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Bone. 2019 Apr;121:221-226. doi: 10.1016/j.bone.2019.01.026. Epub 2019 Jan 31.

Postmenopausal osteoporotic fracture-associated COLIA1 variant impacts bone accretion in girls.

Author information

1
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America; Department of Genetics, University of Pennsylvania, Philadelphia, PA, United States of America; Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America. Electronic address: cousminerd@email.chop.edu.
2
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America; Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
3
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America; Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
4
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America; Department of Genetics, University of Pennsylvania, Philadelphia, PA, United States of America; Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
5
Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
6
Department of Genetics, University of Pennsylvania, Philadelphia, PA, United States of America; Department of Systems Pharmacology and Translation Therapeutics, University of Pennsylvania, Philadelphia, PA, United States of America; Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, United States of America.
7
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
8
Division of Endocrinology, Department of Medicine, Creighton University, Omaha, NB, United States of America.
9
University of Hawaii Cancer Center, Honolulu, HI, United States of America.
10
Division of Pediatric Endocrinology, Diabetes, and Metabolism, Department of Pediatrics, Columbia University Medical Center, New York, NY, United States of America.
11
Department of Radiology, Children's Hospital Los Angeles, Los Angeles, LA, United States of America.
12
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America; Department of Genetics, University of Pennsylvania, Philadelphia, PA, United States of America; Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America. Electronic address: grants@email.chop.edu.

Abstract

Over the past two decades, a low frequency variant (rs1800012) within the first intron of the type I collagen alpha 1 (COLIA1) gene has been implicated in lower areal BMD (aBMD) and increased risk of osteoporotic fracture. This association is particularly strong in postmenopausal women, in whom net bone loss arises in the context of high bone turnover. High bone turnover also accompanies childhood linear growth; however, the role of rs1800012 in this stage of net bone accretion is less well understood. Thus, we assessed the association between rs1800012 and aBMD and bone mineral content (BMC) Z-scores for the 1/3 distal radius, lumbar spine, total hip, and femoral neck total body less head in the Bone Mineral Density in Childhood Study, a mixed-longitudinal cohort of children and adolescents (total n = 804 girls and 771 boys; n = 19 girls and 22 boys with the TT genotype). Mixed effects modeling, stratified by sex, was used to test for associations between rs1800012 and aBMD or BMC Z-scores and for pubertal stage interactions. Separately, SITAR growth modeling of aBMD and BMC in subjects with longitudinal data reduced the complex longitudinal bone accrual curves into three parameters representing a-size, b-timing, and c-velocity. We tested for differences in these three parameters by rs1800012 genotype using t-tests. Girls with the TT genotype had significantly lower aBMD and BMC Z-scores prior to puberty completion (e.g. spine aBMD-Z P-interaction = 1.0 × 10-6), but this association was attenuated post-puberty. SITAR models revealed that TT girls began pubertal bone accrual later (b-timing; e.g. total hip BMC, P = 0.03). BMC and aBMD Z-scores also increased across puberty in TT homozygous boys. Our data, along with previous findings in post-menopausal women, suggest that rs1800012 principally affects female bone density during periods of high turnover. Insights into the genetics of bone gain and loss may be masked during the relatively quiescent state in mid-adulthood, and discovery efforts should focus on early and late life.

KEYWORDS:

Alpha1 type 1 collagen; Bone development; Bone mineral density; Longitudinal study; Puberty

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