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01-12-2005 | Original Article

Association analysis of estrogen receptor α gene polymorphisms with cross-sectional geometry of the femoral neck in Caucasian nuclear families

Authors: Dong-Hai Xiong, Yao-Zhong Liu, Peng-Yuan Liu, Lan-Juan Zhao, Hong-Wen Deng

Published in: Osteoporosis International | Issue 12/2005

Abstract

Bone geometry is a key factor in bone strength, which is the ultimate intrinsic determinant of fracture risk. Though the heritability of bone geometry is high, little effort has been spent on searching for the underlying genes. In this study, employing a sample of 1,873 subjects from 405 Caucasian nuclear families, we studied seven single nucleotide polymorphisms (SNPs) and their haplotypes of the ER-α gene for association with six hip geometric variables, namely, cross-sectional area (CSA), cortical thickness (CT), endocortical diameter (ED), subperiosteal width (W), sectional modulus (Z) and buckling ratio (BR). The major method used was the quantitative transmission disequilibrium test (QTDT). Our major findings were summarized below. The within-family association between SNP4 (rs1801132) in exon 4 with endocortical diameter and subperiosteal width was detected in single locus analyses ( P =0.008 and 0.021, respectively) and verified in haplotype analyses ( P =0.034 and 0.058, respectively). The total association of SNP4 with these two diameters was also observed in both single locus and haplotype analyses ( P =0.005 and 0.031 for ED, plus P =0.003 and 0.070 for W). In addition, the total association between SNP5 ( rs932477) in intron 4 with cortical thickness and buckling ratio was detected (single locus analyses: P =0.035 and 0.041, respectively). Haplotype analyses further supported the above association ( P =0.010 and 0.004, respectively). Similar patterns of associations with the studied SNPs and their haplotypes were present in subsamples stratified by sex, too. However, after permutation tests, the empirical significance level was set as P <0.011, which renders most associations insignificant. Therefore, we concluded that polymorphisms in the ER-α gene were nominally associated with femoral neck (FN) geometry variables estimated from DXA. Such genetic effects on hip geometry were not sex specific.

NIH consensus (2000) Osteoporosis prevention, diagnosis, and therapy. NIH Consens Statement 17:1–45

Cummings SR, Kelsey JL, Nevitt MC et al (1985) Epidemiology of osteoporosis and osteoporotic fractures. Epidemiol Rev 7:178–208PubMed

Melton LJ III, Atkinson EJ, O’Fallon WM et al (1993) Long-term fracture prediction by bone mineral assessed at different skeletal sites. J Bone Miner Res 8:1227–1233PubMed

Stone KL, Seeley DG, Lui LY et al (2003) BMD at multiple sites and risk of fracture of multiple types: long-term results from the Study of Osteoporotic Fractures. J Bone Miner Res 18:1947–1954PubMed

Ammann P, Rizzoli R (2003) Bone strength and its determinants. Osteoporos Int 14 [Suppl 3]:S13–S18

Pulkkinen P, Partanen J, Jalovaara P et al (2004) Combination of bone mineral density and upper femur geometry improves the prediction of hip fracture. Osteoporos Int 15:274–280CrossRefPubMed

Nelson DA, Barondess DA, Hendrix SL et al (2000) Cross-sectional geometry, bone strength, and bone mass in the proximal femur in black and white postmenopausal women. J Bone Miner Res 15:1992–1997PubMed

Faulkner KG, Cummings SR, Nevitt MC et al (1995) Hip axis length and osteoporotic fractures. Study of Osteoporotic Fractures Research Group. J Bone Miner Res 10:506–508PubMed

Duan Y, Beck TJ, Wang XF et al (2003) Structural and biomechanical basis of sexual dimorphism in femoral neck fragility has its origins in growth and aging. J Bone Miner Res 18:1766–1774PubMed

10.

Rivadeneira F, Houwing-Duistermaat JJ, Beck TJ et al (2004) The influence of an insulin-like growth factor I gene promoter polymorphism on hip bone geometry and the risk of nonvertebral fracture in the elderly: the Rotterdam Study. J Bone Miner Res 19:1280–1290PubMed

11.

Slemenda CW, Turner CH, Peacock M et al (1996) The genetics of proximal femur geometry, distribution of bone mass and bone mineral density. Osteoporos Int 6:178–182CrossRefPubMed

12.

Peacock M, Turner CH, Econs MJ et al (2002) Genetics of osteoporosis. Endocr Rev 23:303–326CrossRefPubMed

13.

Koller DL, Liu G, Econs MJ et al (2001) Genome screen for quantitative trait loci underlying normal variation in femoral structure. J Bone Miner Res 16:985–991PubMed

14.

Klein RF, Turner RJ, Skinner LD et al (2002) Mapping quantitative trait loci that influence femoral cross-sectional area in mice. J Bone Miner Res 17:1752–1760PubMed

15.

Koller DL, White KE, Liu G et al (2003) Linkage of structure at the proximal femur to chromosomes 3, 7, 8, and 19. J Bone Miner Res 18:1057–1065PubMed

16.

Qureshi AM, McGuigan FE, Seymour DG et al (2001) Association between COLIA1 Sp1 alleles and femoral neck geometry. Calcif Tissue Int 69:67–72CrossRefPubMed

17.

Khosla S, Riggs BL, Atkinson EJ et al (2004) Relationship of estrogen receptor genotypes to bone mineral density and to rates of bone loss in men. J Clin Endocrinol Metab 89:1808–1816CrossRefPubMed

18.

Khosla S, Bilezikian JP (2003) The role of estrogens in men and androgens in women. Endocrinol Metab Clin North Am 32:195–218CrossRefPubMed

19.

Riggs BL, Khosla S, Melton LJ III (1998) A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res 13:763–773PubMed

20.

van Meurs JB, Schuit SC, Weel AE et al (2003) Association of 5’ estrogen receptor alpha gene polymorphisms with bone mineral density, vertebral bone area and fracture risk. Hum Mol Genet 12:1745–1754CrossRefPubMed

21.

Sowers M, Jannausch ML, Liang W et al (2004) Estrogen receptor genotypes and their association with the 10-year changes in bone mineral density and osteocalcin concentrations. J Clin Endocrinol Metab 89:733–739CrossRefPubMed

22.

Herrington DM (2003) Role of estrogen receptor-alpha in pharmacogenetics of estrogen action. Curr Opin Lipidol 14:145–150CrossRefPubMed

23.

Ongphiphadhanakul B, Chanprasertyothin S, Payattikul P et al (2001) Association of a G2014A transition in exon 8 of the estrogen receptor-alpha gene with postmenopausal osteoporosis. Osteoporos Int 12:1015–1019CrossRefPubMed

24.

Ongphiphadhanakul B, Chanprasertyothin S, Payattikul P et al (2001) Association of a T262C transition in exon 1 of estrogen-receptor-alpha gene with skeletal responsiveness to estrogen in post-menopausal women. J Endocrinol Invest 24:749–755PubMed

25.

Jurada S, Marc J, Prezelj J et al (2001) Codon 325 sequence polymorphism of the estrogen receptor alpha gene and bone mineral density in postmenopausal women. J Steroid Biochem Mol Biol 78:15–20CrossRefPubMed

26.

Liu YZ, Liu YJ, Recker RR et al (2003) Molecular studies of identification of genes for osteoporosis: the 2002 update. J Endocrinol 177:147–196CrossRefPubMed

27.

O’Connell JR, Weeks DE (1998) PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 63:259–266CrossRefPubMed

28.

Beck T (2003) Measuring the structural strength of bones with dual-energy X-ray absorptiometry: principles, technical limitations, and future possibilities. Osteoporos Int 14 [Suppl 5]:81–88

29.

Beck TJ, Ruff CB, Warden KE et al (1990) Predicting femoral neck strength from bone mineral data. A structural approach. Invest Radiol 25:6–18PubMed

30.

Martin RB, Burr DB (1984) Non-invasive measurement of long bone cross-sectional moment of inertia by photon absorptiometry. J Biomech 17:195–201CrossRefPubMed

31.

Filardi S, Zebaze RM, Duan Y et al (2004) Femoral neck fragility in women has its structural and biomechanical basis established by periosteal modeling during growth and endocortical remodeling during aging. Osteoporos Int 15:103–107CrossRefPubMed

32.

Petit MA, Beck TJ, Lin HM et al (2004) Femoral bone structural geometry adapts to mechanical loading and is influenced by sex steroids: the Penn State Young Women’s Health Study. Bone 35:750–759CrossRefPubMed

33.

Saxon LK, Turner CH (2005) Estrogen receptor beta: the antimechanostat? Bone 36:185–192CrossRefPubMed

34.

Beck TJ, Stone KL, Oreskovic TL et al (2001) Effects of current and discontinued estrogen replacement therapy on hip structural geometry: the study of osteoporotic fractures. J Bone Miner Res 16:2103–2110PubMed

35.

Beck TJ, Oreskovic TL, Stone KL et al (2001) Structural adaptation to changing skeletal load in the progression toward hip fragility: the study of osteoporotic fractures. J Bone Miner Res 16:1108–1119PubMed

36.

Almasy L, Blangero J (1998) Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 62:1198–1211CrossRefPubMed

37.

Devlin B, Risch N (1995) A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics 29:311–322CrossRefPubMed

38.

Kruglyak L, Daly MJ, Reeve-Daly MP et al (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 58:1347–1363PubMed

39.

Lachenbruch PA (2003) Proper metrics for clinical trials: transformations and other procedures to remove non-normality effects. Stat Med 22:3823–3842CrossRefPubMed

40.

Wang WY, Barratt BJ, Clayton DG et al (2005) Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 6:109–118CrossRefPubMed

41.

Reich DE, Lander ES (2001) On the allelic spectrum of human disease. Trends Genet 17:502–510CrossRefPubMed

42.

Abecasis GR, Cardon LR, Cookson WO (2000) A general test of association for quantitative traits in nuclear families. Am J Hum Genet 66:279–292CrossRefPubMed

43.

van den Oord EJ (2002) Association studies in psychiatric genetics: what are we doing? Mol Psychiatry 7:827–828CrossRefPubMed

44.

McIntyre LM, Martin ER, Simonsen KL et al (2000) Circumventing multiple testing: a multilocus Monte Carlo approach to testing for association. Genet Epidemiol 19:18–29CrossRefPubMed

45.

Nyholt DR (2001) Genetic case-control association studies—correcting for multiple testing. Hum Genet 109:564–567CrossRefPubMed

46.

Dvornyk V, Long JR, Xiong DH et al (2004) Current limitations of SNP data from the public domain for studies of complex disorders: a test for ten candidate genes for obesity and osteoporosis. BMC Genet 5:4CrossRefPubMed

47.

Wang Y, Localio R, Rebbeck TR (2004) Evaluating bias due to population stratification in case-control association studies of admixed populations. Genet Epidemiol 27:14–20CrossRefPubMed

48.

Deng HW (2001) Population admixture may appear to mask, change or reverse genetic effects of genes underlying complex traits. Genetics 159:1319–1323PubMed

49.

Ioannidis JP, Stavrou I, Trikalinos TA et al (2002) Association of polymorphisms of the estrogen receptor alpha gene with bone mineral density and fracture risk in women: a meta-analysis. J Bone Miner Res 17:2048–2060PubMed

50.

Zhao LJ, Liu PY, Long JR et al (2004) Test of linkage and/or association between the estrogen receptor alpha gene with bone mineral density in Caucasian nuclear families. Bone 35:395–402CrossRefPubMed

51.

Khosla S, Melton LJ III, Riggs BL (2002) Clinical review 144: Estrogen and the male skeleton. J Clin Endocrinol Metab 87:1443–1450CrossRefPubMed

52.

Riggs BL, Khosla S, Melton LJ III (2002) Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23:279–302CrossRefPubMed

53.

Smith EP, Boyd J, Frank GR et al (1994) Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 331:1056–1061CrossRefPubMed

54.

Beck TJ, Looker AC, Ruff CB et al (2000) Structural trends in the aging femoral neck and proximal shaft: analysis of the Third National Health and Nutrition Examination Survey dual-energy X-ray absorptiometry data. J Bone Miner Res 15:2297–2304PubMed

Title: Association analysis of estrogen receptor α gene polymorphisms with cross-sectional geometry of the femoral neck in Caucasian nuclear families
Authors: Dong-Hai Xiong
Yao-Zhong Liu
Peng-Yuan Liu
Lan-Juan Zhao
Hong-Wen Deng
Publication date: 01-12-2005
Publisher: Springer-Verlag
Published in: Osteoporosis International / Issue 12/2005
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-005-2011-4

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Association analysis of estrogen receptor α gene polymorphisms with cross-sectional geometry of the femoral neck in Caucasian nuclear families

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

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