Research Group ABSTRACT. Objective. We sought evidence of interaction between single-nucleotide polymorphisms (SNP) in the calcium-sensing receptor (CASR) gene and early life in determination of bone mineral density (BMD) among individuals from the Hertfordshire Cohort Study. Methods. Four hundred ninety-eight men and 468 women aged 59–71 years were recruited. A lifestyle questionnaire was administered and BMD at lumbar spine and femoral neck was measured. DNA was obtained from whole blood samples using standard extraction techniques. Five SNP of the CASR gene termed CASRV1 (rs1801725, G®T, S986A), CASRV2 (rs7614486, T®G, untranslated), CASRV3 (rs4300957, untranslated), CASRV4 (rs3804592 G®A, intron), and CASRV5 (rs1393189, T®C, intron) were analyzed. Results. Among women the 11 genotype of the CASRV3 SNP was associated with higher lumbar spine BMD within the lowest birthweight tertile, while the opposite pattern was observed among individuals in the highest birthweight tertile (test for interaction on 1 df, p = 0.005, adjusted for age, body mass index, physical activity, dietary calcium intake, cigarette and alcohol consumption, social class, menopausal status, and hormone replacement therapy use). Similar relationships were seen at the total femur (p = 0.042, fully adjusted) with birthweight and at the total femur according to weight at 1 year tertile among women (p < 0.001, fully adjusted). One haplotype was associated with lumbar spine BMD in women (p = 0.008, fully adjusted); these findings were replicated in a second cohort. Conclusion. We have found evidence of an interaction between a SNP of the CASR gene and birthweight in determination of bone mass in a UK female population. (First Release Feb 15 2007; J Rheumatol 2007;34:769–75) Key Indexing Terms:
BONE From the MRC Epidemiology Resource Centre and Human Genetics Research Division, University of Southampton, Southampton General Hospital, Southampton, UK. Supported by grants from the the Arthritis Research Campaign and the Medical Research Council. M.A. Lips, Research Student; H.E. Syddall, MSc, Medical Statistician; C. Cooper, MD, Professor of Rheumatology; E.M. Dennison, PhD, Reader in Rheumatology, MRC Epidemiology Research Centre, University of Southampton; T.R. Gaunt, PhD, Research Fellow; S. Rodriguez, PhD, Research Fellow; I.N.M. Day, PhD, Professor of Human Genetics, Human Genetics Research Division, University of Southampton, School of Medicine, Southampton General Hospital; and the Hertfordshire Cohort Study Group. Address reprint requests to Dr. E. Dennison, MRC Epidemiology Resource Centre, Southampton General Hospital, Southampton SO16 6YD, England. E-mail: emd@mrc.soton.ac.uk Accepted for publication November 29, 2006.
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