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2.  Genetic epidemiology, prevalence, and genotype–phenotype correlations in the Swedish population with osteogenesis imperfecta 
European Journal of Human Genetics  2015;23(8):1042-1050.
Osteogenesis imperfecta (OI) is a rare hereditary bone fragility disorder, caused by collagen I mutations in 90% of cases. There are no comprehensive genotype–phenotype studies on >100 families outside North America, and no population-based studies determining the genetic epidemiology of OI. Here, detailed clinical phenotypes were recorded, and the COL1A1 and COL1A2 genes were analyzed in 164 Swedish OI families (223 individuals). Averages for bone mineral density (BMD), height and yearly fracture rate were calculated and related to OI and mutation type. N-terminal helical mutations in both the α1- and α2-chains were associated with the absence of dentinogenesis imperfecta (P<0.0001 vs 0.0049), while only those in the α1-chain were associated with blue sclera (P=0.0110). Comparing glycine with serine substitutions, α1-alterations were associated with more severe phenotype (P=0.0031). Individuals with type I OI caused by qualitative vs quantitative mutations were shorter (P<0.0001), but did not differ considering fractures or BMD. The children in this cohort were estimated to represent >95% of the complete Swedish pediatric OI population. The prevalence of OI types I, III, and IV was 5.16, 0.89, and 1.35/100 000, respectively (7.40/100 000 overall), corresponding to what has been estimated but not unequivocally proven in any population. Collagen I mutation analysis was performed in the family of 97% of known cases, with causative mutations found in 87%. Qualitative mutations caused 32% of OI type I. The data reported here may be helpful to predict phenotype, and describes for the first time the genetic epidemiology in >95% of an entire OI population.
doi:10.1038/ejhg.2015.81
PMCID: PMC4795106  PMID: 25944380
3.  Fracture Rate, Quality of Life and Back Pain in Patients with Osteoporosis Treated with Teriparatide: 24-Month Results from the Extended Forsteo Observational Study (ExFOS) 
We describe the pre-planned interim analysis of fracture outcomes, health-related quality of life (HRQoL) and back pain in patients with severe osteoporosis treated with teriparatide for up to 24 months in the Extended Forsteo (Forsteo® is a registered trade name of Eli Lilly and Company) Observational Study (ExFOS), a prospective, multinational, observational study. Data on incident clinical fractures, HRQoL (EQ-5D questionnaire) and back pain [100 mm visual analogue scale (VAS)] were collected. The number of patients with fractures was summarised in 6-month intervals and fracture rate over each 6-month period was assessed using logistic regression for repeated measures. Changes from baseline in EQ-5D and back pain VAS were analysed using mixed models for repeated measures. Of 1454 patients in the active treatment cohort, 90.6 % were female and 14.4 % were taking glucocorticoids. During teriparatide treatment (median duration 23.7 months), 103 patients (7.1 %) sustained a total of 122 incident clinical fractures (21 % vertebral, 79 % non-vertebral). A 49 % decrease in the odds of fractures and a 75 % decrease in the odds of clinical vertebral fractures were observed in the >18- to 24-month period versus the first 6-month period (both p < 0.05). EQ-5D scores and back pain VAS scores were significantly improved from baseline at each post-baseline observation during teriparatide treatment. In conclusion, patients with severe osteoporosis showed a significant reduction in the incident fracture rate during 24 months of teriparatide treatment in routine clinical practice, accompanied by a significant improvement in HRQoL and reduction in back pain. Results should be interpreted in the context of the non-controlled design of this observational study.
Electronic supplementary material
The online version of this article (doi:10.1007/s00223-016-0143-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s00223-016-0143-5
PMCID: PMC4960288  PMID: 27137783
Osteoporosis; Observational study; Teriparatide; Fractures; Quality of life; Back pain
4.  Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture 
Zheng, Hou-Feng | Forgetta, Vincenzo | Hsu, Yi-Hsiang | Estrada, Karol | Rosello-Diez, Alberto | Leo, Paul J | Dahia, Chitra L | Park-Min, Kyung Hyun | Tobias, Jonathan H | Kooperberg, Charles | Kleinman, Aaron | Styrkarsdottir, Unnur | Liu, Ching-Ti | Uggla, Charlotta | Evans, Daniel S | Nielson, Carrie M | Walter, Klaudia | Pettersson-Kymmer, Ulrika | McCarthy, Shane | Eriksson, Joel | Kwan, Tony | Jhamai, Mila | Trajanoska, Katerina | Memari, Yasin | Min, Josine | Huang, Jie | Danecek, Petr | Wilmot, Beth | Li, Rui | Chou, Wen-Chi | Mokry, Lauren E | Moayyeri, Alireza | Claussnitzer, Melina | Cheng, Chia-Ho | Cheung, Warren | Medina-Gómez, Carolina | Ge, Bing | Chen, Shu-Huang | Choi, Kwangbom | Oei, Ling | Fraser, James | Kraaij, Robert | Hibbs, Matthew A | Gregson, Celia L | Paquette, Denis | Hofman, Albert | Wibom, Carl | Tranah, Gregory J | Marshall, Mhairi | Gardiner, Brooke B | Cremin, Katie | Auer, Paul | Hsu, Li | Ring, Sue | Tung, Joyce Y | Thorleifsson, Gudmar | Enneman, Anke W | van Schoor, Natasja M | de Groot, Lisette C.P.G.M. | van der Velde, Nathalie | Melin, Beatrice | Kemp, John P | Christiansen, Claus | Sayers, Adrian | Zhou, Yanhua | Calderari, Sophie | van Rooij, Jeroen | Carlson, Chris | Peters, Ulrike | Berlivet, Soizik | Dostie, Josée | Uitterlinden, Andre G | Williams, Stephen R. | Farber, Charles | Grinberg, Daniel | LaCroix, Andrea Z | Haessler, Jeff | Chasman, Daniel I | Giulianini, Franco | Rose, Lynda M | Ridker, Paul M | Eisman, John A | Nguyen, Tuan V | Center, Jacqueline R | Nogues, Xavier | Garcia-Giralt, Natalia | Launer, Lenore L | Gudnason, Vilmunder | Mellström, Dan | Vandenput, Liesbeth | Karlsson, Magnus K | Ljunggren, Östen | Svensson, Olle | Hallmans, Göran | Rousseau, François | Giroux, Sylvie | Bussière, Johanne | Arp, Pascal P | Koromani, Fjorda | Prince, Richard L | Lewis, Joshua R | Langdahl, Bente L | Hermann, A Pernille | Jensen, Jens-Erik B | Kaptoge, Stephen | Khaw, Kay-Tee | Reeve, Jonathan | Formosa, Melissa M | Xuereb-Anastasi, Angela | Åkesson, Kristina | McGuigan, Fiona E | Garg, Gaurav | Olmos, Jose M | Zarrabeitia, Maria T | Riancho, Jose A | Ralston, Stuart H | Alonso, Nerea | Jiang, Xi | Goltzman, David | Pastinen, Tomi | Grundberg, Elin | Gauguier, Dominique | Orwoll, Eric S | Karasik, David | Davey-Smith, George | Smith, Albert V | Siggeirsdottir, Kristin | Harris, Tamara B | Zillikens, M Carola | van Meurs, Joyce BJ | Thorsteinsdottir, Unnur | Maurano, Matthew T | Timpson, Nicholas J | Soranzo, Nicole | Durbin, Richard | Wilson, Scott G | Ntzani, Evangelia E | Brown, Matthew A | Stefansson, Kari | Hinds, David A | Spector, Tim | Cupples, L Adrienne | Ohlsson, Claes | Greenwood, Celia MT | Jackson, Rebecca D | Rowe, David W | Loomis, Cynthia A | Evans, David M | Ackert-Bicknell, Cheryl L | Joyner, Alexandra L | Duncan, Emma L | Kiel, Douglas P | Rivadeneira, Fernando | Richards, J Brent
Nature  2015;526(7571):112-117.
SUMMARY
The extent to which low-frequency (minor allele frequency [MAF] between 1–5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is largely unknown. Bone mineral density (BMD) is highly heritable, is a major predictor of osteoporotic fractures and has been previously associated with common genetic variants1–8, and rare, population-specific, coding variants9. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n=2,882 from UK10K), whole-exome sequencing (n= 3,549), deep imputation of genotyped samples using a combined UK10K/1000Genomes reference panel (n=26,534), and de-novo replication genotyping (n= 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size 4-fold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564[T], MAF = 1.7%, replication effect size = +0.20 standard deviations [SD], Pmeta = 2×10−14), which was also associated with a decreased risk of fracture (OR = 0.85; P = 2×10−11; ncases = 98,742 and ncontrols = 409,511). Using an En1Cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, likely as a consequence of high bone turn-over. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817[T], MAF = 1.1%, replication effect size = +0.39 SD, Pmeta = 1×10−11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
doi:10.1038/nature14878
PMCID: PMC4755714  PMID: 26367794 CAMSID: cams5439
5.  Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study 
Vimaleswaran, Karani S | Cavadino, Alana | Berry, Diane J | Jorde, Rolf | Dieffenbach, Aida Karina | Lu, Chen | Alves, Alexessander Couto | Heerspink, Hiddo J Lambers | Tikkanen, Emmi | Eriksson, Joel | Wong, Andrew | Mangino, Massimo | Jablonski, Kathleen A | Nolte, Ilja M | Houston, Denise K | Ahluwalia, Tarunveer Singh | van der Most, Peter J | Pasko, Dorota | Zgaga, Lina | Thiering, Elisabeth | Vitart, Veronique | Fraser, Ross M | Huffman, Jennifer E | de Boer, Rudolf A | Schöttker, Ben | Saum, Kai-Uwe | McCarthy, Mark I | Dupuis, Josée | Herzig, Karl-Heinz | Sebert, Sylvain | Pouta, Anneli | Laitinen, Jaana | Kleber, Marcus E | Navis, Gerjan | Lorentzon, Mattias | Jameson, Karen | Arden, Nigel | Cooper, Jackie A | Acharya, Jayshree | Hardy, Rebecca | Raitakari, Olli | Ripatti, Samuli | Billings, Liana K | Lahti, Jari | Osmond, Clive | Penninx, Brenda W | Rejnmark, Lars | Lohman, Kurt K | Paternoster, Lavinia | Stolk, Ronald P | Hernandez, Dena G | Byberg, Liisa | Hagström, Emil | Melhus, Håkan | Ingelsson, Erik | Mellström, Dan | Ljunggren, Östen | Tzoulaki, Ioanna | McLachlan, Stela | Theodoratou, Evropi | Tiesler, Carla M T | Jula, Antti | Navarro, Pau | Wright, Alan F | Polasek, Ozren | Hayward, Caroline | Wilson, James F | Rudan, Igor | Salomaa, Veikko | Heinrich, Joachim | Campbell, Harry | Price, Jacqueline F | Karlsson, Magnus | Lind, Lars | Michaëlsson, Karl | Bandinelli, Stefania | Frayling, Timothy M | Hartman, Catharina A | Sørensen, Thorkild I A | Kritchevsky, Stephen B | Langdahl, Bente Lomholt | Eriksson, Johan G | Florez, Jose C | Spector, Tim D | Lehtimäki, Terho | Kuh, Diana | Humphries, Steve E | Cooper, Cyrus | Ohlsson, Claes | März, Winfried | de Borst, Martin H | Kumari, Meena | Kivimaki, Mika | Wang, Thomas J | Power, Chris | Brenner, Hermann | Grimnes, Guri | van der Harst, Pim | Snieder, Harold | Hingorani, Aroon D | Pilz, Stefan | Whittaker, John C | Järvelin, Marjo-Riitta | Hyppönen, Elina
Summary
Background
Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk.
Methods
In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium.
Findings
In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, −0·12 mm Hg, 95% CI −0·20 to −0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97−0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, −0·02 mm Hg, −0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of −0·10 mm Hg in systolic blood pressure (−0·21 to −0·0001; p=0·0498) and a change of −0·08 mm Hg in diastolic blood pressure (−0·15 to −0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96−0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of −0·29 mm Hg in diastolic blood pressure (−0·52 to −0·07; p=0·01), a change of −0·37 mm Hg in systolic blood pressure (−0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87–0·97; p=0·002).
Interpretation
Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.
doi:10.1016/S2213-8587(14)70113-5
PMCID: PMC4582411  PMID: 24974252
6.  Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium 
Moayyeri, Alireza | Hsu, Yi-Hsiang | Karasik, David | Estrada, Karol | Xiao, Su-Mei | Nielson, Carrie | Srikanth, Priya | Giroux, Sylvie | Wilson, Scott G. | Zheng, Hou-Feng | Smith, Albert V. | Pye, Stephen R. | Leo, Paul J. | Teumer, Alexander | Hwang, Joo-Yeon | Ohlsson, Claes | McGuigan, Fiona | Minster, Ryan L. | Hayward, Caroline | Olmos, José M. | Lyytikäinen, Leo-Pekka | Lewis, Joshua R. | Swart, Karin M.A. | Masi, Laura | Oldmeadow, Chris | Holliday, Elizabeth G. | Cheng, Sulin | van Schoor, Natasja M. | Harvey, Nicholas C. | Kruk, Marcin | del Greco M, Fabiola | Igl, Wilmar | Trummer, Olivia | Grigoriou, Efi | Luben, Robert | Liu, Ching-Ti | Zhou, Yanhua | Oei, Ling | Medina-Gomez, Carolina | Zmuda, Joseph | Tranah, Greg | Brown, Suzanne J. | Williams, Frances M. | Soranzo, Nicole | Jakobsdottir, Johanna | Siggeirsdottir, Kristin | Holliday, Kate L. | Hannemann, Anke | Go, Min Jin | Garcia, Melissa | Polasek, Ozren | Laaksonen, Marika | Zhu, Kun | Enneman, Anke W. | McEvoy, Mark | Peel, Roseanne | Sham, Pak Chung | Jaworski, Maciej | Johansson, Åsa | Hicks, Andrew A. | Pludowski, Pawel | Scott, Rodney | Dhonukshe-Rutten, Rosalie A.M. | van der Velde, Nathalie | Kähönen, Mika | Viikari, Jorma S. | Sievänen, Harri | Raitakari, Olli T. | González-Macías, Jesús | Hernández, Jose L. | Mellström, Dan | Ljunggren, Östen | Cho, Yoon Shin | Völker, Uwe | Nauck, Matthias | Homuth, Georg | Völzke, Henry | Haring, Robin | Brown, Matthew A. | McCloskey, Eugene | Nicholson, Geoffrey C. | Eastell, Richard | Eisman, John A. | Jones, Graeme | Reid, Ian R. | Dennison, Elaine M. | Wark, John | Boonen, Steven | Vanderschueren, Dirk | Wu, Frederick C.W. | Aspelund, Thor | Richards, J. Brent | Bauer, Doug | Hofman, Albert | Khaw, Kay-Tee | Dedoussis, George | Obermayer-Pietsch, Barbara | Gyllensten, Ulf | Pramstaller, Peter P. | Lorenc, Roman S. | Cooper, Cyrus | Kung, Annie Wai Chee | Lips, Paul | Alen, Markku | Attia, John | Brandi, Maria Luisa | de Groot, Lisette C.P.G.M. | Lehtimäki, Terho | Riancho, José A. | Campbell, Harry | Liu, Yongmei | Harris, Tamara B. | Akesson, Kristina | Karlsson, Magnus | Lee, Jong-Young | Wallaschofski, Henri | Duncan, Emma L. | O'Neill, Terence W. | Gudnason, Vilmundur | Spector, Timothy D. | Rousseau, François | Orwoll, Eric | Cummings, Steven R. | Wareham, Nick J. | Rivadeneira, Fernando | Uitterlinden, Andre G. | Prince, Richard L. | Kiel, Douglas P. | Reeve, Jonathan | Kaptoge, Stephen K.
Human Molecular Genetics  2014;23(11):3054-3068.
Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10−8) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10−14). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10−6 also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
doi:10.1093/hmg/ddt675
PMCID: PMC4038791  PMID: 24430505
7.  The prevalence and severity of low back pain and associated symptoms in 3,009 old men 
European Spine Journal  2013;23(4):814-820.
Purpose
The aim of this study is to evaluate the prevalence and severity of low back pain (LBP) and the influence of sciatica and neurological deficits in old men.
Material and method
Mister osteoporosis Sweden includes 3,014 community-dwelling men aged 69–81 years. At study start 3,009 participants answered questions on LBP, low back pain and sciatica (LBP + SCI) or low back pain and sciatica with associated neurological deficits (LBP + SCI + NEU) during the preceding 12 months. Data are presented as proportions or medians with mid-quartile ranges. Differences between groups were tested by χ2 test and Kruskall-Wallis test.
Results
24 % had experienced LBP without SCI, 8 % LBP + SCI and 14 % LBP + SCI + NEU. 10 % of the men with LBP, 22 % of those with LBP + SCI, and 36 % of those with LBP + SCI + NEU rated the pain as severe (p < 0.001). 23 % of the men with LBP, 31 % of those with LBP + SCI and 50 % of those with LBP + SCI + NEU reported limitation in activity of daily living (ADL) (p < 0.001). Men with only LBP had to restrict their activities for 7 days (3–14), those with LBP + SCI 6 days (2–14) and those with LBP + SCI + NEU 10 days (3–30) (p < 0.05).
Conclusions
The 1-year prevalence of LBP in community living men aged 69–81 years was close to 50 % but for individuals with LBP or LBP + SCI the morbidity was low with more than two-thirds having no limitations in ADL. In men with LBP + SCI + NEU more than one-third rated the pain as severe and close to half had limitations in ADL.
doi:10.1007/s00586-013-3139-0
PMCID: PMC3960441  PMID: 24370858
Elderly men; Epidemiology; Low back pain; Neurological deficits; Sciatica
8.  High-Sensitivity CRP Is an Independent Risk Factor for All Fractures and Vertebral Fractures in Elderly Men: The MrOS Sweden Study 
Epidemiological studies have shown low-grade inflammation measured by high-sensitivity C-reactive protein (hs-CRP) to be associated with fracture risk in women. However, it is still unclear whether hs-CRP is also associated with fracture risk in men. We therefore measured serum levels of hs-CRP in 2910 men, mean age 75 years, included in the prospective population-based MrOS Sweden cohort. Study participants were divided into tertile groups based on hs-CRP level. Fractures occurring after the baseline visit were validated (average follow-up 5.4 years). The incidence for having at least one fracture after baseline was 23.9 per 1000 person-years. In Cox proportional hazard regression analyses adjusted for age, hs-CRP was related to fracture risk. The hazard ratio (HR) of fracture for the highest tertile of hs-CRP, compared with the lowest and the medium tertiles combined, was 1.48 (95% CI, 1.20–1.82). Multivariate adjustment for other risk factors for fractures had no major effect on the associations between hs-CRP and fracture. Results were essentially unchanged after exclusion of subjects with hs-CRP levels greater than 7.5 mg/L, as well as after exclusion of subjects with a first fracture within 3 years of follow-up, supporting that the associations between hs-CRP and fracture risk were not merely a reflection of a poor health status at the time of serum sampling. Femoral neck bone mineral density (BMD) was not associated with hs-CRP, and the predictive role of hs-CRP for fracture risk was essentially unchanged when femoral neck BMD was added to the model (HR, 1.37; 95% CI, 1.09–1.72). Exploratory subanalyses of fracture type demonstrated that hs-CRP was clearly associated with clinical vertebral fractures (HR, 1.61; 95% CI, 1.12–2.29). We demonstrate, using a large prospective population-based study, that elderly men with high hs-CRP have increased risk of fractures, and that these fractures are mainly vertebral. The association between hs-CRP and fractures was independent of BMD.
doi:10.1002/jbmr.2037
PMCID: PMC4238816  PMID: 23857741
FRACTURE RISK; AGING, DXA; LOW GRADE INFLAMMATION; hs-CRP
9.  Inferior physical performance tests in 10,998 men in the MrOS study is associated with recurrent falls 
Age and Ageing  2012;41(6):740-746.
Background: recurrent fallers are at especially high risk for injuries.
Objective: to study whether tests of physical performance are associated with recurrent falls.
Subjects: a total of 10,998 men aged 65 years or above.
Methods: questionnaires evaluated falls sustained 12 months preceding testing of grip strength, timed stand, 6-m walk and 20-cm narrow walk test. Means with 95% confidence interval (95% CI) are reported. P < 0.01 is a statistically significant difference.
Results: in comparison to both occasional fallers and non-fallers, recurrent fallers performed more poorly on all the physical ability tests (all P < 0.001). A score below −2 standard deviations (SDs) in the right-hand grip strength test was associated with an odds ratio of 2.4 (95% CI 1.7, 3.4) for having had recurrent falls compared with having had no fall and of 2.0 (95% CI 1.3, 3.4) for having had recurrent falls compared with having had an occasional fall.
Conclusion: low performance in physical ability tests are in elderly men associated with recurrent falls.
doi:10.1093/ageing/afs104
PMCID: PMC3476829  PMID: 22923607
falls; men; muscle; older people; physical performance tests; recurrent
10.  Assessment of Gene-by-Sex Interaction Effect on Bone Mineral Density 
Liu, Ching-Ti | Estrada, Karol | Yerges-Armstrong, Laura M. | Amin, Najaf | Evangelou, Evangelos | Li, Guo | Minster, Ryan L. | Carless, Melanie A. | Kammerer, Candace M. | Oei, Ling | Zhou, Yanhua | Alonso, Nerea | Dailiana, Zoe | Eriksson, Joel | García-Giralt, Natalia | Giroux, Sylvie | Husted, Lise Bjerre | Khusainova, Rita I. | Koromila, Theodora | Kung, Annie WaiChee | Lewis, Joshua R. | Masi, Laura | Mencej-Bedrac, Simona | Nogues, Xavier | Patel, Millan S. | Prezelj, Janez | Richards, J Brent | Sham, Pak Chung | Spector, Timothy | Vandenput, Liesbeth | Xiao, Su-Mei | Zheng, Hou-Feng | Zhu, Kun | Balcells, Susana | Brandi, Maria Luisa | Frost, Morten | Goltzman, David | González-Macías, Jesús | Karlsson, Magnus | Khusnutdinova, Elza K. | Kollia, Panagoula | Langdahl, Bente Lomholt | Ljunggren, Östen | Lorentzon, Mattias | Marc, Janja | Mellström, Dan | Ohlsson, Claes | Olmos, José M. | Ralston, Stuart H. | Riancho, José A. | Rousseau, François | Urreizti, Roser | Van Hul, Wim | Zarrabeitia, María T. | Castano-Betancourt, Martha | Demissie, Serkalem | Grundberg, Elin | Herrera, Lizbeth | Kwan, Tony | Medina-Gómez, Carolina | Pastinen, Tomi | Sigurdsson, Gunnar | Thorleifsson, Gudmar | vanMeurs, Joyce B.J. | Blangero, John | Hofman, Albert | Liu, Yongmei | Mitchell, Braxton D. | O’Connell, Jeffrey R. | Oostra, Ben A. | Rotter, Jerome I | Stefansson, Kari | Streeten, Elizabeth A. | Styrkarsdottir, Unnur | Thorsteinsdottir, Unnur | Tylavsky, Frances A. | Uitterlinden, Andre | Cauley, Jane A. | Harris, Tamara B. | Ioannidis, John P.A. | Psaty, Bruce M. | Robbins, John A | Zillikens, M. Carola | vanDuijn, Cornelia M. | Prince, Richard L. | Karasik, David | Rivadeneira, Fernando | Kiel, Douglas P. | Cupples, L. Adrienne | Hsu, Yi-Hsiang
Background
Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed eQTL analysis and bioinformatics network analysis.
Methods
We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS-) and femoral neck (FN-) BMD, in 25,353 individuals from eight cohorts. In a second stage, we followed up the 12 top SNPs (P<1×10−5) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs.
Results
We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 & p-value = 3.0×10−5; female effect = −0.007 & p-value=3.3×10−2) and eleven suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (P<5×10−8) gene-by-sex interaction in the joint analysis of discovery and replication cohorts.
Conclusion
Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found influencing BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP.
doi:10.1002/jbmr.1679
PMCID: PMC3447125  PMID: 22692763
gene-by-sex; interaction; BMD; association; aging
11.  Effective osteoporosis treatment with teriparatide is associated with enhanced quality of life in postmenopausal women with osteoporosis: the European Forsteo Observational Study 
Background
To describe changes in health-related quality of life (HRQoL) of postmenopausal women with osteoporosis treated with teriparatide for up to 18 months and followed-up for a further 18 months, and to assess the influence of recent prior and incident fractures.
Methods
The European Forsteo Observational Study (EFOS) is an observational, prospective, multinational study measuring HRQoL using the EQ-5D. The primary objective was to assess changes in HRQoL during 36 months in the whole study population. A secondary post-hoc analysis examined fracture impact on HRQoL in four subgroups classified based on recent prior fracture 12 months before baseline and incident clinical fractures during the study. Changes from baseline were analysed using a repeated measures model.
Results
Of the 1581 patients, 48.4% had a recent prior fracture and 15.6% of these patients had an incident fracture during follow-up. 10.9% of the 816 patients with no recent prior fracture had an incident fracture. Baseline mean EQ-VAS scores were similar across the subgroups. In the total study cohort (n = 1581), HRQoL (EQ-VAS and EQ-5D index scores) improved significantly from baseline to 18 months and this improvement was maintained over the 18-month post-teriparatide period. Improvements were seen across all five EQ-5D domains during teriparatide treatment that were maintained after teriparatide was discontinued. Subjects with incident clinical fractures had significantly less improvement in EQ-VAS than those without incident fractures. Recent prior fracture did not influence the change in EQ-VAS during treatment.
Conclusions
EFOS is the first longitudinal study in women with severe postmenopausal osteoporosis in the real world setting to show a substantial improvement in HRQoL during teriparatide treatment that was sustained during subsequent treatment with other medications. The increase in HRQoL was lower in the subgroups with incident fracture but was not influenced by recent prior fracture. The results should be interpreted in the context of the design of an observational study.
doi:10.1186/1471-2474-14-251
PMCID: PMC3765934  PMID: 23968239
EQ-5D; Fracture; Osteoporosis; Quality of life; Teriparatide
12.  Inferior physical performance test results of 10,998 men in the MrOS Study is associated with high fracture risk 
Age and Ageing  2012;41(3):339-344.
Background: most fractures are preceded by falls.
Objective: the aim of this study was to determine whether tests of physical performance are associated with fractures.
Subjects: a total of 10,998 men aged 65 years or above were recruited.
Methods: questionnaires evaluated falls sustained 12 months before administration of the grip strength test, the timed stand test, the six-metre walk test and the twenty-centimetre narrow walk test. Means with 95% confidence interval (95% CI) are reported. P < 0.05 is a statistically significant difference.
Results: fallers with a fracture performed worse than non-fallers on all tests (all P < 0.001). Fallers with a fracture performed worse than fallers with no fractures both on the right-hand-grip strength test and on the six-metre walk test (P < 0.001). A score below –2 standard deviations in the right-hand-grip strength test was associated with an odds ratio of 3.9 (95% CI: 2.1–7.4) for having had a fall with a fracture compared with having had no fall and with an odds ratio of 2.6 (95% CI: 1.3–5.2) for having had a fall with a fracture compared with having had a fall with no fracture.
Conclusion: the right-hand-grip strength test and the six-metre walk test performed by old men help discriminate fallers with a fracture from both fallers with no fracture and non-fallers.
doi:10.1093/ageing/afs010
PMCID: PMC3335372  PMID: 22314696
falls; fractures; men; old; physical performance tests; elderly
13.  Comparisons of Immunoassay and Mass Spectrometry Measurements of Serum Estradiol Levels and Their Influence on Clinical Association Studies in Men 
Context:
Immunoassay-based techniques, routinely used to measure serum estradiol (E2), are known to have reduced specificity, especially at lower concentrations, when compared with the gold standard technique of mass spectrometry (MS). Different measurement techniques may be responsible for the conflicting results of associations between serum E2 and clinical phenotypes in men.
Objective:
Our objective was to compare immunoassay and MS measurements of E2 levels in men and evaluate associations with clinical phenotypes.
Design and Setting:
Middle-aged and older male subjects participating in the population-based Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2599), MrOS US (n = 688), and the European Male Aging Study (n = 2908) were included.
Main Outcome Measures:
Immunoassay and MS measurements of serum E2 were compared and related to bone mineral density (BMD; measured by dual energy x-ray absorptiometry) and ankle-brachial index.
Results:
Within each cohort, serum E2 levels obtained by immunoassay and MS correlated moderately (Spearman rank correlation coefficient rS 0.53–0.76). Serum C-reactive protein (CRP) levels associated significantly (albeit to a low extent, rS = 0.29) with immunoassay E2 but not with MS E2 levels. Similar associations of immunoassay E2 and MS E2 were seen with lumbar spine and total hip BMD, independent of serum CRP. However, immunoassay E2, but not MS E2, associated inversely with ankle-brachial index, and this correlation was lost after adjustment for CRP.
Conclusions:
Our findings suggest interference in the immunoassay E2 analyses, possibly by CRP or a CRP-associated factor. Although associations with BMD remain unaffected, this might imply for a reevaluation of previous association studies between immunoassay E2 levels and inflammation-related outcomes.
doi:10.1210/jc.2012-3861
PMCID: PMC3667264  PMID: 23633197
14.  Fibroblast growth factor 23, mineral metabolism and mortality among elderly men (Swedish MrOs) 
BMC Nephrology  2013;14:85.
Background
Fibroblast growth factor 23 (FGF23) is the earliest marker of disturbed mineral metabolism as renal function decreases. Its serum levels are associated with mortality in dialysis patients, persons with chronic kidney disease (CKD) and prevalent cardiovascular disease (CVD), and it is associated with atherosclerosis, endothelial dysfunction and left ventricular hypertrophy in the general population. The primary aim of this study is to examine the association between FGF23 and mortality, in relation to renal function in the community. A secondary aim is to examine the association between FGF23 and CVD related death.
Methods
The population-based cohort of MrOS Sweden included 3014 men (age 69–81 years). At inclusion intact FGF23, intact parathyroid hormone (PTH), 25 hydroxyl vitamin D (25D), calcium and phosphate were measured. Mortality data were collected after an average of 4.5 years follow-up. 352 deaths occurred, 132 of CVD. Association between FGF23 and mortality was analyzed in quartiles of FGF23. Kaplan-Meier curves and Log-rank test were used to examine time to events. Cox proportional hazards regression was used to examine the association between FGF23, in quartiles and as a continuous variable, with mortality. The associations were also analyzed in the sub-cohort with estimated glomerular filtration rate (eGFR) above 60 ml/min/1.73 m2.
Results
There was no association between FGF23 and all-cause mortality, Hazard ratio (HR) 95% confidence interval (CI): 1.02 (0.89-1.17). For CVD death the HR (95% CI) was 1.26 (0.99 - 1.59)/(1-SD) increase in log(10)FGF23 after adjustment for eGFR, and other confounders. In the sub-cohort with eGFR > 60 ml/min/1.73 m2 the HR (95% CI) for CVD death was 55% (13–111)/(1-SD) increase in log(10)FGF23.
Conclusions
FGF23 is not associated with mortality of all-cause in elderly community living men, but there is a weak association with CVD death, even after adjustment for eGFR and the other confounders. The association with CVD death is noticeable only in the sub-cohort with preserved renal function.
doi:10.1186/1471-2369-14-85
PMCID: PMC3637557  PMID: 23587028
FGF-23; FGF23; Mineral metabolism; Phosphatonin; Mortality; Elderly
15.  Genetic Determinants of Trabecular and Cortical Volumetric Bone Mineral Densities and Bone Microstructure 
PLoS Genetics  2013;9(2):e1003247.
Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n = 5,878) followed by replication (n = 1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p = 3.6×10−14; LOC285735, rs271170, p = 2.7×10−12; OPG, rs7839059, p = 1.2×10−10; and ESR1/C6orf97, rs6909279, p = 1.1×10−9). The trabecular vBMD GWA meta-analysis (n = 2,500) followed by replication (n = 1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p = 1.9×10−9). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n = 729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60–0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.
Author Summary
Osteoporosis is a common highly heritable skeletal disease characterized by reduced bone mineral density (BMD) and deteriorated bone microstructure, resulting in an increased risk of fracture. Most previous genetic epidemiology studies have focused on the genetics of the complex trait BMD, not being able to separate genetic determinants of the trabecular and cortical bone compartments and bone microstructure. The trabecular and cortical BMDs can be analysed separately by computed tomography. Therefore, we performed separate genome-wide association studies for trabecular and cortical BMDs, demonstrating that the genetic determinants of cortical and trabecular BMDs differ. Genetic variants in the RANKL, LOC285735, OPG, and ESR1 loci were associated with cortical BMD, while a genetic variant in the FMN2/GREM2 locus was associated with trabecular BMD. Two of these are novel bone-related loci. Follow-up analyses of bone microstructure demonstrated that a genetic variant in the RANKL locus is associated with cortical porosity and that the FMN2/GREM2 locus is associated with trabecular number and thickness. We propose that a genetic variant in the RANKL locus influences cortical BMD via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences trabecular BMD and fracture risk via effects on both trabecular number and thickness.
doi:10.1371/journal.pgen.1003247
PMCID: PMC3578773  PMID: 23437003
16.  Allele Dependent Silencing of Collagen Type I Using Small Interfering RNAs Targeting 3'UTR Indels - a Novel Therapeutic Approach in Osteogenesis Imperfecta 
Osteogenesis imperfecta, also known as “brittle bone disease”, is a heterogeneous disorder of connective tissue generally caused by dominant mutations in the genes COL1A1 and COL1A2, encoding the α1 and α2 chains of type I (pro)collagen. Symptomatic patients are usually prescribed bisphosphonates, but this treatment is neither curative nor sufficient. A promising field is gene silencing through RNA interference. In this study small interfering RNAs (siRNAs) were designed to target each allele of 3'UTR insertion/deletion polymorphisms (indels) in COL1A1 (rs3840870) and COL1A2 (rs3917). For both indels, the frequency of heterozygous individuals was determined to be approximately 50% in Swedish cohorts of healthy controls as well as in patients with osteogenesis imperfecta. Cultures of primary human bone derived cells were transfected with siRNAs through magnet-assisted transfection. cDNA from transfected cells was sequenced in order to measure targeted allele/non-targeted allele ratios and the overall degree of silencing was assessed by quantitative PCR. Successful allele dependent silencing was observed, with promising results for siRNAs complementary to both the insertion and non-insertion harboring alleles. In COL1A1 cDNA the indel allele ratios were shifted from 1 to 0.09 and 0.19 for the insertion and non-insertion allele respectively while the equivalent resulting ratios for COL1A2 were 0.05 and 0.01. Reductions in mRNA abundance were also demonstrated; in cells treated with siRNAs targeting the COL1A1 alleles the average COL1A1 mRNA levels were reduced 65% and 78% compared to negative control levels and in cells treated with COL1A2 siRNAs the average COL1A2 mRNA levels were decreased 26% and 49% of those observed in the corresponding negative controls. In conclusion, allele dependent silencing of collagen type I utilizing 3'UTR indels common in the general population constitutes a promising mutation independent therapeutic approach for osteogenesis imperfecta.
doi:10.7150/ijms.5774
PMCID: PMC3752721  PMID: 23983594
osteogenesis imperfecta; collagen type I; siRNA
17.  Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture 
Estrada, Karol | Styrkarsdottir, Unnur | Evangelou, Evangelos | Hsu, Yi-Hsiang | Duncan, Emma L | Ntzani, Evangelia E | Oei, Ling | Albagha, Omar M E | Amin, Najaf | Kemp, John P | Koller, Daniel L | Li, Guo | Liu, Ching-Ti | Minster, Ryan L | Moayyeri, Alireza | Vandenput, Liesbeth | Willner, Dana | Xiao, Su-Mei | Yerges-Armstrong, Laura M | Zheng, Hou-Feng | Alonso, Nerea | Eriksson, Joel | Kammerer, Candace M | Kaptoge, Stephen K | Leo, Paul J | Thorleifsson, Gudmar | Wilson, Scott G | Wilson, James F | Aalto, Ville | Alen, Markku | Aragaki, Aaron K | Aspelund, Thor | Center, Jacqueline R | Dailiana, Zoe | Duggan, David J | Garcia, Melissa | Garcia-Giralt, Natàlia | Giroux, Sylvie | Hallmans, Göran | Hocking, Lynne J | Husted, Lise Bjerre | Jameson, Karen A | Khusainova, Rita | Kim, Ghi Su | Kooperberg, Charles | Koromila, Theodora | Kruk, Marcin | Laaksonen, Marika | Lacroix, Andrea Z | Lee, Seung Hun | Leung, Ping C | Lewis, Joshua R | Masi, Laura | Mencej-Bedrac, Simona | Nguyen, Tuan V | Nogues, Xavier | Patel, Millan S | Prezelj, Janez | Rose, Lynda M | Scollen, Serena | Siggeirsdottir, Kristin | Smith, Albert V | Svensson, Olle | Trompet, Stella | Trummer, Olivia | van Schoor, Natasja M | Woo, Jean | Zhu, Kun | Balcells, Susana | Brandi, Maria Luisa | Buckley, Brendan M | Cheng, Sulin | Christiansen, Claus | Cooper, Cyrus | Dedoussis, George | Ford, Ian | Frost, Morten | Goltzman, David | González-Macías, Jesús | Kähönen, Mika | Karlsson, Magnus | Khusnutdinova, Elza | Koh, Jung-Min | Kollia, Panagoula | Langdahl, Bente Lomholt | Leslie, William D | Lips, Paul | Ljunggren, Östen | Lorenc, Roman S | Marc, Janja | Mellström, Dan | Obermayer-Pietsch, Barbara | Olmos, José M | Pettersson-Kymmer, Ulrika | Reid, David M | Riancho, José A | Ridker, Paul M | Rousseau, François | Slagboom, P Eline | Tang, Nelson LS | Urreizti, Roser | Van Hul, Wim | Viikari, Jorma | Zarrabeitia, María T | Aulchenko, Yurii S | Castano-Betancourt, Martha | Grundberg, Elin | Herrera, Lizbeth | Ingvarsson, Thorvaldur | Johannsdottir, Hrefna | Kwan, Tony | Li, Rui | Luben, Robert | Medina-Gómez, Carolina | Palsson, Stefan Th | Reppe, Sjur | Rotter, Jerome I | Sigurdsson, Gunnar | van Meurs, Joyce B J | Verlaan, Dominique | Williams, Frances MK | Wood, Andrew R | Zhou, Yanhua | Gautvik, Kaare M | Pastinen, Tomi | Raychaudhuri, Soumya | Cauley, Jane A | Chasman, Daniel I | Clark, Graeme R | Cummings, Steven R | Danoy, Patrick | Dennison, Elaine M | Eastell, Richard | Eisman, John A | Gudnason, Vilmundur | Hofman, Albert | Jackson, Rebecca D | Jones, Graeme | Jukema, J Wouter | Khaw, Kay-Tee | Lehtimäki, Terho | Liu, Yongmei | Lorentzon, Mattias | McCloskey, Eugene | Mitchell, Braxton D | Nandakumar, Kannabiran | Nicholson, Geoffrey C | Oostra, Ben A | Peacock, Munro | Pols, Huibert A P | Prince, Richard L | Raitakari, Olli | Reid, Ian R | Robbins, John | Sambrook, Philip N | Sham, Pak Chung | Shuldiner, Alan R | Tylavsky, Frances A | van Duijn, Cornelia M | Wareham, Nick J | Cupples, L Adrienne | Econs, Michael J | Evans, David M | Harris, Tamara B | Kung, Annie Wai Chee | Psaty, Bruce M | Reeve, Jonathan | Spector, Timothy D | Streeten, Elizabeth A | Zillikens, M Carola | Thorsteinsdottir, Unnur | Ohlsson, Claes | Karasik, David | Richards, J Brent | Brown, Matthew A | Stefansson, Kari | Uitterlinden, André G | Ralston, Stuart H | Ioannidis, John P A | Kiel, Douglas P | Rivadeneira, Fernando
Nature genetics  2012;44(5):491-501.
Bone mineral density (BMD) is the most important predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and East Asian ancestry. We tested the top-associated BMD markers for replication in 50,933 independent subjects and for risk of low-trauma fracture in 31,016 cases and 102,444 controls. We identified 56 loci (32 novel)associated with BMD atgenome-wide significant level (P<5×10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal-stem-cell differentiation, endochondral ossification and the Wnt signalling pathways. However, we also discovered loci containing genes not known to play a role in bone biology. Fourteen BMD loci were also associated with fracture risk (P<5×10−4, Bonferroni corrected), of which six reached P<5×10−8 including: 18p11.21 (C18orf19), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
doi:10.1038/ng.2249
PMCID: PMC3338864  PMID: 22504420
19.  A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation 
Coviello, Andrea D. | Haring, Robin | Wellons, Melissa | Vaidya, Dhananjay | Lehtimäki, Terho | Keildson, Sarah | Lunetta, Kathryn L. | He, Chunyan | Fornage, Myriam | Lagou, Vasiliki | Mangino, Massimo | Onland-Moret, N. Charlotte | Chen, Brian | Eriksson, Joel | Garcia, Melissa | Liu, Yong Mei | Koster, Annemarie | Lohman, Kurt | Lyytikäinen, Leo-Pekka | Petersen, Ann-Kristin | Prescott, Jennifer | Stolk, Lisette | Vandenput, Liesbeth | Wood, Andrew R. | Zhuang, Wei Vivian | Ruokonen, Aimo | Hartikainen, Anna-Liisa | Pouta, Anneli | Bandinelli, Stefania | Biffar, Reiner | Brabant, Georg | Cox, David G. | Chen, Yuhui | Cummings, Steven | Ferrucci, Luigi | Gunter, Marc J. | Hankinson, Susan E. | Martikainen, Hannu | Hofman, Albert | Homuth, Georg | Illig, Thomas | Jansson, John-Olov | Johnson, Andrew D. | Karasik, David | Karlsson, Magnus | Kettunen, Johannes | Kiel, Douglas P. | Kraft, Peter | Liu, Jingmin | Ljunggren, Östen | Lorentzon, Mattias | Maggio, Marcello | Markus, Marcello R. P. | Mellström, Dan | Miljkovic, Iva | Mirel, Daniel | Nelson, Sarah | Morin Papunen, Laure | Peeters, Petra H. M. | Prokopenko, Inga | Raffel, Leslie | Reincke, Martin | Reiner, Alex P. | Rexrode, Kathryn | Rivadeneira, Fernando | Schwartz, Stephen M. | Siscovick, David | Soranzo, Nicole | Stöckl, Doris | Tworoger, Shelley | Uitterlinden, André G. | van Gils, Carla H. | Vasan, Ramachandran S. | Wichmann, H.-Erich | Zhai, Guangju | Bhasin, Shalender | Bidlingmaier, Martin | Chanock, Stephen J. | De Vivo, Immaculata | Harris, Tamara B. | Hunter, David J. | Kähönen, Mika | Liu, Simin | Ouyang, Pamela | Spector, Tim D. | van der Schouw, Yvonne T. | Viikari, Jorma | Wallaschofski, Henri | McCarthy, Mark I. | Frayling, Timothy M. | Murray, Anna | Franks, Steve | Järvelin, Marjo-Riitta | de Jong, Frank H. | Raitakari, Olli | Teumer, Alexander | Ohlsson, Claes | Murabito, Joanne M. | Perry, John R. B.
PLoS Genetics  2012;8(7):e1002805.
Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×10−106), PRMT6 (rs17496332, 1p13.3, p = 1.4×10−11), GCKR (rs780093, 2p23.3, p = 2.2×10−16), ZBTB10 (rs440837, 8q21.13, p = 3.4×10−09), JMJD1C (rs7910927, 10q21.3, p = 6.1×10−35), SLCO1B1 (rs4149056, 12p12.1, p = 1.9×10−08), NR2F2 (rs8023580, 15q26.2, p = 8.3×10−12), ZNF652 (rs2411984, 17q21.32, p = 3.5×10−14), TDGF3 (rs1573036, Xq22.3, p = 4.1×10−14), LHCGR (rs10454142, 2p16.3, p = 1.3×10−07), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×10−08), and UGT2B15 (rs293428, 4q13.2, p = 5.5×10−06). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×10−08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ∼15.6% and ∼8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.
Author Summary
Sex hormone-binding globulin (SHBG) is the key protein responsible for binding and transporting the sex steroid hormones, testosterone and estradiol, in the circulatory system. SHBG regulates their bioavailability and therefore their effects in the body. SHBG has been linked to chronic diseases including type 2 diabetes and to hormone-sensitive cancers such as breast and prostate cancer. SHBG concentrations are approximately 50% heritable in family studies, suggesting SHBG concentrations are under significant genetic control; yet, little is known about the specific genes that influence SHBG. We conducted a large study of the association of SHBG concentrations with markers in the human genome in ∼22,000 white men and women to determine which loci influence SHBG concentrations. Genes near the identified genomic markers in addition to the SHBG protein coding gene included PRMT6, GCKR, ZBTB10, JMJD1C, SLCO1B1, NR2F2, ZNF652, TDGF3, LHCGR, BAIAP2L1, and UGT2B15. These genes represent a wide range of biologic pathways that may relate to SHBG function and sex steroid hormone biology, including liver function, lipid metabolism, carbohydrate metabolism and type 2 diabetes, and the development and progression of sex steroid hormone-responsive cancers.
doi:10.1371/journal.pgen.1002805
PMCID: PMC3400553  PMID: 22829776
20.  COL1 C-propeptide Cleavage Site Mutations Cause High Bone Mass Osteogenesis Imperfecta 
Human mutation  2011;32(6):598-609.
Osteogenesis imperfecta (OI) is most often caused by mutations in the type I procollagen genes (COL1A1/COL1A2). We identified two children with substitutions in the type I procollagen C-propeptide cleavage site, which disrupt a unique processing step in collagen maturation and define a novel phenotype within OI. The patients have mild OI caused by mutations in COL1A1 (Patient 1: p.Asp1219Asn) or COL1A2 (Patient 2: p.Ala1119Thr), respectively. Patient 1 L1-L4 DXA z-score was +3.9 and pQCT vBMD was +3.1; Patient 2 had L1-L4 DXA z-score of 0.0 and pQCT vBMD of −1.8. Patient BMD contrasts with radiographic osteopenia and histomorphometry without osteosclerosis. Mutant procollagen processing is impaired in pericellular and in vitro assays. Patient dermal collagen fibrils have irregular borders. Incorporation of pC-collagen into matrix leads to increased bone mineralization. FT-IR imaging confirms elevated mineral/matrix ratios in both patients, along with increased collagen maturation in trabecular bone, compared to normal or OI controls. Bone mineralization density distribution revealed a marked shift toward increased mineralization density for both patients. Patient 1 has areas of higher and lower bone mineralization than controls; Patient 2’s bone matrix has a mineral content exceeding even classical OI bone. These patients define a new phenotype of high BMD OI and demonstrate that procollagen C-propeptide cleavage is crucial to normal bone mineralization.
doi:10.1002/humu.21475
PMCID: PMC3103631  PMID: 21344539
Osteogenesis imperfecta; C-propeptide; collagen; C-proteinase; mineralization; high bone mass
21.  Oncogenic osteomalacia illustrating the effect of fibroblast growth factor 23 on phosphate homeostasis 
Clinical Kidney Journal  2012;5(3):240-243.
In oncogenic osteomalacia (OOM), fibroblast growth factor 23 (FGF23) induces renal phosphate wasting and inhibits the appropriate increase of calcitriol. A patient suffering from OOM is described. Serum calcium, phosphate, biointact parathyroid hormone and intact FGF23 as well as the calcitriol and 24,25-vitamin D levels were measured before and after tumour removal. The clinical approach to a patient with hypophosphataemia is discussed and the changes in mineral metabolism after removal of a FGF23-producing tumour are described.
doi:10.1093/ckj/sfs031
PMCID: PMC4400509  PMID: 26069775
FGF23; mineral metabolism; osteomalacia; phosphate
22.  Large-Scale Analysis of Association Between LRP5 and LRP6 Variants and Osteoporosis 
Jama  2008;299(11):1277-1290.
Context
Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population.
Objective
To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk.
Design and Setting
Prospective, multicenter, collaborative study of individual-level data on 37 534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures.
Main Outcome Measures
Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures.
Results
The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n =25 052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P=3.3 × 10−8), as was the Val1330 allele (n = 24 812; 14-mg/cm2 lower BMD per Val1330 copy; P=2.6 × 10−9). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P =3.8 × 10−5) and 8 mg/cm2 (P=5.0×10−6) for the Met667 and Val1330 alleles, respectively (n=25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08–1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01–1.24 for Val1330 [1988 fractures among 20 096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05–1.24 per allele [7876 fractures among 31 435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01–1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments.
Conclusions
Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P<10−7] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
doi:10.1001/jama.299.11.1277
PMCID: PMC3282142  PMID: 18349089
23.  Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile 
Kilpeläinen, Tuomas O | Zillikens, M Carola | Stančáková, Alena | Finucane, Francis M | Ried, Janina S | Langenberg, Claudia | Zhang, Weihua | Beckmann, Jacques S | Luan, Jian’an | Vandenput, Liesbeth | Styrkarsdottir, Unnur | Zhou, Yanhua | Smith, Albert Vernon | Zhao, Jing-Hua | Amin, Najaf | Vedantam, Sailaja | Shin, So Youn | Haritunians, Talin | Fu, Mao | Feitosa, Mary F | Kumari, Meena | Halldorsson, Bjarni V | Tikkanen, Emmi | Mangino, Massimo | Hayward, Caroline | Song, Ci | Arnold, Alice M | Aulchenko, Yurii S | Oostra, Ben A | Campbell, Harry | Cupples, L Adrienne | Davis, Kathryn E | Döring, Angela | Eiriksdottir, Gudny | Estrada, Karol | Fernández-Real, José Manuel | Garcia, Melissa | Gieger, Christian | Glazer, Nicole L | Guiducci, Candace | Hofman, Albert | Humphries, Steve E | Isomaa, Bo | Jacobs, Leonie C | Jula, Antti | Karasik, David | Karlsson, Magnus K | Khaw, Kay-Tee | Kim, Lauren J | Kivimäki, Mika | Klopp, Norman | Kühnel, Brigitte | Kuusisto, Johanna | Liu, Yongmei | Ljunggren, Östen | Lorentzon, Mattias | Luben, Robert N | McKnight, Barbara | Mellström, Dan | Mitchell, Braxton D | Mooser, Vincent | Moreno, José Maria | Männistö, Satu | O’Connell, Jeffery R | Pascoe, Laura | Peltonen, Leena | Peral, Belén | Perola, Markus | Psaty, Bruce M | Salomaa, Veikko | Savage, David B | Semple, Robert K | Skaric-Juric, Tatjana | Sigurdsson, Gunnar | Song, Kijoung S | Spector, Timothy D | Syvänen, Ann-Christine | Talmud, Philippa J | Thorleifsson, Gudmar | Thorsteinsdottir, Unnur | Uitterlinden, André G | van Duijn, Cornelia M | Vidal-Puig, Antonio | Wild, Sarah H | Wright, Alan F | Clegg, Deborah J | Schadt, Eric | Wilson, James F | Rudan, Igor | Ripatti, Samuli | Borecki, Ingrid B | Shuldiner, Alan R | Ingelsson, Erik | Jansson, John-Olov | Kaplan, Robert C | Gudnason, Vilmundur | Harris, Tamara B | Groop, Leif | Kiel, Douglas P | Rivadeneira, Fernando | Walker, Mark | Barroso, Inês | Vollenweider, Peter | Waeber, Gérard | Chambers, John C | Kooner, Jaspal S | Soranzo, Nicole | Hirschhorn, Joel N | Stefansson, Kari | Wichmann, H-Erich | Ohlsson, Claes | O’Rahilly, Stephen | Wareham, Nicholas J | Speliotes, Elizabeth K | Fox, Caroline S | Laakso, Markku | Loos, Ruth J F
Nature Genetics  2011;43(8):753-760.
Genome-wide association studies have identified 32 loci associated with body mass index (BMI), a measure that does not allow distinguishing lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ~2.5 million SNPs and body fat percentage from 36,626 individuals, and followed up the 14 most significant (P<10−6) independent loci in 39,576 individuals. We confirmed the previously established adiposity locus in FTO (P=3×10−26), and identified two new loci associated with body fat percentage, one near IRS1 (P=4×10−11) and one near SPRY2 (P=3×10−8). Both loci harbour genes with a potential link to adipocyte physiology, of which the locus near IRS1 shows an intriguing association pattern. The body-fat-decreasing allele associates with decreased IRS1 expression and with an impaired metabolic profile, including decreased subcutaneous-to-visceral fat ratio, increased insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease, and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.
doi:10.1038/ng.866
PMCID: PMC3262230  PMID: 21706003
24.  Genetic Determinants of Serum Testosterone Concentrations in Men 
PLoS Genetics  2011;7(10):e1002313.
Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2×10−41 and rs6258, p = 2.3×10−22). Subjects with ≥3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6×10−16). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.
Author Summary
Testosterone is the most important testicular androgen in men. Low serum testosterone concentrations are associated with cardiovascular morbidity, metabolic syndrome, type 2 diabetes mellitus, atherosclerosis, osteoporosis, sarcopenia, and increased mortality risk. Thus, there is growing evidence that serum testosterone is a valuable biomarker of men's overall health status. Studies in male twins indicate that there is a strong heritability of serum testosterone. Here we perform a large-scale genome-wide association study to examine the effects of common genetic variants on serum testosterone concentrations. By examining 14,429 men, we show that genetic variants in the sex hormone-binding globulin (SHBG) locus and on the X chromosome are associated with a substantial variation in serum testosterone concentrations and increased risk of low testosterone. The reported associations may now be used in order to better understand the functional background of recently identified disease associations related to low testosterone. Importantly, we identified the first known genetic variant, which affects SHBG's affinity for binding testosterone and the free testosterone fraction and could therefore influence the calculation of free testosterone. This finding suggests that individual-based SHBG-testosterone affinity constants are required depending on the genotype of this single-nucleotide polymorphism.
doi:10.1371/journal.pgen.1002313
PMCID: PMC3188559  PMID: 21998597
25.  A Variant near the Interleukin-6 Gene Is Associated with Fat Mass in Caucasian Men 
Context
Regulation of fat mass appears to be associated with immune functions. Studies of knockout mice show that endogenous interleukin (IL)-6 can suppress mature-onset obesity.
Objective
To systematically investigate associations of single nucleotide polymorphisms (SNPs) near the IL-6 (IL6) and IL-6 receptor (IL6R) genes with body fat mass, in support for our hypothesis that variants of these genes can be associated with obesity.
Design and Study Subjects
The Gothenburg Osteoporosis and Obesity Determinants (GOOD) study is a population-based cross-sectional study of 18-20 years old men (n=1 049), from the Gothenburg area (Sweden). Major findings were confirmed in two additional cohorts consisting of elderly men from the Osteoporotic Fractures in Men (MrOS) Sweden (n=2 851) and MrOS US (n=5 611) multicenter population-based studies.
Main Outcome
The genotype distributions and their association with fat mass in different compartments, measured with dual-energy X-ray absorptiometry (DXA).
Results
Out of 18 evaluated tag single nucleotide polymorphisms (SNPs) near the IL6 and IL6R genes, a recently identified SNP rs10242595 G/A [minor allele frequency (MAF) = 29%] 3′ of the IL6 gene was negatively associated with the primary outcome total body fat mass (effect size -0.11 standard deviation (SD) units/A allele, P=0.02). This negative association with fat mass was also confirmed in the combined MrOS Sweden and MrOS US cohorts (effect size -0.05 SD units/A allele; P=0.002). When all three cohorts were combined (n= 8 927, Caucasian subjects), rs10242595*A showed a negative association with total body fat mass (effect size -0.05 SD units/A allele, P<0.0002). Furthermore, the rs10242595*A was associated with low body mass index [(BMI, effect size -0.03, P<0.001)] and smaller regional fat masses. None of the other SNPs investigated in the GOOD study were reproducibly associated with body fat.
Conclusions
The IL6 gene polymorphism rs10242595*A is associated with decreased fat mass in three combined cohorts of 8 927 Caucasian men.
doi:10.1038/ijo.2010.27
PMCID: PMC2885503  PMID: 20157327
IL6; IL6R; obesity; SNP; rs10242595

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