Evidence of association and linkage disequilibrium between a novel polymorphism in the transforming growth factor beta1 gene and hip bone mineral density: a study of female twins

Keen, R W; Snieder, Harold; Molloy, Helen; Daniels, Jess; Chiano, M.; Gibson, Frank C.; Fairbairn, L; Smith, Pamela D.; MacGregor, AJ; Gewert, Dirk R.; Spector, TD

doi:10.1093/rheumatology/40.1.48

Cited by 54 publications

(38 citation statements)

References 17 publications

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“…To control for population stratification bias, DZ twin pairs discordant for genotype were also used in a sib-TDT association analysis as described elsewhere. 26,27 The program ARLE-QUIN 1.1 was used to test deviation of the genotype tingency table but extended to a triangular contingency table of arbitary size and is carried out using a modified version of the Markov-chain random walk algorithm. 28 To prevent inflated significance caused by the dependency between genotypes of twin pairs, this test was performed in a sample consisting of one twin of each MZ and DZ pair chosen at random as well as all singleton DZ twins.…”

Section: Discussionmentioning

confidence: 99%

Proopiomelanocortin gene variants are associated with serum leptin and body fat in a normal female population

et al. 2005

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A major quantitative trait locus (QTL) determining leptin levels has been linked to the proopiomelanocortin (POMC) region on chromosome 2. Most studies, based on under 350 lean or obese subjects, have shown no association between POMC SNP 8246 C/T and serum leptin, but significant associations have been reported with RsaI 8246 C/T SNP haplotypes. We have investigated association of four POMC SNPs with body composition and serum leptin in 2758 normal Caucasian female subjects (mean age 47.4712.5 years), from the St Thomas' UK Adult Twin Registry (Twins UK): RsaI and 51 G/C in the 5 0 UTR and 8246 C/T and 7965 C/T in the 3 0 UTR. Under the recessive model, the 8246 T allele (freq. 0.18) was significantly associated with higher mean BMI (P ¼ 0.032) and total fat (P ¼ 0.046, both after age adjustment). Significant associations were maintained in sib-TDT with waist (P ¼ 0.049), total fat (P ¼ 0.037) and emerged with serum leptin (P ¼ 0.016). Initial significant associations between RsaI (À) allele (freq. 0.30) and higher waist (P ¼ 0.04) or % central fat (P ¼ 0.02) were not maintained in sib-TDT. No significant associations were found between body composition or serum leptin and RsaI/8246 C/T haplotype and none with 51 G/C (freq. 0.01) or 7965 C/T (freq. 0.004). There was minimal pairwise LD between the four loci, apart from RsaI and 8246 C/T (D 0 ¼ À0.78 (Po0.0001)). Associations of BMI, weight and total fat with SNPs in regions flanking the POMC gene in this powerful study suggest that regulation of POMC expression may be influential in determining body weight.

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Section: Discussionmentioning

confidence: 99%

Proopiomelanocortin gene variants are associated with serum leptin and body fat in a normal female population

et al. 2005

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“…При этом носители генотипа (861-20)ТТ имели более высокую МПКТ позвоночника и отделов бедра по срав-нению с носителями других комбинаций генотипов [25]. Кроме того, в группе женщин-близнецов из Великобри-тании генотип (861-20)СС также ассоциировался с по-нижением костной массы в области шейки бедра, но не позвоночника [28]. Поэтому наличие генотипа (861-20)СС гена TФР β1 может указывать на риск развития ОП у его носителей.…”

Section: Discussionunclassified

“…Полиморфизм Т(861-20)С гена TФР β1 локализо-ван в 5-м интроне [25,28]. Показано, что этот ОНП свя-зан с пониженной костной массой в нескольких евро-пеоидных популяциях, однако он отсутствует у китайцев [24,25,28].…”

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“…Показано, что этот ОНП свя-зан с пониженной костной массой в нескольких евро-пеоидных популяциях, однако он отсутствует у китайцев [24,25,28]. В то же время этот полиморфизм не влияет на показатели ультразвукового исследования кости.…”

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“…В то же время этот полиморфизм не влияет на показатели ультразвукового исследования кости. Это означает, что ОНП Т(861-20)С гена TФР β1 влияет в большей степени на МПКТ, чем на структуру кости [28]. Функциональное значение интронного полимор-физма Т(861-20)С гена TФР β1 в настоящее время неяс-но.…”

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Association of transforming growth factor (TGF) p1 T(861-20)C polymorphism with bone mineral density and TGFip gene expression in postmenopausal osteoporosis

Четина¹,

Krylov²,

Demin³

et al. 2012

rsp

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Marked phenotypic variability in progressive diaphyseal dysplasia (Camurati–Engelmann disease): Report of a four‐generation pedigree, identification of a mutation in TGFB1, and review

Wallace

Lachman

Mekikian

et al. 2004

American J of Med Genetics Pt A

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Progressive diaphyseal dysplasia (PDD) (Camurati-Engelmann disease) is an autosomal dominant craniotubular dysplasia characterized by hyperostosis and sclerosis of the diaphyses of the long bones and the skull. Mutations in transforming growth factor beta-1 (TGFB1) were recently found in patients with PDD. We report on a four-generation pedigree with seven individuals affected by PDD, linkage and mutational analysis results, and review the literature. This pedigree demonstrates the autosomal dominant inheritance pattern, remarkable variation in expressivity, and reduced penetrance. The most severely affected individual had progression of mild skull hyperostosis to severe skull thickening and cranial nerve compression over 30 years. His carrier father remained asymptomatic into his ninth decade and had no radiographic hyperostosis or sclerosis of the bones. Symptomatic relatives presented with lower limb pain and weakness. They were initially diagnosed with a variety of other conditions. Two of the symptomatic individuals were treated successfully with prednisone. We genotyped 7 markers from chromosome region 19q13.1-13.3 in 15 relatives and confirmed linkage to this region in this family. We screened the TGFB1 gene for mutations and identified a missense mutation resulting in an R218H substitution in the affected individuals, the asymptomatic obligate carrier, and another unaffected relative. We genotyped the family for seven known TGFB1 polymorphisms and a novel TAAA tetranucleotide repeat in intron 1. These polymorphisms did not appear to account for the variability in disease severity in this family. Our review illustrates how the disorder can significantly compromise health. Cranial involvement, which occurs in 61% of patients, can be severe, entrapping cranial nerves or causing increased intracranial pressure. Therapy with corticosteroids should be attempted in all symptomatic patients.

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Evidence of association and linkage disequilibrium between a novel polymorphism in the transforming growth factor beta1 gene and hip bone mineral density: a study of female twins

Abstract: These results indicate that allelic variation at the TGF-beta 1 gene contributes to the development of osteoporosis at the hip. The study also highlights the power of candidate gene analysis in twins, in whom loci having modest effects on disease risk can be identified.

Cited by 54 publications

References 17 publications

Proopiomelanocortin gene variants are associated with serum leptin and body fat in a normal female population

Proopiomelanocortin gene variants are associated with serum leptin and body fat in a normal female population

Association of transforming growth factor (TGF) p1 T(861-20)C polymorphism with bone mineral density and TGFip gene expression in postmenopausal osteoporosis

Marked phenotypic variability in progressive diaphyseal dysplasia (Camurati–Engelmann disease): Report of a four‐generation pedigree, identification of a mutation in TGFB1, and review

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