Common polymorphisms rather than rare genetic variants of the Runx2 gene are associated with femoral neck BMD in Spanish women.
RUNX2 is a transcription factor essential for osteoblast differentiation and skeletal morphogenesis. Its mutation creates cleidocranial dysplasia (CCD), a disorder characterized by skeletal abnormalities and bone mineral density (BMD) alterations. The purpose of the present study has been to clarify whether polymorphisms affecting this gene could be associated with changes in BMD in women. To that end, we performed an association study of BMD values from 776 women with two single nucleotide polymorphisms (SNPs) located at P2 promoter (-1025 T>C) and at exon 2 (+198 G>A), and with a deletion polymorphism (17Ala>11Ala), also located at exon 2. We found an association of -1025 T>C SNP with femoral neck BMD (FN-BMD), being the women of TC/CC genotype who have higher BMD than women of TT genotype (P = 0.006). This association was independent of age, weight, menopausal status, or hormone replacement therapy (HRT) use as shown by regression analysis. When women of highest versus lowest quartile of BMD were compared, this association became more evident (P = 0.002), extending also to +198 G>A SNP (GA/AA women with higher FN-BMD; P < 0.05). In addition, we describe herein three novel rare variants in the polyglutamine domain of RUNX2 protein: an in-frame insertion and two deletions in exon 2, resulting in the insertions of 7 and deletions of 7 and 5 glutamines, respectively. These variants do not produce CCD, increased frequency of bone fracture, or BMD alterations. In conclusion, common polymorphisms in Runx2 are associated with FN-BMD. Nevertheless, rare variants that modify the polyglutamine domain of RUNX2 neither have any effect on BMD nor produce the CCD phenotype. These results underscore the significance of polymorphisms in the 5'-region of Runx2 in the determination of FN-BMD.
Pineda
Begoña
B
Research Foundation, Hospital Clínico Universitario, Avenida Blasco Ibáñez 17, Valencia, Spain.
Hermenegildo
Carlos
C
Laporta
Paz
P
Tarín
Juan J
JJ
Cano
Antonio
A
García-Pérez
Miguel Ángel
MÁ
D020816:Amino Acid Motifs / Q000235:genetics; D015519:Bone Density / Q000235:genetics*; D015331:Cohort Studies; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics*; D005091:Exons; D005260:Female; D005272:Femur Neck / Q000737:chemistry*; D005787:Gene Frequency; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D008593:Menopause; D008875:Middle Aged; D009154:Mutation; D015663:Osteoporosis, Postmenopausal / Q000235:genetics; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017384:Sequence Deletion; D013030:Spain
D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human
J Clin Endocrinol Metab. 2001 Mar;86(3):1212-21
11238511
Ann Hum Genet. 2008 Jul;72(Pt 4):510-8
18373722
Osteoporos Int. 2008 Apr;19(4):399-428
18266020
J Musculoskelet Neuronal Interact. 2006 Jan-Mar;6(1):16-26
16675886
Nat Genet. 2009 Jan;41(1):15-7
19079262
J Bone Miner Res. 1997 Jul;12(7):1083-91
9200008
Bone. 2004 Jun;34(6):1029-36
15193550
Osteoporos Int. 2008 Aug;19(8):1147-52
18097708
Bone. 2006 Feb;38(2):199-205
16198163
Osteoporos Int. 2007 Aug;18(8):1033-46
17323110
J Bone Miner Res. 1997 Sep;12(9):1463-70
9286763
Cell. 1997 May 30;89(5):773-9
9182765
Genes Dev. 2006 Sep 15;20(18):2492-506
16980579
JAMA. 2007 Dec 19;298(23):2761-7
18165669
Calcif Tissue Int. 2007 Oct;81(4):327-32
17878995
Osteoporos Int. 2001;12(6):438-44
11446558
Cell. 1997 May 30;89(5):765-71
9182764
Calcif Tissue Int. 2008 May;82(5):348-53
18465072
J Bone Miner Res. 2003 Feb;18(2):213-21
12568398
Arthritis Res Ther. 2008;10(5):214
18828878
Hum Mutat. 2002 Mar;19(3):209-16
11857736
J Bone Miner Res. 2002 Aug;17(8):1527-34
12162506
Hum Mol Genet. 1999 Nov;8(12):2311-6
10545612
Bioinformatics. 2005 Jan 15;21(2):263-5
15297300
Calcif Tissue Int. 2009 Jun;84(6):439-45
19424741
Osteoporos Int. 2005 Jun;16(6):581-9
15616758
J Bone Miner Res. 2007 Sep;22(9):1455-62
17547536
Bioinformatics. 2006 Aug 1;22(15):1928-9
16720584
Lancet. 2008 May 3;371(9623):1505-12
18455228
Cell. 1997 May 30;89(5):755-64
9182763
Genetics. 2000 Jun;155(2):945-59
10835412
J Bone Miner Res. 2000 Aug;15(8):1526-36
10934651
N Engl J Med. 2008 May 29;358(22):2355-65
18445777
J Bone Miner Res. 2006 Feb;21(2):265-73
16418782
Mamm Genome. 1998 Jan;9(1):54-7
9434946
Am J Epidemiol. 2002 Mar 1;155(5):478-84
11867360