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

Diana L. Cousminer, Shana E. McCormack, Jonathan A. Mitchell, Alessandra Chesi, Joseph M. Kindler, Andrea Kelly, Benjamin F. Voight, Heidi J. Kalkwarf, Joan M. Lappe, John A. Shepherd, Sharon E. Oberfield, Vicente Gilsanz, Babette S. Zemel, Struan F.A. Grant

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)221-226
Number of pages6
JournalBone
Volume121
DOIs
StatePublished - Apr 1 2019

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Osteoporotic Fractures
Bone Density
Bone and Bones
Puberty
Bone Remodeling
Genotype
Spine
Pelvic Bones
Femur Neck
Growth
Introns
Hip
Head

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

Cite this

Cousminer, D. L., McCormack, S. E., Mitchell, J. A., Chesi, A., Kindler, J. M., Kelly, A., ... Grant, S. F. A. (2019). Postmenopausal osteoporotic fracture-associated COLIA1 variant impacts bone accretion in girls. Bone, 121, 221-226. https://doi.org/10.1016/j.bone.2019.01.026

Postmenopausal osteoporotic fracture-associated COLIA1 variant impacts bone accretion in girls. / Cousminer, Diana L.; McCormack, Shana E.; Mitchell, Jonathan A.; Chesi, Alessandra; Kindler, Joseph M.; Kelly, Andrea; Voight, Benjamin F.; Kalkwarf, Heidi J.; Lappe, Joan M.; Shepherd, John A.; Oberfield, Sharon E.; Gilsanz, Vicente; Zemel, Babette S.; Grant, Struan F.A.

In: Bone, Vol. 121, 01.04.2019, p. 221-226.

Research output: Contribution to journalArticle

Cousminer, DL, McCormack, SE, Mitchell, JA, Chesi, A, Kindler, JM, Kelly, A, Voight, BF, Kalkwarf, HJ, Lappe, JM, Shepherd, JA, Oberfield, SE, Gilsanz, V, Zemel, BS & Grant, SFA 2019, 'Postmenopausal osteoporotic fracture-associated COLIA1 variant impacts bone accretion in girls', Bone, vol. 121, pp. 221-226. https://doi.org/10.1016/j.bone.2019.01.026
Cousminer DL, McCormack SE, Mitchell JA, Chesi A, Kindler JM, Kelly A et al. Postmenopausal osteoporotic fracture-associated COLIA1 variant impacts bone accretion in girls. Bone. 2019 Apr 1;121:221-226. https://doi.org/10.1016/j.bone.2019.01.026
Cousminer, Diana L. ; McCormack, Shana E. ; Mitchell, Jonathan A. ; Chesi, Alessandra ; Kindler, Joseph M. ; Kelly, Andrea ; Voight, Benjamin F. ; Kalkwarf, Heidi J. ; Lappe, Joan M. ; Shepherd, John A. ; Oberfield, Sharon E. ; Gilsanz, Vicente ; Zemel, Babette S. ; Grant, Struan F.A. / Postmenopausal osteoporotic fracture-associated COLIA1 variant impacts bone accretion in girls. In: Bone. 2019 ; Vol. 121. pp. 221-226.
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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.",
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N2 - 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.

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