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1.  Genetic Epidemiology and Genome-Wide Linkage Analysis of Carotid Artery Ultrasound Traits in Multigenerational African Ancestry Families 
Atherosclerosis  2013;231(1):10.1016/j.atherosclerosis.2013.09.005.
Objective
Intima-media thickness, adventitial diameter and lumen diameter are indicators of cardiovascular disease risk. The influence of genetic factors on these measures in African ancestry populations is not well defined. Therefore, we estimated heritability and performed genome-wide linkage analysis of carotid ultrasound traits in 7 multigenerational families of African ancestry.
Methods
A total of 395 individuals (7 pedigrees; mean family size = 56; 2,392 relative pairs) aged ≥18 years had a common carotid artery ultrasound scan. Statistical analyses were conducted using pedigree-based maximum likelihood methods.
Results
Significant covariates included age, sex, body mass index or height and waist, and systolic blood pressure. Residual heritabilities ranged from 0.35±0.10 to 0.64±0.12 (P<0.0001). We identified a novel quantitative trait locus for adventitial and lumen diameters on chromosome 11 (max LOD=4.09, 133cM).
Conclusion
Further fine mapping of this region may identify specific mutations predisposing to subclinical vascular disease among African ancestry individuals.
doi:10.1016/j.atherosclerosis.2013.09.005
PMCID: PMC3837479  PMID: 24125421
carotid ultrasound; intima-media thickness; arterial diameter; genome-wide linkage; African ancestry
2.  Evidence for a Genetic Link Between Bone and Vascular Measures in African Ancestry Families 
Bone mineral density (BMD) has been inversely associated with subclinical and clinical cardiovascular disease (CVD) in population studies, but the potential mechanisms underlying this relationship are unclear. To test if there is a genetic basis underlying this association, we determined the phenotypic and genetic correlations between BMD and carotid artery ultrasound measures in families. Dual-energy X-ray absorptiometry and peripheral quantitative computed tomography were used to measure BMD in 461 African ancestry individuals belonging to 7 large, multigenerational families (mean family size 66; 3,414 total relative pairs). Carotid artery ultrasound was used to measure adventitial diameter (AD) and intima-media thickness (IMT). Phenotypic and genetic correlations between BMD and carotid measures were determined using pedigree-based maximum likelihood methods. We adjusted for potential confounding factors, including age, sex, body weight, height, menopausal status, smoking, alcohol intake, walking for exercise, diabetes, hypertension, serum lipid and lipoprotein levels, inflammation markers and kidney function. We found statistically significant phenotypic (ρ = −0.19) and genetic (ρG = −0.70) correlations (P < 0.05 for both) between lumbar spine BMD and AD in fully adjusted models. There was also a significant genetic correlation between trabecular BMD at the radius and IMT in fully adjusted models (ρG = −0.398; P < 0.05). Our findings indicate that the previously observed association between osteoporosis and CVD in population-based studies may be partly mediated by genetic factors and that the pleiotropic effects of these genes may operate independently of traditional risk pathways.
doi:10.1002/jbmr.1922
PMCID: PMC3720825  PMID: 23505032
bone mineral density; adventitial diameter; intima-media thickness; genetic correlation; African ancestry
3.  Biogenetic Mechanisms Predisposing to Complex Phenotypes in Parents May Function Differently in Their Children 
This study focuses on the participants of the Long Life Family Study to elucidate whether biogenetic mechanisms underlying relationships among heritable complex phenotypes in parents function in the same way for the same phenotypes in their children. Our results reveal 3 characteristic groups of relationships among phenotypes in parents and children. One group composed of 3 pairs of phenotypes confirms that associations among some phenotypes can be explained by the same biogenetic mechanisms working in parents and children. Two other groups including 9 phenotype pairs show that this is not a common rule. Our findings suggest that biogenetic mechanisms underlying relationships among different phenotypes, even if they are causally related, can function differently in successive generations or in different age groups of biologically related individuals. The results suggest that the role of aging-related processes in changing environment may be conceptually underestimated in current genetic association studies using genome wide resources.
doi:10.1093/gerona/gls243
PMCID: PMC3674715  PMID: 23213029
Heritability; Longevity regulation; Aging; Disease; Genetics of healthspan
4.  Association of total and computed tomographic measures of regional adiposity with incident cancer risk: a prospective population-based study of older adults 
Obesity is associated with increased risk of many types of cancer. Less is known regarding associations between adipose depots and cancer risk. We aimed to explore relationships between adipose depots, risk of cancer and obesity-related cancer (per NCI definition) in participants initially aged 70–79 without prevalent cancer (1,179 men, 1,340 women), and followed for incident cancer for 13 years. Measures included body mass index (BMI), total adipose tissue from dual-energy X-ray absorptiometry and computed tomography measures: visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (SAT), thigh intermuscular adipose tissue and thigh muscle attenuation (Hounsfield Unit, HU), low HU indicates fatty infiltration. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression adjusted for demographics, lifestyle variables and medical conditions. During follow-up 617 participants developed cancer of which 224 were obesity-related cancers. Total adipose tissue and VAT were positively associated with cancer risk among women (HR 1.14, 95% CI 1.01–1.30 per SD increase, HR 1.15, 95% CI 1.02–1.30 per SD increase). There were no associations with cancer risk among men. Total adipose tissue was positively associated with obesity-related cancer risk among women (HR 1.23, 95% CI 1.03–1.46 per SD increase). VAT was positively associated with obesity-related cancer risk among men (HR 1.30, 95% CI 1.06–1.60 per SD increase) and remained associated even with adjustment for BMI (HR 1.40, 95% CI 1.08–1.82 per SD increase). These findings provide insight into relationships between specific adipose depots and cancer risk and suggest differential relationships among men and women.
doi:10.1139/apnm-2013-0360
PMCID: PMC4071344  PMID: 24869972
Obesity; weight; adipose; body fat; cancer incidence; cancer risk; aging
5.  Genetic Association Study of Adiposity and Melanocortin-4 Receptor (MC4R) Common Variants: Replication and Functional Characterization of Non-Coding Regions 
PLoS ONE  2014;9(5):e96805.
Common genetic variants 3′ of MC4R within two large linkage disequilibrium (LD) blocks spanning 288 kb have been associated with common and rare forms of obesity. This large association region has not been refined and the relevant DNA segments within the association region have not been identified. In this study, we investigated whether common variants in the MC4R gene region were associated with adiposity-related traits in a biracial population-based study. Single nucleotide polymorphisms (SNPs) in the MC4R region were genotyped with a custom array and a genome-wide array and associations between SNPs and five adiposity-related traits were determined using race-stratified linear regression. Previously reported associations between lower BMI and the minor alleles of rs2229616/Val103Ile and rs52820871/Ile251Leu were replicated in white female participants. Among white participants, rs11152221 in a proximal 3′ LD block (closer to MC4R) was significantly associated with multiple adiposity traits, but SNPs in a distal 3′ LD block (farther from MC4R) were not. In a case-control study of severe obesity, rs11152221 was significantly associated. The association results directed our follow-up studies to the proximal LD block downstream of MC4R. By considering nucleotide conservation, the significance of association, and proximity to the MC4R gene, we identified a candidate MC4R regulatory region. This candidate region was sequenced in 20 individuals from a study of severe obesity in an attempt to identify additional variants, and the candidate region was tested for enhancer activity using in vivo enhancer assays in zebrafish and mice. Novel variants were not identified by sequencing and the candidate region did not drive reporter gene expression in zebrafish or mice. The identification of a putative insulator in this region could help to explain the challenges faced in this study and others to link SNPs associated with adiposity to altered MC4R expression.
doi:10.1371/journal.pone.0096805
PMCID: PMC4018404  PMID: 24820477
6.  Mitochondrial DNA variation in human metabolic rate and energy expenditure 
Mitochondrion  2011;11(6):855-861.
The role of climate in driving selection of mtDNA as Homo sapiens migrated out of Africa into Eurasia remains controversial. We evaluated the role of mtDNA variation in resting metabolic rate (RMR) and total energy expenditure (TEE) among 294 older, community-dwelling African and European American adults from the Health, Aging and Body Composition Study. Common African haplogroups L0, L2 and L3 had significantly lower RMRs than European haplogroups H, JT and UK with haplogroup L1 RMR being intermediate to these groups. This study links mitochondrial haplogroups with ancestry-associated differences in metabolic rate and energy expenditure.
doi:10.1016/j.mito.2011.04.005
PMCID: PMC3998521  PMID: 21586348
Metabolic rate; Energetics; Mitochondria; Mitochondrial haplogroups; mtDNA; Oxidative phosphorylation
7.  Abdominal Myosteatosis is Independently Associated to Hyperinsulinemia and Insulin Resistance among Older Men without Diabetes 
Obesity (Silver Spring, Md.)  2013;21(10):2118-2125.
Design and Methods
Skeletal muscle adipose tissue (AT) infiltration (myosteatosis) increases with aging and may contribute to the development of type 2 diabetes mellitus (T2DM). It remains unclear if myosteatosis is associated to glucose and insulin homeostasis independent of total and central adiposity. We evaluated the association between intermuscular AT (IMAT) in the abdominal skeletal muscles (total, paraspinal and psoas) and fasting serum glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) in 393 non-diabetic Caucasian men aged 65+. Abdominal IMAT, visceral (VAT) and subcutaneous (SAT) AT (cm3) were measured by quantitative computed tomography at the L4-L5 intervertebral space.
Results
In age, study site, height and muscle volume adjusted regression analyses, total abdominal and psoas (but not paraspinal) IMAT were positively associated with glucose, insulin and HOMA-IR (all P < 0.003). The associations between total abdominal and psoas IMAT and insulin and HOMA-IR remained significant after further adjusting for lifestyle factors, as well as DXA total body fat, VAT or SAT in separate models (all P <0.009).
Conclusions
Our study indicates a previously unreported, independent association between abdominal myosteatosis and hyperinsulinemia and insulin resistance among older Caucasian men. These associations may be specific for particular abdominal muscle depots, illustrating the potential importance of separately studying specific muscle groups.
doi:10.1002/oby.20346
PMCID: PMC3661705  PMID: 23408772
Myosteatosis; intermuscular fat; skeletal muscle; fat distribution; insulin; insulin resistance
8.  Hyperleptinemia, Adiposity, and Risk of Metabolic Syndrome in Older Adults 
Background. Abdominal adiposity and serum leptin increase with age as does risk of metabolic syndrome. This study investigates the prospective association between leptin and metabolic syndrome risk in relation to adiposity and cytokines. Methods. The Health, Aging, and Body Composition study is a prospective cohort of older adults aged 70 to 79 years. Baseline measurements included leptin, cytokines, BMI, total percent fat, and visceral and subcutaneous fat. Multivariate logistic regression was used to determine the association between leptin and metabolic syndrome (defined per NCEP ATP III) incidence after 6 years of follow-up among 1,120 men and women. Results. Leptin predicted metabolic syndrome in men (P for trend = 0.0002) and women (P for trend = 0.0001). In women, risk of metabolic syndrome increased with higher levels of leptin (compared with quintile 1, quintile 2 RR = 3.29, CI = 1.36, 7.95; quintile 3 RR = 3.25, CI = 1.33, 7.93; quintile 4 RR = 5.21, CI = 2.16, 12.56; and quintile 5 RR = 7.97, CI = 3.30, 19.24) after adjusting for potential confounders. Leptin remained independently associated with metabolic syndrome risk after additional adjustment for adiposity, cytokines, and CRP. Among men, this association was no longer significant after controlling for adiposity. Conclusion. Among older women, elevated concentrations of leptin may increase the risk of metabolic syndrome independent of adiposity and cytokines.
doi:10.1155/2013/327079
PMCID: PMC3888758  PMID: 24455217
9.  Genome-wide association analysis identifies TYW3/CRYZ and NDST4 loci associated with circulating resistin levels 
Human Molecular Genetics  2012;21(21):4774-4780.
Resistin is a polypeptide hormone that was reported to be associated with insulin resistance, inflammation and risk of type 2 diabetes and cardiovascular disease. We conducted a genome-wide association (GWA) study on circulating resistin levels in individuals of European ancestry drawn from the two independent studies: the Nurses' Health Study (n = 1590) and the Health, Aging and Body Composition Study (n = 1658). Single-nucleotide polymorphisms (SNPs) identified in the GWA analysis were replicated in an independent cohort of Europeans: the Gargano Family Study (n = 659). We confirmed the association with a previously known locus, the RETN gene (19p13.2), and identified two novel loci near the TYW3/CRYZ gene (1p31) and the NDST4 gene (4q25), associated with resistin levels at a genome-wide significant level, best represented by SNP rs3931020 (P = 6.37 × 10–12) and SNP rs13144478 (P = 6.19 × 10−18), respectively. Gene expression quantitative trait loci analyses showed a significant cis association between the SNP rs3931020 and CRYZ gene expression levels (P = 3.68 × 10−7). We also found that both of these two SNPs were significantly associated with resistin gene (RETN) mRNA levels in white blood cells from 68 subjects with type 2 diabetes (both P = 0.02). In addition, the resistin-rising allele of the TYW3/CRYZ SNP rs3931020, but not the NDST4 SNP rs13144478, showed a consistent association with increased coronary heart disease risk [odds ratio = 1.18 (95% CI, 1.03–1.34); P = 0.01]. Our results suggest that genetic variants in TYW3/CRYZ and NDST4 loci may be involved in the regulation of circulating resistin levels. More studies are needed to verify the associations of the SNP rs13144478 with NDST4 gene expression and resistin-related disease.
doi:10.1093/hmg/dds300
PMCID: PMC3471394  PMID: 22843503
10.  Ethnic difference in liver fat content: A cross-sectional observation among Japanese American in Hawaii, Japanese in Japan, and non-Hispanic whites in United States 
Background
We recently reported that Japanese had higher liver fat at a lower level of BMI compared with non-Hispanic whites (NHW).
Objective
We hypothesize that ethnic difference in fat storage capacity contributes to this ethnic difference in liver fat.
Design
To examine this, we assessed liver fat among 244 Japanese-American aged 40-49, using regional computed-tomography images, along with metabolic variables.
Results
Despite the similar BMI between Japanese-Americans and NHW men, Japanese-Americans had more liver fat (liver to spleen attenuation ratio: 1.03 ± 0.22 for Japanese-Americans, and 1.07 ± 0.15 for NHW men; p<0.05) and tended to have a greater disposition for fatty liver with an increase in BMI than NHW, indicating a clear difference between the two groups. In addition, liver fat is less in Japanese-Americans compared with Japanese men (1.03 ± 0.22 vs. 1.01 ± 0.16; p<0.05), despite of a much higher BMI. These ethnic differences support the hypothesis that higher fat storage capacity indeed seems to be associated with less liver fat. In all the groups, liver fat content strongly correlated with triglycerides, homeostasis model assessment-insulin resistance, and C-reactive protein (CRP). Nevertheless, these metabolic variables were worse in Japanese-Americans, despite of less liver fat, compared with Japanese. Moreover, CRP levels were least among Japanese with highest liver fat, and highest among NHW men with least liver fat, despite of a strong positive association between CRP and fatty liver within each population.
Conclusions
Fat content in the liver is intermediate for Japanese-Americans compared with Japanese and NHW men, which supports the hypothesis of less fat storage capacity among Japanese, closely linked to ethnic difference in predisposition to fatty liver.
doi:10.1016/j.orcp.2011.11.007
PMCID: PMC3664948  PMID: 23697588
Ethnicity; Fatty liver; Genetic; Environmental; CRP
11.  Thyroid Function and Prevalent and Incident Metabolic Syndrome in Older Adults: The Health, Aging, and Body Composition Study 
Clinical Endocrinology  2012;76(6):911-918.
Objective
Both subclinical hypothyroidism and the metabolic syndrome have been associated with increased risk of coronary heart disease events. It is unknown if the prevalence and incidence of metabolic syndrome is higher as TSH levels increase, or in individuals with subclinical hypothyroidism. We sought to determine the association between thyroid function and the prevalence and incidence of the metabolic syndrome in a cohort of older adults.
Design
Data was analyzed from the Health, Aging, and Body Composition Study, a prospective cohort of 3,075 community-dwelling US adults.
Participants
2,119 participants with measured TSH and data on metabolic syndrome components were included in the analysis.
Measurements
TSH was measured by immunoassay. Metabolic syndrome was defined per revised ATP III criteria.
Results
At baseline, 684 participants met criteria for metabolic syndrome. At 6yr follow-up, incident metabolic syndrome developed in 239 individuals. In fully adjusted models, each unit increase in TSH was associated with a 3% increase in the odds of prevalent metabolic syndrome (OR 1.03, 95% CI 1.01–1.06, p=0.02), and the association was stronger for TSH within the normal range (OR 1.16, 95% CI 1.03–1.30, p=0.02). Subclinical hypothyroidism with a TSH>10mIU/L was significantly associated with increased odds of prevalent metabolic syndrome (OR 2.3, 95% CI 1.0–5.0, p=0.04); the odds of incident MetS was similar (OR 2.2), but the confidence interval was wide (0.6–7.5).
Conclusions
Higher TSH levels and subclinical hypothyroidism with a TSH>10 mIU/L are associated with increased odds of prevalent but not incident metabolic syndrome.
doi:10.1111/j.1365-2265.2011.04328.x
PMCID: PMC3334430  PMID: 22187968
Thyroid Function; Metabolic Syndrome; Subclinical Hypothyroidism
12.  A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance 
Manning, Alisa K. | Hivert, Marie-France | Scott, Robert A. | Grimsby, Jonna L. | Bouatia-Naji, Nabila | Chen, Han | Rybin, Denis | Liu, Ching-Ti | Bielak, Lawrence F. | Prokopenko, Inga | Amin, Najaf | Barnes, Daniel | Cadby, Gemma | Hottenga, Jouke-Jan | Ingelsson, Erik | Jackson, Anne U. | Johnson, Toby | Kanoni, Stavroula | Ladenvall, Claes | Lagou, Vasiliki | Lahti, Jari | Lecoeur, Cecile | Liu, Yongmei | Martinez-Larrad, Maria Teresa | Montasser, May E. | Navarro, Pau | Perry, John R. B. | Rasmussen-Torvik, Laura J. | Salo, Perttu | Sattar, Naveed | Shungin, Dmitry | Strawbridge, Rona J. | Tanaka, Toshiko | van Duijn, Cornelia M. | An, Ping | de Andrade, Mariza | Andrews, Jeanette S. | Aspelund, Thor | Atalay, Mustafa | Aulchenko, Yurii | Balkau, Beverley | Bandinelli, Stefania | Beckmann, Jacques S. | Beilby, John P. | Bellis, Claire | Bergman, Richard N. | Blangero, John | Boban, Mladen | Boehnke, Michael | Boerwinkle, Eric | Bonnycastle, Lori L. | Boomsma, Dorret I. | Borecki, Ingrid B. | Böttcher, Yvonne | Bouchard, Claude | Brunner, Eric | Budimir, Danijela | Campbell, Harry | Carlson, Olga | Chines, Peter S. | Clarke, Robert | Collins, Francis S. | Corbatón-Anchuelo, Arturo | Couper, David | de Faire, Ulf | Dedoussis, George V | Deloukas, Panos | Dimitriou, Maria | Egan, Josephine M | Eiriksdottir, Gudny | Erdos, Michael R. | Eriksson, Johan G. | Eury, Elodie | Ferrucci, Luigi | Ford, Ian | Forouhi, Nita G. | Fox, Caroline S | Franzosi, Maria Grazia | Franks, Paul W | Frayling, Timothy M | Froguel, Philippe | Galan, Pilar | de Geus, Eco | Gigante, Bruna | Glazer, Nicole L. | Goel, Anuj | Groop, Leif | Gudnason, Vilmundur | Hallmans, Göran | Hamsten, Anders | Hansson, Ola | Harris, Tamara B. | Hayward, Caroline | Heath, Simon | Hercberg, Serge | Hicks, Andrew A. | Hingorani, Aroon | Hofman, Albert | Hui, Jennie | Hung, Joseph | Jarvelin, Marjo Riitta | Jhun, Min A. | Johnson, Paul C.D. | Jukema, J Wouter | Jula, Antti | Kao, W.H. | Kaprio, Jaakko | Kardia, Sharon L. R. | Keinanen-Kiukaanniemi, Sirkka | Kivimaki, Mika | Kolcic, Ivana | Kovacs, Peter | Kumari, Meena | Kuusisto, Johanna | Kyvik, Kirsten Ohm | Laakso, Markku | Lakka, Timo | Lannfelt, Lars | Lathrop, G Mark | Launer, Lenore J. | Leander, Karin | Li, Guo | Lind, Lars | Lindstrom, Jaana | Lobbens, Stéphane | Loos, Ruth J. F. | Luan, Jian’an | Lyssenko, Valeriya | Mägi, Reedik | Magnusson, Patrik K. E. | Marmot, Michael | Meneton, Pierre | Mohlke, Karen L. | Mooser, Vincent | Morken, Mario A. | Miljkovic, Iva | Narisu, Narisu | O’Connell, Jeff | Ong, Ken K. | Oostra, Ben A. | Palmer, Lyle J. | Palotie, Aarno | Pankow, James S. | Peden, John F. | Pedersen, Nancy L. | Pehlic, Marina | Peltonen, Leena | Penninx, Brenda | Pericic, Marijana | Perola, Markus | Perusse, Louis | Peyser, Patricia A | Polasek, Ozren | Pramstaller, Peter P. | Province, Michael A. | Räikkönen, Katri | Rauramaa, Rainer | Rehnberg, Emil | Rice, Ken | Rotter, Jerome I. | Rudan, Igor | Ruokonen, Aimo | Saaristo, Timo | Sabater-Lleal, Maria | Salomaa, Veikko | Savage, David B. | Saxena, Richa | Schwarz, Peter | Seedorf, Udo | Sennblad, Bengt | Serrano-Rios, Manuel | Shuldiner, Alan R. | Sijbrands, Eric J.G. | Siscovick, David S. | Smit, Johannes H. | Small, Kerrin S. | Smith, Nicholas L. | Smith, Albert Vernon | Stančáková, Alena | Stirrups, Kathleen | Stumvoll, Michael | Sun, Yan V. | Swift, Amy J. | Tönjes, Anke | Tuomilehto, Jaakko | Trompet, Stella | Uitterlinden, Andre G. | Uusitupa, Matti | Vikström, Max | Vitart, Veronique | Vohl, Marie-Claude | Voight, Benjamin F. | Vollenweider, Peter | Waeber, Gerard | Waterworth, Dawn M | Watkins, Hugh | Wheeler, Eleanor | Widen, Elisabeth | Wild, Sarah H. | Willems, Sara M. | Willemsen, Gonneke | Wilson, James F. | Witteman, Jacqueline C.M. | Wright, Alan F. | Yaghootkar, Hanieh | Zelenika, Diana | Zemunik, Tatijana | Zgaga, Lina | Wareham, Nicholas J. | McCarthy, Mark I. | Barroso, Ines | Watanabe, Richard M. | Florez, Jose C. | Dupuis, Josée | Meigs, James B. | Langenberg, Claudia
Nature genetics  2012;44(6):659-669.
Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction, but contributed little to our understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways may be uncovered by accounting for differences in body mass index (BMI) and potential interaction between BMI and genetic variants. We applied a novel joint meta-analytical approach to test associations with fasting insulin (FI) and glucose (FG) on a genome-wide scale. We present six previously unknown FI loci at P<5×10−8 in combined discovery and follow-up analyses of 52 studies comprising up to 96,496non-diabetic individuals. Risk variants were associated with higher triglyceride and lower HDL cholesterol levels, suggestive of a role for these FI loci in insulin resistance pathways. The localization of these additional loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
doi:10.1038/ng.2274
PMCID: PMC3613127  PMID: 22581228
13.  Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways 
Scott, Robert A | Lagou, Vasiliki | Welch, Ryan P | Wheeler, Eleanor | Montasser, May E | Luan, Jian’an | Mägi, Reedik | Strawbridge, Rona J | Rehnberg, Emil | Gustafsson, Stefan | Kanoni, Stavroula | Rasmussen-Torvik, Laura J | Yengo, Loïc | Lecoeur, Cecile | Shungin, Dmitry | Sanna, Serena | Sidore, Carlo | Johnson, Paul C D | Jukema, J Wouter | Johnson, Toby | Mahajan, Anubha | Verweij, Niek | Thorleifsson, Gudmar | Hottenga, Jouke-Jan | Shah, Sonia | Smith, Albert V | Sennblad, Bengt | Gieger, Christian | Salo, Perttu | Perola, Markus | Timpson, Nicholas J | Evans, David M | Pourcain, Beate St | Wu, Ying | Andrews, Jeanette S | Hui, Jennie | Bielak, Lawrence F | Zhao, Wei | Horikoshi, Momoko | Navarro, Pau | Isaacs, Aaron | O’Connell, Jeffrey R | Stirrups, Kathleen | Vitart, Veronique | Hayward, Caroline | Esko, Tönu | Mihailov, Evelin | Fraser, Ross M | Fall, Tove | Voight, Benjamin F | Raychaudhuri, Soumya | Chen, Han | Lindgren, Cecilia M | Morris, Andrew P | Rayner, Nigel W | Robertson, Neil | Rybin, Denis | Liu, Ching-Ti | Beckmann, Jacques S | Willems, Sara M | Chines, Peter S | Jackson, Anne U | Kang, Hyun Min | Stringham, Heather M | Song, Kijoung | Tanaka, Toshiko | Peden, John F | Goel, Anuj | Hicks, Andrew A | An, Ping | Müller-Nurasyid, Martina | Franco-Cereceda, Anders | Folkersen, Lasse | Marullo, Letizia | Jansen, Hanneke | Oldehinkel, Albertine J | Bruinenberg, Marcel | Pankow, James S | North, Kari E | Forouhi, Nita G | Loos, Ruth J F | Edkins, Sarah | Varga, Tibor V | Hallmans, Göran | Oksa, Heikki | Antonella, Mulas | Nagaraja, Ramaiah | Trompet, Stella | Ford, Ian | Bakker, Stephan J L | Kong, Augustine | Kumari, Meena | Gigante, Bruna | Herder, Christian | Munroe, Patricia B | Caulfield, Mark | Antti, Jula | Mangino, Massimo | Small, Kerrin | Miljkovic, Iva | Liu, Yongmei | Atalay, Mustafa | Kiess, Wieland | James, Alan L | Rivadeneira, Fernando | Uitterlinden, Andre G | Palmer, Colin N A | Doney, Alex S F | Willemsen, Gonneke | Smit, Johannes H | Campbell, Susan | Polasek, Ozren | Bonnycastle, Lori L | Hercberg, Serge | Dimitriou, Maria | Bolton, Jennifer L | Fowkes, Gerard R | Kovacs, Peter | Lindström, Jaana | Zemunik, Tatijana | Bandinelli, Stefania | Wild, Sarah H | Basart, Hanneke V | Rathmann, Wolfgang | Grallert, Harald | Maerz, Winfried | Kleber, Marcus E | Boehm, Bernhard O | Peters, Annette | Pramstaller, Peter P | Province, Michael A | Borecki, Ingrid B | Hastie, Nicholas D | Rudan, Igor | Campbell, Harry | Watkins, Hugh | Farrall, Martin | Stumvoll, Michael | Ferrucci, Luigi | Waterworth, Dawn M | Bergman, Richard N | Collins, Francis S | Tuomilehto, Jaakko | Watanabe, Richard M | de Geus, Eco J C | Penninx, Brenda W | Hofman, Albert | Oostra, Ben A | Psaty, Bruce M | Vollenweider, Peter | Wilson, James F | Wright, Alan F | Hovingh, G Kees | Metspalu, Andres | Uusitupa, Matti | Magnusson, Patrik K E | Kyvik, Kirsten O | Kaprio, Jaakko | Price, Jackie F | Dedoussis, George V | Deloukas, Panos | Meneton, Pierre | Lind, Lars | Boehnke, Michael | Shuldiner, Alan R | van Duijn, Cornelia M | Morris, Andrew D | Toenjes, Anke | Peyser, Patricia A | Beilby, John P | Körner, Antje | Kuusisto, Johanna | Laakso, Markku | Bornstein, Stefan R | Schwarz, Peter E H | Lakka, Timo A | Rauramaa, Rainer | Adair, Linda S | Smith, George Davey | Spector, Tim D | Illig, Thomas | de Faire, Ulf | Hamsten, Anders | Gudnason, Vilmundur | Kivimaki, Mika | Hingorani, Aroon | Keinanen-Kiukaanniemi, Sirkka M | Saaristo, Timo E | Boomsma, Dorret I | Stefansson, Kari | van der Harst, Pim | Dupuis, Josée | Pedersen, Nancy L | Sattar, Naveed | Harris, Tamara B | Cucca, Francesco | Ripatti, Samuli | Salomaa, Veikko | Mohlke, Karen L | Balkau, Beverley | Froguel, Philippe | Pouta, Anneli | Jarvelin, Marjo-Riitta | Wareham, Nicholas J | Bouatia-Naji, Nabila | McCarthy, Mark I | Franks, Paul W | Meigs, James B | Teslovich, Tanya M | Florez, Jose C | Langenberg, Claudia | Ingelsson, Erik | Prokopenko, Inga | Barroso, Inês
Nature genetics  2012;44(9):991-1005.
Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have raised the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional follow-up of these newly discovered loci will further improve our understanding of glycemic control.
doi:10.1038/ng.2385
PMCID: PMC3433394  PMID: 22885924
14.  Insulin Sensitizers May Attenuate Lean Mass Loss in Older Men With Diabetes 
Diabetes Care  2011;34(11):2381-2386.
OBJECTIVE
To examine longitudinal changes in total and appendicular lean body mass in older men with impaired fasting glucose (IFG) or diabetes and to determine whether these changes differ by diabetes treatment.
RESEARCH DESIGN AND METHODS
A total of 3,752 ambulatory men aged ≥65 years at baseline participated in a multicenter longitudinal cohort study. Baseline glycemic status was categorized as normoglycemia, IFG, undiagnosed/untreated diabetes, or treated diabetes. Insulin sensitizer medication use (metformin and/or thiazolidinediones) was assessed by prescription medication inventory. The change in total lean and appendicular lean mass was derived from dual X-ray absorptiometry scans taken at baseline and 3.5 ± 0.7 years later.
RESULTS
This male cohort included 1,853 individuals with normoglycemia, 1,403 with IFG, 234 with untreated diabetes, 151 with diabetes treated with insulin sensitizers, and 111 with diabetes treated without insulin sensitizers. Men with untreated diabetes, diabetes treated without insulin sensitizers, or IFG had greater percentage loss in total or appendicular lean mass (P ≤ 0.05 in comparison to normoglycemic men). There remained a significantly greater percentage loss in appendicular lean mass for these groups even after adjustment for medical comorbidities or lifestyle factors. In contrast, the percentage loss in total or appendicular lean mass in men with diabetes treated with insulin sensitizers was significantly less than that in normoglycemic men in minimally and fully adjusted models.
CONCLUSIONS
Skeletal muscle loss was accelerated in men with IFG and diabetes, except when the latter was treated with insulin sensitizers. These findings suggest that insulin sensitizers may attenuate muscle loss.
doi:10.2337/dc11-1032
PMCID: PMC3198278  PMID: 21926282
15.  Bioactive Androgens and Glucuronidated Androgen Metabolites are Associated with Subcutaneous and Ectopic Skeletal Muscle Adiposity among Older Black Men 
Aging is associated with declining serum levels of androgenic hormones and with increased skeletal muscle fat infiltration, an emerging risk factor for type 2 diabetes mellitus (T2DM). Androgens regulate fat mass and glucose homeostasis, but the effect of androgenic hormones on skeletal muscle fat infiltration is largely unknown. Thus, the aim of the current study was to examine the association of serum androgens and their precursors and metabolites with skeletal muscle fat infiltration and T2DM in a black male population group at high risk of T2DM. Serum androgens, estrogens, and androgen precursors and metabolites were measured using mass spectrometry, and calf skeletal muscle fat distribution [subcutaneous and intermuscular fat; skeletal muscle density] were measured using quantitative computed tomography in 472 Afro-Caribbean men aged 65 and older. Bioactive androgens, testosterone, free testosterone and dihydrotestosterone, were associated with less skeletal muscle fat infiltration (r=−0.14 to −0.18, P<0.05) and increased skeletal muscle density (r=0.10 to 0.14, P<0.05), independent of total adiposity. Additionally, glucuronidated androgen metabolites were associated with less subcutaneous fat (r=−0.11 to −0.15, P<0.05). Multivariate logistic regression analysis identified an increased level of 3α-diol-3 glucuronide (OR=1.38, P<0.01) and a decreased level of dihydrotestosterone (OR=0.66, P<0.01) to be significantly associated with T2DM. Our findings suggest that in elderly black men, independent of total adiposity, bioactive androgens and glucuronidated androgen metabolites may play previously unrecognized role in skeletal muscle fat distribution. Longitudinal studies are needed to further evaluate the relationship between androgens and androgen metabolites with changes in skeletal muscle fat distribution with aging and the incidence of T2DM.
doi:10.1016/j.metabol.2010.12.014
PMCID: PMC3106138  PMID: 21353258
sex hormones; androgen; skeletal muscle; adipose tissue; type 2 diabetes mellitus; aging; black men
16.  Markers of Inflammation Are Heritable and Associated with Subcutaneous and Ectopic Skeletal Muscle Adiposity in African Ancestry Families 
Abstract
Background
Skeletal muscle adipose tissue (AT) infiltration, or myosteatosis, appears to be greater in African compared with European ancestry individuals and may play a role in type 2 diabetes mellitus (T2DM), a disease that disproportionally affects African ancestry populations. Inflammation is one mechanism that may link myosteatosis with increased T2DM risk, but studies examining the relationship between inflammation and myosteatosis are lacking.
Methods
To examine these associations, we measured skeletal muscle subcutaneous AT, intermuscular AT, and skeletal muscle density using quantitative computed tomography and serum markers of inflammation in 471 individuals from 8 Afro-Caribbean multigenerational families [mean family size 67; mean age 43 years; mean body mass index (BMI) 28 kg/m2].
Results
After removing the variation attributable to significant covariates, heritabilities of inflammation markers [C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)] ranged from 33% (TNFα) to 40% (CRP); all P<0.01. Higher CRP, IL-6, and TNF-α were associated with lower subcutaneous AT around skeletal muscle (r=−0.13 to −0.19, P<0.05). Higher CRP was additionally associated with lower skeletal muscle density, indicative of greater intramuscular AT (r=−0.10, P<0.05), hyperinsulinemia (r=0.12, P<0.05), and increased homeostasis model assessment of insulin resistance (HOMA-IR) (r=0.17, P<0.01).
Conclusions
Our findings suggest that heredity may play a significant role in the determination of several markers of inflammation in African ancestry individuals. Higher concentrations of CRP appear to be associated with greater skeletal muscle AT infiltration, lower subcutaneous AT, hyperinsulinemia, and insulin resistance. Longitudinal studies are needed to further evaluate the relationship between inflammation with changes in skeletal muscle AT distribution with aging and the incidence of T2DM.
doi:10.1089/met.2010.0133
PMCID: PMC3142634  PMID: 21501070
17.  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
18.  Genome-Wide Association for Abdominal Subcutaneous and Visceral Adipose Reveals a Novel Locus for Visceral Fat in Women 
PLoS Genetics  2012;8(5):e1002695.
Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ∼2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1×10E-09), previously identified in association with waist–hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9×10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6×10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.
Author Summary
Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. We quantified subcutaneous and visceral fat in more than 10,000 women and men who also had genome-wide association data available. Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, near the THNSL2 gene. These findings were not observed in men. We also interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed for 7 of these loci, most notably for VAT/SAT ratio. We conclude that genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not uncovered in large-scale GWAS of anthropometric traits.
doi:10.1371/journal.pgen.1002695
PMCID: PMC3349734  PMID: 22589738
19.  Meta-analysis of Gene-Environment interaction: joint estimation of SNP and SNP×Environment regression coefficients 
Genetic Epidemiology  2011;35(1):11-18.
Introduction
Genetic discoveries are validated through the meta-analysis of genome-wide association scans in large international consortia. Because environmental variables may interact with genetic factors, investigation of differing genetic effects for distinct levels of an environmental exposure in these large consortia may yield additional susceptibility loci undetected by main effects analysis. We describe a method of joint meta-analysis of SNP and SNP by Environment (SNP×E) regression coefficients for use in gene-environment interaction studies.
Methods
In testing SNP×E interactions, one approach uses a two degree of freedom test to identify genetic variants that influence the trait of interest. This approach detects both main and interaction effects between the trait and the SNP. We propose a method to jointly meta-analyze the SNP and SNP×E coefficients using multivariate generalized least squares. This approach provides confidence intervals of the two estimates, a joint significance test for SNP and SNP×E terms, and a test of homogeneity across samples.
Results
We present a simulation study comparing this method to four other methods of meta-analysis and demonstrate that the joint meta-analysis performs better than the others when both main and interaction effects are present. Additionally, we implemented our methods in a meta-analysis of the association between SNPs from the type 2 diabetes-associated gene PPARG and log-transformed fasting insulin levels and interaction by body mass index in a combined sample of 19,466 individuals from 5 cohorts.
doi:10.1002/gepi.20546
PMCID: PMC3312394  PMID: 21181894
2 degree of freedom meta-analysis; joint meta-analysis; PPARG; Gene-environment interaction meta-analysis
20.  LOW PREVALENCE OF VITAMIN D DEFICIENCY IN ELDERLY AFRO-CARIBBEAN MEN 
Ethnicity & disease  2011;21(1):79-84.
Vitamin D deficiency is highly prevalent worldwide, and is linked to several major chronic, inflammatory and autoimmune diseases. Vitamin D deficiency has not been evaluated in dark skinned individuals living in areas of high sun exposure utilizing more reliable mass spectrometry assay techniques. We determined the prevalence of 25(OH)D deficiency in Afro-Caribbean men on the tropical island of Tobago, where there is a high level of sunshine year round. Serum 25(OH)D2 and 25(OH)D3 metabolites were measured following extraction and purification using liquid chromatography and tandem mass spectrometry in 424 Afro-Caribbean men aged 65+ from a larger population-based cohort study. The mean (±SD) serum total 25(OH)D concentration was 35.1 ± 8.9 ng/ml. Deficiency (< 20 ng/mL) was present in only 2.8% and insufficiency (< 30 ng/mL) in 24% of the men. Multiple linear regression analysis identified age, BMI and daily vitamin D supplementation as the independent correlates of 25(OH)D. None of the men who consumed fish more than once per week had vitamin D deficiency, compared to 4% of the men who consumed fish once per week or less (P=0.01, adjusted for age, BMI, and daily vitamin D supplementation). In conclusion, vitamin D deficiency is very uncommon in this Afro-Caribbean population. Longitudinal studies are needed to delineate the possible effects of high vitamin D levels in this population on major diseases hypothesized to be associated with vitamin D deficiency.
PMCID: PMC3095488  PMID: 21462735
Vitamin D; 25(OH)D; Afro-Caribbean; Tobago; Men
21.  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
22.  Adipose Tissue and Volumetric Bone Mineral Density of Older Afro-Caribbean Men 
Although low body weight is a risk factor for osteoporosis related fractures, conflicting data exists for the association between adiposity and bone mineral density (BMD). Studies examining these relationships have measured body fat and BMD with dual energy X-ray absorptiometry (DXA) which cannot distinguish subcutaneous adipose tissue area (SAT) from total adiposity or trabecular from cortical bone. To investigate the relationship between adiposity and BMD further, we analyzed body composition and adipose tissue distribution by quantitative computed tomography (QCT) in 1829 Afro-Caribbean men aged ≥40 years from a population-based sample. Cortical volumetric BMD, muscle cross-sectional area, total adipose tissue area (TAT), and percentage SAT were measured at the proximal tibia. Trabecular volumetric BMD was measured at the distal tibia. We used analysis of covariance to test for associations between quartile of the adipose tissue measures and BMD adjusting for anthropometric, health and lifestyle factors. Higher TAT was associated with lower cortical BMD in both unadjusted and adjusted models (p<0.001). Men with a higher percentage SAT had greater cortical BMD (p<0.001). Similar associations were seen between percent SAT and trabecular BMD at the distal tibia. These results indicate that total adiposity is a potentially important correlate of bone mass in older men and that different fat depots may have opposing associations with bone mass. Additional research is needed to better understand the mechanisms underlying the relationship between body fat distribution and bone mass.
doi:10.1002/jbmr.107
PMCID: PMC3119489  PMID: 20499353
Osteoporosis; BMD; adiposity; men; QCT
23.  A Meta-analysis of Four Genome-Wide Association Studies of Survival to Age 90 Years or Older: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium 
Background.
Genome-wide association studies (GWAS) may yield insights into longevity.
Methods.
We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort.
Results.
There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 × 10−8. Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 × 10−7 for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage.
Conclusion.
Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.
doi:10.1093/gerona/glq028
PMCID: PMC2854887  PMID: 20304771
Longevity; Genome-wide association study; Meta-analysis
24.  Epidemiology of Myosteatosis 
Structured Abstract
Purpose of review
To summarize the epidemiology of myosteatosis and its association with diabetes.
Recent findings
The role of myosteatosis (fat infiltration in skeletal muscle) in diabetes has received considerable attention. There is reasonably consistent evidence that myosteatosis contributes to glucose and insulin abnormalities and diabetes, possibly even independent of overall obesity. Novel hypotheses that link myosteatosis with insulin resistance and type 2 diabetes have also recently been proposed. These hypotheses suggest that impaired secretion of adipokines and/or modulation of nutritive blood flow to skeletal muscle may be of importance for the development of myosteatosis. Recent longitudinal data also suggests that myosteatosis increases with aging, regardless of changes in body weight.
Summary
Further studies are needed to identify the specific physiological mechanisms that influence myosteatosis, and the mechanisms that link this fat depot with insulin resistance. Longitudinal studies are also needed to evaluate the remodeling of skeletal muscle fat with aging, across a wider age spectrum, and across different populations, especially those at high-risk of developing diabetes. There is also a need to evaluate if myosteatosis influences the incidence of type 2 diabetes independent of overall adiposity. A better understanding of the factors that regulate myosteatosis may lead to the development of novel therapies that influence a more metabolically “healthy” skeletal muscle.
doi:10.1097/MCO.0b013e328337d826
PMCID: PMC2872135  PMID: 20179586
Skeletal muscle; fat; myosteatosis; intramyocellular fat; intermuscular fat; diabetes; insulin resistance; aging
25.  Eight Common Genetic Variants Associated with Serum DHEAS Levels Suggest a Key Role in Ageing Mechanisms 
PLoS Genetics  2011;7(4):e1002025.
Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands—yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10−36), SULT2A1 (rs2637125; p = 2.61×10−19), ARPC1A (rs740160; p = 1.56×10−16), TRIM4 (rs17277546; p = 4.50×10−11), BMF (rs7181230; p = 5.44×10−11), HHEX (rs2497306; p = 4.64×10−9), BCL2L11 (rs6738028; p = 1.72×10−8), and CYP2C9 (rs2185570; p = 2.29×10−8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.
Author Summary
Dehydroepiandrosterone sulphate (DHEAS), mainly secreted by the adrenal gland, is the most abundant circulating steroid in humans. It shows a significant physiological decline after the age of 25 and diminishes about 95% by the age of 85 years, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. Twin- and family-based studies have shown that there is a substantial genetic effect with heritability estimate of 60%, but no specific genes regulating serum DHEAS concentration have been identified to date. Here we take advantage of recent technical and methodological advances to examine the effects of common genetic variants on serum DHEAS concentrations. By examining 14,846 Caucasian individuals, we show that eight common genetic variants are associated with serum DHEAS concentrations. Genes at or near these genetic variants include BCL2L11, ARPC1A, ZKSCAN5, TRIM4, HHEX, CYP2C9, BMF, and SULT2A1. These genes have various associations with steroid hormone metabolism—co-morbidities of ageing including type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins—suggesting a wider functional role for DHEAS than previously thought.
doi:10.1371/journal.pgen.1002025
PMCID: PMC3077384  PMID: 21533175

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