- Email: [email protected]
Snipping away at osteoporosis susceptibility
Comment
Snipping away at osteoporosis susceptibility
www.thelancet.com Vol 371 May 3, 2008
The paper also reports associations of decreased bone mineral density and osteoporosis with three SNPs near TNFRSF11B, which encodes osteoprotegerin, a decoy receptor that regulates bone resorption.12 Results from a recent well-powered candidate gene study13 and the observation in the current study that one of the three SNPs was associated with decreased osteoprotegerin expression in lymphoblast cell lines, implicate this gene in osteoporosis susceptibility. Clinical trials are underway to investigate the therapeutic potential of inhibiting the osteoprotegerin pathway;12 and individual genetic profiles, in addition to information on other risk factors, may one day enable targeting of specific therapeutic strategies to those at the greatest risk of developing osteoporosis. The overall variation in bone mineral density explained by the LRP5 and TNFRSF11B polymorphisms in the current study was small (around 0·2–0·6% of the total variance), but similar to genome-wide association results for other quantitative traits.14 Thus many more common variants for bone mineral density remain unidentified, and large studies will be needed to detect them. Although genome-wide association studies can be very informative, they do have limitations. For example, the effects of rare variants15 or structural genomic variants16 with large effects on a trait might be missed. Likewise, efficient methods to detect possible gene–gene or gene–environment interactions, which may have large effects on a phenotype,17 are still being developed. Increased risk of osteoporosis, or heritability of bone
Published Online May 1, 2008 DOI:10.1016/S01406736(08)60600-5 See Editorial page 1478 See Articles page 1505
Science Photo Library
Osteoporosis is a skeletal disorder characterised by a loss of bone mineral density and a consequent increase in risk of fragility fractures, which are a common cause of disability and major contributor to medical-care costs worldwide. The societal burden of osteoporosis is expected to increase substantially in the next half century because of demographic changes and improvements in life expectancy.1 Multiple risk factors for osteoporosis have been identified,2 of which heredity is one of the strongest but least well understood. For example, a family history of fracture is associated with a doubling of relative risk of fracture among older women,3 and up to 80% of the phenotypic variation in bone mineral density is genetic.4 But few genes that robustly influence these traits have been identified. The past few years have witnessed unprecedented advances in ultrahigh-throughput genotyping capabilities and cataloguing of millions of sequence variations across the human genome.5 These advances have enabled well-powered genome-wide association studies that are illuminating new genetic variations, especially single-nucleotide polymorphisms (SNPs), and biological pathways that influence multifactorial diseases and medically relevant traits.5 In today’s Lancet, J Brent Richards and colleagues6 report a genome-wide association analysis of nearly 315 000 SNPs, in more than 8500 white adults and with stringent statistical criteria, to identify reproducible associations of bone mineral density and fracture with SNPs in or near genes encoding the lowdensity lipoprotein-receptor-related protein 5 (LRP5) and osteoprotegerin (TNFRSF11B), two proteins involved in bone metabolism. LRP5 encodes a cell-surface receptor in osteoblasts that mediates Wnt signalling to stimulate bone formation.7 LRP5 was initially identified by linkage analysis in a single large family with extremely high bone mineral density segregated with a rare gain-of-function mutation.8–10 Richards and colleagues report that a common Ala1330Val variant in LRP5 is associated with low bone mineral density, osteoporosis, and a 1·3-times increased risk of fracture. Thus the current report and a recent meta-analysis11 convincingly show that common polymorphisms in LRP5 also influence bone mineral density and osteoporosis risk in the general population.
Scanning electron micrograph of osteoporotic bone
1479
Comment
mineral density, is likely to result from the summation of these effects; and the relative size of the above effects, as well as the ability of a set of genotyped SNPs to mark potential causal variants within a specific population, will influence the success of any genome-wide association study. Another potential limitation of the current study is that participants were mostly white women of European descent. Thus the effects of LRP5 and TNFRSF11B will also need to be investigated in men and individuals of non-European ancestry. Finally, the current study illustrates that genome-wide association results are only the beginning; follow-up studies like the osteoprotegerin expression experiments are necessary to identify possible mechanisms. Nonetheless, the current report represents an important step toward understanding the genetic basis of osteoporosis.
3 4 5 6
7 8
9
10 11
12
13
*Joseph M Zmuda, Candace M Kammerer Department of Epidemiology (JMZ) and Department of Human Genetics (JMZ, CMK), Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA [email protected]
14
15
We declare that we have no conflict of interest. 1 2
Cooper C, Campion G, Melton LJ. Hip fractures in the elderly: a world-wide projection. Osteoporos Int 1992; 2: 285–89. Cummings SR, Nevitt MC, Browner WS, et al, for the Study of Osteoporotic Fractures Research Group. Risk factors for hip fracture in white women. N Engl J Med 1995; 332: 767–73.
16
17
Fox KM, Cummings SR, Powell-Threets K, Stone K. Family history and risk of osteoporotic fracture. Osteoporos Int 1998; 8: 557–62. Zmuda JM, Sheu YT, Moffett SP. Genetic epidemiology of osteoporosis: past, present, and future. Curr Osteoporos Rep 2005; 3: 111–15. Pennisi E. Breakthrough of the year: human genetic variation. Science 2007; 318: 1842–43. Richards JB, Rivadeneira F, Inouye M, et al. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 2008; published online April 29. DOI:10.1016/S0140-6736(08)60599-1. Krishnan V, Bryant HU, Macdougald OA. Regulation of bone mass by Wnt signaling. J Clin Invest 2006; 116: 1202–09. Johnson ML, Gong G, Kimberling W, Recker SM, Kimmel DB, Recker RB. Linkage of a gene causing high bone mass to human chromosome 11 (11q12-13). Am J Hum Genet 1997; 60: 1326–32. Little RD, Carulli JP, Del Mastro RG, et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet 2002; 70: 11–19. Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 2002; 346: 1513–21. van Meurs JB, Trikalinos TA, Ralston SH, et al. Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA. 2008; 299: 1277–90. Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor κB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 2008; 29: 155–92. Moffett SP, Oakley JI, Cauley JA, et al. Osteoprotegerin Lys3Asn polymorphism and the risk of fracture in older women. J Clin Endocrinol Metab 2008; published online March 4. DOI:10.1210/jc.2007-1019. Lettre G, Jackson AU, Gieger C, et al. Identification of ten loci associated with height highlights new biological pathways in human growth. Nat Genet 2008; published online April 6. DOI:10.1038/ng.125. Ji W, Foo JN, O’Roak BJ, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet 2008; published online April 6. DOI:10.1038/ng.118. Autism Genome Project Consortium, Szatmari P, Paterson AD, et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 2007; 39: 319–28. Hunter DJ. Gene-environment interactions in human diseases. Nat Rev Genet 2005; 6: 287–98.
Blood-pressure-related disease is a global health priority See Articles page 1513
1480
In global-health politics, cardiovascular disease is the elephant in the room—a massive problem that few want to acknowledge and even fewer want to tackle. In today’s Lancet, Carlene Lawes and colleagues, on behalf of the International Society of Hypertension, estimate that blood-pressure-related diseases cause about half this burden, killing around 8 million people each year.1 Low-income and middle-income countries shoulder about 80% of the cardiovascular-disease burden, half of which is in people of working age. This situation was all predicted a decade ago by the Global Burden of Disease Project,2 but none of the major health-development funds—including the Bill & Melinda Gates Foundation, the World Bank, the major regional development banks, and major bilateral donors—have made any substantive or sustained effort to address this issue. Similarly, none of the major international
drug companies have offered material assistance in this global-health crisis, despite gargantuan profits from the sales of blood-pressure-lowering drugs in high-income countries. Hence, in the time that has passed since the Global Burden of Disease reports appeared, blood-pressure-related diseases have killed more than 50 million people, disabled many more, and taken billions of dollars from already fragile economies. So how big a problem does this have to become before anyone with resources takes meaningful action? Reports from WHO3 and the World Bank4 provide some hope that real action may be imminent. Both reports highlight the importance of chronic disease as an obstacle to economic development as well as a barrier to improved national health-status. They recommend action to control the huge epidemics of cardiovascular diseases already affecting Asia and South America and threatening other www.thelancet.com Vol 371 May 3, 2008
Snipping away at osteoporosis susceptibility
www.thelancet.com Vol 371 May 3, 2008
The paper also reports associations of decreased bone mineral density and osteoporosis with three SNPs near TNFRSF11B, which encodes osteoprotegerin, a decoy receptor that regulates bone resorption.12 Results from a recent well-powered candidate gene study13 and the observation in the current study that one of the three SNPs was associated with decreased osteoprotegerin expression in lymphoblast cell lines, implicate this gene in osteoporosis susceptibility. Clinical trials are underway to investigate the therapeutic potential of inhibiting the osteoprotegerin pathway;12 and individual genetic profiles, in addition to information on other risk factors, may one day enable targeting of specific therapeutic strategies to those at the greatest risk of developing osteoporosis. The overall variation in bone mineral density explained by the LRP5 and TNFRSF11B polymorphisms in the current study was small (around 0·2–0·6% of the total variance), but similar to genome-wide association results for other quantitative traits.14 Thus many more common variants for bone mineral density remain unidentified, and large studies will be needed to detect them. Although genome-wide association studies can be very informative, they do have limitations. For example, the effects of rare variants15 or structural genomic variants16 with large effects on a trait might be missed. Likewise, efficient methods to detect possible gene–gene or gene–environment interactions, which may have large effects on a phenotype,17 are still being developed. Increased risk of osteoporosis, or heritability of bone
Published Online May 1, 2008 DOI:10.1016/S01406736(08)60600-5 See Editorial page 1478 See Articles page 1505
Science Photo Library
Osteoporosis is a skeletal disorder characterised by a loss of bone mineral density and a consequent increase in risk of fragility fractures, which are a common cause of disability and major contributor to medical-care costs worldwide. The societal burden of osteoporosis is expected to increase substantially in the next half century because of demographic changes and improvements in life expectancy.1 Multiple risk factors for osteoporosis have been identified,2 of which heredity is one of the strongest but least well understood. For example, a family history of fracture is associated with a doubling of relative risk of fracture among older women,3 and up to 80% of the phenotypic variation in bone mineral density is genetic.4 But few genes that robustly influence these traits have been identified. The past few years have witnessed unprecedented advances in ultrahigh-throughput genotyping capabilities and cataloguing of millions of sequence variations across the human genome.5 These advances have enabled well-powered genome-wide association studies that are illuminating new genetic variations, especially single-nucleotide polymorphisms (SNPs), and biological pathways that influence multifactorial diseases and medically relevant traits.5 In today’s Lancet, J Brent Richards and colleagues6 report a genome-wide association analysis of nearly 315 000 SNPs, in more than 8500 white adults and with stringent statistical criteria, to identify reproducible associations of bone mineral density and fracture with SNPs in or near genes encoding the lowdensity lipoprotein-receptor-related protein 5 (LRP5) and osteoprotegerin (TNFRSF11B), two proteins involved in bone metabolism. LRP5 encodes a cell-surface receptor in osteoblasts that mediates Wnt signalling to stimulate bone formation.7 LRP5 was initially identified by linkage analysis in a single large family with extremely high bone mineral density segregated with a rare gain-of-function mutation.8–10 Richards and colleagues report that a common Ala1330Val variant in LRP5 is associated with low bone mineral density, osteoporosis, and a 1·3-times increased risk of fracture. Thus the current report and a recent meta-analysis11 convincingly show that common polymorphisms in LRP5 also influence bone mineral density and osteoporosis risk in the general population.
Scanning electron micrograph of osteoporotic bone
1479
Comment
mineral density, is likely to result from the summation of these effects; and the relative size of the above effects, as well as the ability of a set of genotyped SNPs to mark potential causal variants within a specific population, will influence the success of any genome-wide association study. Another potential limitation of the current study is that participants were mostly white women of European descent. Thus the effects of LRP5 and TNFRSF11B will also need to be investigated in men and individuals of non-European ancestry. Finally, the current study illustrates that genome-wide association results are only the beginning; follow-up studies like the osteoprotegerin expression experiments are necessary to identify possible mechanisms. Nonetheless, the current report represents an important step toward understanding the genetic basis of osteoporosis.
3 4 5 6
7 8
9
10 11
12
13
*Joseph M Zmuda, Candace M Kammerer Department of Epidemiology (JMZ) and Department of Human Genetics (JMZ, CMK), Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA [email protected]
14
15
We declare that we have no conflict of interest. 1 2
Cooper C, Campion G, Melton LJ. Hip fractures in the elderly: a world-wide projection. Osteoporos Int 1992; 2: 285–89. Cummings SR, Nevitt MC, Browner WS, et al, for the Study of Osteoporotic Fractures Research Group. Risk factors for hip fracture in white women. N Engl J Med 1995; 332: 767–73.
16
17
Fox KM, Cummings SR, Powell-Threets K, Stone K. Family history and risk of osteoporotic fracture. Osteoporos Int 1998; 8: 557–62. Zmuda JM, Sheu YT, Moffett SP. Genetic epidemiology of osteoporosis: past, present, and future. Curr Osteoporos Rep 2005; 3: 111–15. Pennisi E. Breakthrough of the year: human genetic variation. Science 2007; 318: 1842–43. Richards JB, Rivadeneira F, Inouye M, et al. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 2008; published online April 29. DOI:10.1016/S0140-6736(08)60599-1. Krishnan V, Bryant HU, Macdougald OA. Regulation of bone mass by Wnt signaling. J Clin Invest 2006; 116: 1202–09. Johnson ML, Gong G, Kimberling W, Recker SM, Kimmel DB, Recker RB. Linkage of a gene causing high bone mass to human chromosome 11 (11q12-13). Am J Hum Genet 1997; 60: 1326–32. Little RD, Carulli JP, Del Mastro RG, et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet 2002; 70: 11–19. Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 2002; 346: 1513–21. van Meurs JB, Trikalinos TA, Ralston SH, et al. Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA. 2008; 299: 1277–90. Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor κB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 2008; 29: 155–92. Moffett SP, Oakley JI, Cauley JA, et al. Osteoprotegerin Lys3Asn polymorphism and the risk of fracture in older women. J Clin Endocrinol Metab 2008; published online March 4. DOI:10.1210/jc.2007-1019. Lettre G, Jackson AU, Gieger C, et al. Identification of ten loci associated with height highlights new biological pathways in human growth. Nat Genet 2008; published online April 6. DOI:10.1038/ng.125. Ji W, Foo JN, O’Roak BJ, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet 2008; published online April 6. DOI:10.1038/ng.118. Autism Genome Project Consortium, Szatmari P, Paterson AD, et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 2007; 39: 319–28. Hunter DJ. Gene-environment interactions in human diseases. Nat Rev Genet 2005; 6: 287–98.
Blood-pressure-related disease is a global health priority See Articles page 1513
1480
In global-health politics, cardiovascular disease is the elephant in the room—a massive problem that few want to acknowledge and even fewer want to tackle. In today’s Lancet, Carlene Lawes and colleagues, on behalf of the International Society of Hypertension, estimate that blood-pressure-related diseases cause about half this burden, killing around 8 million people each year.1 Low-income and middle-income countries shoulder about 80% of the cardiovascular-disease burden, half of which is in people of working age. This situation was all predicted a decade ago by the Global Burden of Disease Project,2 but none of the major health-development funds—including the Bill & Melinda Gates Foundation, the World Bank, the major regional development banks, and major bilateral donors—have made any substantive or sustained effort to address this issue. Similarly, none of the major international
drug companies have offered material assistance in this global-health crisis, despite gargantuan profits from the sales of blood-pressure-lowering drugs in high-income countries. Hence, in the time that has passed since the Global Burden of Disease reports appeared, blood-pressure-related diseases have killed more than 50 million people, disabled many more, and taken billions of dollars from already fragile economies. So how big a problem does this have to become before anyone with resources takes meaningful action? Reports from WHO3 and the World Bank4 provide some hope that real action may be imminent. Both reports highlight the importance of chronic disease as an obstacle to economic development as well as a barrier to improved national health-status. They recommend action to control the huge epidemics of cardiovascular diseases already affecting Asia and South America and threatening other www.thelancet.com Vol 371 May 3, 2008