Relationship of volumetric BMD and structural parameters at different skeletal sites to sex steroid levels in men.

In a population-based, cross-sectional study, we related age-associated changes in vBMD and in bone structural parameters to circulating bioavailable estradiol and testosterone levels in men. Associations between these bone mass/structural parameters and sex steroid levels were progressively stronger with age. Our previously postulated "threshold" for skeletal estrogen deficiency was most evident at cortical sites. INTRODUCTION: Serum sex steroids, particularly estrogen levels, are associated with bone mass in men, and previous work has suggested that there may be a "threshold" bioavailable estradiol (bio E(2)) level below which the male skeleton becomes estrogen deficient. However, previous studies addressing this issue have exclusively used DXA, which cannot separate trabecular from cortical bone or provide information on bone geometry or structure. MATERIALS AND METHODS: In an age-stratified population sample of 314 men (age, 22-91 years), we assessed volumetric BMD (vBMD) and bone geometry by QCT at the lumbar spine, femoral neck, distal radius, and distal tibia and related these to circulating bio E(2) and bio testosterone (T) levels. RESULTS: Compared with young men (age, 20-39 years), middle-aged men (age, 40-59 years) had significantly lower bio T (-26%, p < 0.001) and bio E(2) (-9%, p = 0.038) levels, and these decreases were even greater in the elderly men (age > or = 60 years, -60% and -38% for bio T and bio E(2), respectively, p < 0.001 for both). Reflecting their intact gonadal status, vBMD/structural parameters were not related to sex steroid levels in young men, whereas bio E(2) levels were associated consistently with vBMD and variably with bone geometric parameters in the elderly men; middle-aged men showed associations with bio E(2) and bio T at some sites. At all cortical sites, vBMD was associated with bio E(2) at low (<30 pM, R = 0.27-0.41, p < 0.05-0.001) but not high (> or =30 pM, R = -0.003 to 0.12, p = not significant) levels; no such differences were evident at trabecular sites. CONCLUSIONS: In men, bio E(2) is the most consistent predictor of vBMD and some bone geometric variables as assessed by QCT. We also extend our previous findings on a possible "threshold" for skeletal estrogen deficiency by showing that this is most evident for cortical sites.     

Chromosome 2q32 may harbor a QTL affecting BMD variation at different skeletal sites.

BMDs at different skeletal sites share some common genetic determinants. Using PCA and bivariate linkage analysis, we identified a QTL on chromosome 2q32 with significant pleiotropic effects on BMDs at different skeletal sites. INTRODUCTION: BMDs at the hip, spine, and forearm are genetically correlated, suggesting the existence of quantitative trait loci (QTLs) with concurrent effects on BMDs at these three skeletal sites. Consequently, it is important to identify these QTLs in the human genome and, for those implicated QTLs, it is important to differentiate between pleiotropic effects, caused by a single gene that concurrently effects these traits, and co-incident linkage, caused by multiple, closely linked, genes that independently effect these traits. MATERIALS AND METHODS: For a sample of 451 American white pedigrees made up of 4,498 individuals, we evaluated the correlations between BMDs at the three skeletal sites. We carried out principal component analysis (PCA) for the three correlated traits and obtained a major component, PC1, which accounts for >75% of the co-variation of BMDs at the three sites. We subsequently conducted a whole genome linkage scan for PC1 and performed bivariate linkage analysis for pairs of the three traits (i.e., forearm/spine BMD, hip/forearm BMD, and hip/spine BMD). RESULTS: Chromosome region 2q32, near the marker GATA65C03M, showed strong linkage to PC1 (LOD = 3.35). Subsequent bivariate linkage analysis substantiated linkage at 2q32 for each trait pair (LOD scores were 2.65, 2.42, and 2.13 for forearm/spine BMD, hip/forearm BMD, and hip/spine BMD, respectively). Further analyses rejected the hypothesis of co-incident linkage (p(0)[forearm/spine] = 0.0005, p(0)[hip/forearm] = 0.004, p(0)(hip/spine] = 0.001) but failed to reject the hypothesis of pleiotropy (p(1)[forearm/spine] = 0.35, p(1)[hip/forearm] = 0.07, p(1)[hip/spine] = 0.15). CONCLUSIONS: Our results strongly support the conclusion that chromosome region 2q32 may harbor a QTL with pleiotropic effects on BMDs at different skeletal sites.     

Establishment of BMD reference curves at different skeletal sites in women, using a Cartesian coordinate numeration system

The BMD reference curve is the reference value used for diagnosing osteoporosis and assessing bone mass changes. Its accuracy would affect the correctness of T -score and Z -score values and thus the reliability of diagnostic results. In this paper, we report the use of a new method, a Cartesian coordinate numeration system, to establish BMD reference curves at different skeletal sites in women. In a reference population of 3,919 women ranging in age from 5–85 years, we used the dual X-ray absorptiometry (DXA) bone densitometer to measure BMD at the posteroanterior spine (PA; vertebrae L1–L4), followed by a paired PA/lateral spine scan of the vertebral bodies of L2–L4, expressed in g/cm² and g/cm³, and of the hip and forearm. We chose the cubic regression model to best fit BMD curves that varied with age at different skeletal sites. We then referred the BMD of the fitting curves established by the method of the coordinate numeration system as reference curves, compared them to BMD reference curves derived from the fitting curve equation or age cross-section, and calculated the deflection degrees of the BMD reference curves acquired from the fitting curve equation. At the PA spine, lateral spine (expressed in g/cm³), femoral neck, Wards triangle and radius + ulna ultradistal, the reference curves calculated from the equation were significantly lower than those confirmed by the method of the coordinate numeration system; whereas, at the lateral spine (expressed in g/cm²), total hip, and radius + ulna 1/3 sites, the reference curves derived from the equation were markedly higher than those acquired from the coordinate numeration system. The differences in the two kinds of reference curves calculated by these two different methods gradually increased along with the increment in ages of the women. At the peak value of the reference curves, the BMD calculated from the equation deflected from 2.02% to –10.0% from the BMD acquired from the coordinate numeration system at different skeletal sites, and from 21.5% to –121.8% until the age of 85 years. The highest positive deflection of 65.2% existed at the lateral spine (expressed in g/cm²) and the lowest positive deflection of 21.5% at the total hip. The maximum negative deflection of –121.8% was at the radius + ulna ultradistal, and the minimum negative deflection of –32.6% at the PA spine. The BMD curve acquired from age cross-section was highly positive compared with the one derived from the coordinate numeration system ( r =0.955–0.985 p =0.000) with no significant difference between them. Various analysts used such a method to obtain the coefficient of variance (CV) in BMD precision on each curve that was from 0.05–0.19%. Our study shows that the Cartesian coordinate numeration system is an accurate, precise and reliable method and can serve to reveal the serious drawbacks of using the fitting curve equation to calculate BMD. The BMD reference curves established by this coordinate numeration system maintained the authenticity of the fitting curve, whereas, using the fitting curve equation to obtain BMD reference curves at different skeletal sites led to distortion, and resulted in false increases or decreases in T -score and Z -score values.     

Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families

Type 1 diabetes is a common, multifactorial disease with strong familial clustering (genetic risk ratio [lambda(S)] approximately 15). Approximately 40% of the familial aggregation of type 1 diabetes can be attributed to allelic variation of HLA loci in the major histocompatibility complex on chromosome 6p21 (locus-specific lambda(S) approximately 3). Three other disease susceptibility loci have been clearly demonstrated based on their direct effect on risk, INS (chromosome 11p15, allelic odds ratio [OR] approximately 1.9), CTLA4 (chromosome 2q33, allelic OR approximately 1.2), and PTPN22 (chromosome 1p13, allelic OR approximately 1.7). However, a large proportion of type 1 diabetes clustering remains unexplained. We report here on a combined linkage analysis of four datasets, three previously published genome scans, and one new genome scan of 254 families, which were consolidated through an international consortium for type 1 diabetes genetic studies (www.t1dgc.org) and provided a total sample of 1,435 families with 1,636 affected sibpairs. In addition to the HLA region (nominal P = 2.0 x 10(-52)), nine non-HLA-linked regions showed some evidence of linkage to type 1 diabetes (nominal P < 0.01), including three at (or near) genome-wide significance (P < 0.05): 2q31-q33, 10p14-q11, and 16q22-q24. In addition, after taking into account the linkage at the 6p21 (HLA) region, there was evidence supporting linkage for the 6q21 region (empiric P < 10(-4)). More than 80% of the genome could be excluded as harboring type 1 diabetes susceptibility genes of modest effect (lambda(S) > or = 1.3) that could be detected by linkage. This study represents one of the largest linkage studies ever performed for any common disease. The results demonstrate some consistency emerging for the existence of susceptibility loci on chromosomes 2q31-q33, 6q21, 10p14-q11, and 16q22-q24 but diminished support for some previously reported locations.     

Quantitative trait loci for BMD identified by autosome-wide linkage scan to chromosomes 7q and 21q in men from the Amish Family Osteoporosis Study.

Using autosome-wide linkage analysis in 964 Amish, strong evidence was found for the presence of genes affecting hip and spine BMD in men on chromosomes 7q31 and 21q22 (LOD = 4.15 and 3.36, respectively). INTRODUCTION: BMD is highly heritable, with genetic factors accounting for 60-88% of variation. The goal of this study was to localize genes contributing to BMD variation. MATERIALS AND METHODS: The Amish Family Osteoporosis Study was designed to identify genes affecting bone health. The Amish are a genetically closed population with a homogeneous lifestyle. BMD was measured at the spine, hip, and radius using DXA in 964 participants (mean age, 50.2 +/- 16.3 [SD] years; range, 18-99 years) from large multigenerational families. Genotyping of 731 highly polymorphic microsatellite markers (average spacing of 5.4 cM) and autosome-wide multipoint linkage analysis were performed. RESULTS: In the overall study population, no strong evidence for linkage was detected to any chromosomal region (peak LOD: 2.11 for radius BMD on chromosome 3q26). In a subgroup analysis of men (n = 371), strong evidence was detected for a quantitative trait locus (QTL) influencing BMD variation on chromosome 7q31 at the total hip (LOD = 4.15) and femoral neck (LOD = 3.09) and for a second QTL influencing spine BMD at 21q22 (LOD = 3.36). Suggestive evidence of linkage was found in men for a QTL at 12q24 affecting total hip BMD (LOD = 2.60) and at 18p11 for femoral neck (LOD = 2.07), and in women (n = 593) at 1p36 for femoral neck BMD (LOD = 2.02) and at 1q21 for spine BMD (LOD = 2.11). In age subgroup analyses, suggestive evidence for linkage was found for those <50 years of age (n = 521) on chromosomes 11q22 and 14q23 (LODs = 2.11 and 2.16, respectively) and for those >50 years of age (n = 443) on 3p25.2 (LOD = 2.32). CONCLUSIONS: These results strongly suggest the presence of genes affecting hip and spine BMD in men on chromosomes 7q31 and 21q22. Modest evidence was found for genes affecting BMD in women on chromosomes 1p36 and 1q21 and in men at 12q24, replicating results from other populations.     

大鼠不同部位骨骼对外源性甲状腺激素反应性的研究

目的：用左旋甲状腺素（L－T4）制备实验性甲状腺功能亢进（甲亢）大鼠模型，以探讨甲亢大鼠的胫骨和椎骨对外源性甲状腺激素的反应性，为临床监测长期L-T4治疗提供依据。方法：9周龄雄性Sprague-Dawley(SD)大鼠18只，随机分为甲亢组11只、对照组7只。甲 亢组予L－T4腹腔内注射，对照组予生理盐水注射，连续注射3周后取大鼠的胫骨近端、第四腰椎用非脱钙骨组织形态学计量法进行同期观察和研究。结果：在胫骨甲亢组的骨小梁数量降低，骨形成表面、吸收表面均增加，但骨吸收表面增加更明显，骨小梁平均宽度、骨纵向生长率降低，而骨矿化率增加。椎骨未观察到此变化。结论：L－T4引起继发性胫骨骨量减少，骨转换增加，椎骨无反应，表明不同部位的骨骼对甲状腺激素的反应存在异质性。     

Variation in risk factors for fractures at different sites

Fractures in older people are important medical problems. Knowledge of risk factors is essential for successful preventive measures, but when fracture sites of diverse etiology are combined, risk factors for any one site are difficult to identify and may be missed entirely. Among older people, incidence rates of hip, proximal humerus, and vertebral fractures increase with age, but not rates of distal forearm and foot fractures. Low bone mineral density is strongly associated with hip, distal forearm, vertebral, and proximal humerus fractures, but not foot fracture. Most fractures of the hip, distal forearm, and proximal humerus result from a fall, whereas smaller proportions of fractures of the foot and vertebrae follow a fall. Frail people are likely to fracture their hip or proximal humerus, while healthy, active people tend to fracture their distal forearm. We strongly recommend that studies identify risk factors on a site-specific basis.     

An autosomal genome-wide scan for loci linked to pre-diabetic phenotypes in nondiabetic Chinese subjects from the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance Family Study

Type 2 diabetes is a complex disease involving both genetic and environmental components. Abnormalities in insulin secretion and insulin action usually precede the development of type 2 diabetes and can serve as good quantitative measures for genetic mapping. We therefore undertook an autosomal genomic search to locate the quantitative trait locus (QTL) linked to these traits in 1,365 nondiabetic Chinese subjects from 411 nuclear families. Residuals of these log-transformed quantitative traits were analyzed in multipoint linkage analysis using a variance-components approach. The most significant QTL for fasting insulin, which coincides with the QTL for homeostasis model assessment of insulin resistance, was located at 37 cM on chromosome 20, with a maximum empirical logarithm of odds (LOD) score of 3.01 (empirical P = 0.00006) when adjusted for age, sex, BMI, antihypertensive medications, recruitment centers, and environmental factors. In the same region, a QTL for fasting glucose was identified at 51 cM, with an empirical LOD score of 2.03 (empirical P = 0.0012). There were other loci with maximum empirical LOD scores >or=1.29 located on chromosomes 1q, 2p, 5q, 7p, 9q, 10p, 14q, 18q, and 19q for different diabetes-related traits. These loci may harbor genes that regulate glucose homeostasis either independently or via interactions of the genes within these regions.     

Bone mineral density (BMD) assessment of central skeletal sites from peripheral BMD and ultrasonographic measurements: an improved solution employing age and weight in type 3 regression.

The objective of this study was to develop a method whereby bone mineral density measurements of the heel and finger, as well as ultrasonographic measurements of calcaneal sound transmission, could identify individuals with a diagnosis of osteoporosis or osteopenia by the World Health Organization criteria for these diagnoses in the central skeleton (i.e., the lumbar spine (LS) and hip [femoral neck] [FN]). Two hundred and forty-four women in a university hospital laboratory setting had dual-energy X-ray absorptiometry measurements of bone mineral density (BMD) in the calcaneus, finger, hip, and spine, and quantitative ultrasound of the calcaneus. Regression equations were developed to predict central bone mineral T-scores from T-scores of peripheral measurements, adjusted by age and weight. Equations were validated by predicting the cut point for osteopenia at the lumbar spine and hip (T-score=-1.0). Ninety-five percent confidence intervals of the mean predicted LS or FN T-score from each peripheral site included -1.0. We conclude that our derived regression equations (taking into account interaction of peripheral BMD with patient age and weight) are useful for predicting T-scores in the central skeleton. This approach reduces the potential for misdiagnosis, which can result if one uses unadjusted peripheral T-scores, which are only moderately correlated with the central measurements of BMD.     

North American male reference population for speed of sound in bone at multiple skeletal sites.

Alternatives to dual-energy X-ray absorptiometry (DXA) have been sought to increase access to low-cost osteoporosis risk assessment. Early quantitative ultrasound (QUS) systems measured speed of sound (SOS) and broadband ultrasound attenuation (BUA) at the calcaneus, and these were demonstrated to be good predictors of hip fracture risk. Recent studies have demonstrated the usefulness of other peripheral sites to assess bone status. The Sunlight Omnisense (Sunlight Medical, Rehovot, Israel) is a portable, inexpensive QUS device capable of multiple-site SOS measurement. To provide a robust male reference database, 588 healthy Caucasian males aged 20-90 yr were recruited from 6 centers across North America. SOS measurements were taken at the distal 1/3 radius, proximal third phalanx, midshaft tibia, and fifth metatarsal. A female reference database has previously been collected at North American sites. The results indicate that SOS in males exhibits an age-related decline beginning in the fifth decade at the radius, phalanx, and metatarsal, whereas the tibial SOS remains nearly constant until the ninth decade. Although females reach a higher-peak SOS than males at most sites, SOS is higher in males at all sites after the sixth decade, as a result of a more gradual decline in SOS. Longitudinal monitoring of healthy men should be performed to confirm these cross-sectional results.     

The effect of enterocystoplasty on bone strength assessed at four different skeletal sites in a rat model

The objective of the study was to investigate bone strength at four different skeletal sites in a chronic animal model of urinary diversion. Young male Wistar rats (120) were allocated randomly to four groups undergoing ileocystoplasty; ileocystoplasty and resection of the ileocecal segment; colocystoplasty; or sham operation (controls). After 8 months the lumbar vertebrae, femora, and tibiae were harvested at necropsy. Bone strength was assessed biomechanically at four different skeletal sites: vertebra L3, femoral middiaphysis, femoral neck, and distal femoral metaphysis. Bone mass and architecture were assessed using standard static histomorphometry of the proximal tibial metaphysis (trabecular bone volume [BV/TV]; trabecular number [Tb.N]) and ash weight. Statistically significant differences of biomechanical parameters between groups were observed at three skeletal sites with corresponding changes in tibial histomorphometry. Isolated ileocystoplasty resulted in decreased maximum load values of L3 (-16.4%; p < 0.0035) and a substantial reduction in tibial BV/TV (-34.7%; p < 0.05). Ileocystoplasty combined with resection of the ileocecal segment led to a significant loss of bone strength of L3 (-32.4%; p < 0.0015) and a dramatic reduction of tibial BV/TV (-45.9%; p < 0.01). Loss of tibial metaphyseal bone mass was predominantly caused by a decrease in Tb.N. (p < 0.01). Colonic augmentation had no significant effect on bone strength or histomorphometric values. In conclusion, this is the first experimental study to demonstrate the relevance of histomorphometrically proven bone loss after enterocystoplasty in terms of biomechanical variables.     

Quantitative trait loci for BMD and bone strength in an intercross between domestic and wildtype chickens.

With chicken used as a model species, we used QTL analysis to examine the genetic contribution to bone traits. We report the identification of four QTLs for femoral traits: one for bone strength, one for endosteal circumference, and two affecting mineral density of noncortical bone. INTRODUCTION: BMD is a highly heritable phenotype, governed by elements at numerous loci. In studies examining the genetic contribution to bone traits, many loci have been identified in humans and in other species. The goal of this study was to identify quantitative trait loci (QTLs) controlling BMD and bone strength in an intercross between wildtype and domestic chickens. MATERIALS AND METHODS: A set of 164 markers, covering 30 chromosomes (chr.), were used to genotype 337 F2-individuals from an intercross of domesticated white Leghorn and wildtype red junglefowl chicken. DXA and pQCT were used to measure BMD and bone structure. Three-point bending tests and torsional strength tests were performed to determine the biomechanical strength of the bone. QTLs were mapped using forward selection for loci with significant marginal effects. RESULTS: Four QTLs for femoral bone traits were identified in QTL analysis with body weight included as a covariate. A QTL on chr. 1 affected female noncortical BMD (LOD 4.6) and is syntenic to human 12q21-12q23. Also located on chr. 1, a locus with synteny to human 12q13-14 affected endosteal circumference (LOD 4.6). On chr. 2, a QTL corresponding to human 5p13-p15, 7p12, 18q12, 18q21, and 9q22-9q31 affected BMD in females; noncortical (LOD 4.0) and metaphyseal (LOD 7.0) BMD by pQCT and BMD by DXA (LOD 5.9). A QTL located on chr. 20 (LOD 5.2) affected bone biomechanical strength and had sex-dependent effects. In addition to the significant QTLs, 10 further loci with suggestive linkage to bone traits were identified. CONCLUSIONS: Four QTLs were identified: two for noncortical BMD, one for endosteal circumference, and one affecting bone biomechanical strength. The future identification of genes responsible for these QTLs will increase the understanding of vertebrate skeletal biology.     

Gender differences in bone density at different skeletal sites of acquisition with age in Chinese children and adolescents

Bone mass acquisition from different genders and races of children and adolescents may vary. To explore gender- and age-related differences in bone mineral density (BMD) measurements in Chinese children and adolescents, we used the dual-energy X-ray absorptiometry (DXA) bone densitometer to take BMD measurements at the posteroanterior (PA) and lateral spine, hip, and forearm in 1286 healthy children and adolescents, ranging from 6 to 24 years of age. Our results show a correlation between BMD measurements taken from different skeletal sites and from different ages of subjects. Male data were best fit to a power regression model, yielding the largest determinant coefficients (R ²), whereas S regression was the best fitting model for females. In individuals younger than 17 years of age, the rate of BMD accumulation in the PA spine is more rapid in females than in males, whereas in individuals older than 19 years of age, the converse was found to be true. In children younger than 14 years of age, BMD measurements, taken from the lateral spine, the neck and trochanter of the femur, and the total hip, correlated with age similarly in both genders. Additionally, in measurements taken from the forearm ultradistal and 1/3 region, BMD measurements from similar ages of both genders are similar. With increasing age, BMD measurements in males become significantly higher than those of females. However, volumetric BMD (vBMD) measurements from both genders show good uniformity at the lateral spine with a near overlap of the two models. Our findings suggest that vBMD acquisition measurements in Chinese children and adolescents show no gender differences, with gender differences only demonstrated in areal BMD (aBMD) measurements taken from different skeletal sites.     

Optimization of BMD measurements to identify high risk groups for treatment--a test analysis.

INTRODUCTION: The aim of this study was to develop a methodology to optimize the role of BMD measurements in a case finding strategy. We studied 2113 women > or = 75 years of age randomly selected from Sheffield, UK, and adjacent regions. Baseline assessment included hip BMD and clinical risk factors. Outcomes included death and fracture in women followed for 6723 person-years. MATERIALS AND METHODS: Poisson models were used to identify significant risk factors for all fractures and for death with and without BMD and the hazard functions were used to compute fracture probabilities. Women were categorized by fracture probability with and without a BMD assessment. A 10-year fracture probability threshold of 35% was taken as an intervention threshold. Discordance in categorization of risk (i.e., above or below the threshold probability) between assessment with and without BMD was examined by logistic regression as probabilities of re-classification. Age, prior fracture, use of corticosteroids, and low body mass index were identified as significant clinical risk factors. RESULTS: A total of 16.8% of women were classified as high risk based on these clinical risk factors. The average BMD in these patients was approximately 1 SD lower than in low-risk women; 21.5% of women were designated to be at high risk with the addition of BMD. Fifteen percent of all women were reclassified after adding BMD to clinical risk factors, most of whom lay near the intervention threshold. When a high probability of reclassification was accepted (without a BMD test) for high risk to low risk (p1< or = 0.8) and a low probability accepted for low to high risk (P2 < or = 0.2), BMD tests would be required in only 21% of the population. CONCLUSION: We conclude that the use of clinical risk factors can identify elderly women at high fracture risk and that such patients have a low average BMD. BMD testing is required, however, in a minority of women--a fraction that depends on the probabilities accepted for classification and the thresholds of risk chosen. These findings need to be validated in other cohorts at different ages and from different regions of the world.     

女性不同骨骼部位骨密度峰值和参考图的建立方法

目的建立女性不同骨骼部位骨密度(BMD)参考图和确定峰值BMD(PBMD). 方法 用DXA QDR 4500A型扇形束骨密度仪测量3378例5～96岁女性腰椎前后位(AP)和仰卧侧位、髋部和前臂的BMD,用8种回归模型拟合BMD随年龄的变化,找出最佳拟合模型方程建立参考图和确定PBMD.结果三次回归模型拟合程度最佳,即方程的决定系数(R2)最大.我们应用拟合曲线建立了BMD参考图,拟合曲线方程计算各骨骼部位最高的BMD(A方法)和BMD最高的5岁年龄组(B方法)及年龄横断面(C方法)计算PBMD,发现在大多数骨骼部位,三种方法计算的PBMD的差异有显著性.结论此研究建立了女性不同骨骼部位BMD参考图.应用拟合曲线方程计算PBMD(A方法)可获得符合骨骼部位特异性的真正的PBMD,不同方法计算PBMD将对PBMD和诊断骨质疏松产生严重影响.     

A genome-wide scan for loci linked to plasma levels of glucose and HbA(1c) in a community-based sample of Caucasian pedigrees: The Framingham Offspring Study

Elevated blood glucose levels are the hallmark of type 2 diabetes as well as a powerful risk factor for development of the disease. We conducted a genome-wide search for diabetes-related genes, using measures of glycemia as quantitative traits in 330 pedigrees from the Framingham Heart Study. Of 3,799 attendees at the 5th Offspring Study exam cycle (1991--1995), 1,461, 1,251, and 771 men (49%) and women provided information on levels of 20-year mean fasting glucose, current fasting glucose, and HbA(1c), respectively, and 1,308 contributed genotype data (using 401 microsatellite markers with an average spacing of 10 cM). Levels of glycemic traits were adjusted for age, cigarette smoking, alcohol and estrogen use, physical activity, and BMI. We ranked standardized residuals from these models, created normalized deviates from the ranks, and used the variance component model implemented in SOLAR (Sequential Oligogenic Linkage Analysis Routines) to evaluate linkage to normalized deviates as quantitative traits. We found peak evidence for linkage to 20-year mean fasting glucose levels on chromosome 1 at approximately 247 cM from p-telomere (pter) (multipoint logarithm of odds [LOD] 2.33) and on chromosome 10 at approximately 86 cM from pter (multipoint LOD 2.07); to current fasting glucose levels on chromosome 1 at approximately 218 cM from pter (multipoint LOD 1.80) and on chromosome 10 at approximately 96 cM from pter (multipoint LOD 2.15); and to HbA(1c) levels on chromosome 1 at approximately 187 cM (multipoint LOD 2.81). This analysis of unselected European Caucasian pedigrees suggests localization of quantitative trait loci influencing glucose homeostasis on chromosomes 1q and 10q. Findings at approximately 187--218 cM on chromosome 1 appear to replicate linkage reported in previous studies of other populations, pointing to this large chromosomal region as worthy of more detailed scrutiny in the search for type 2 diabetes susceptibility genes.     

Discordance between changes in bone mineral density measured at different skeletal sites in perimenopausal women--implications for assessment of bone loss and response to therapy: The Danish Osteoporosis Prevention Study.

Assessing bone loss and gain is important in clinical decision-making, both in evaluating treatment and in following untreated patients. The aim of this study was to correlate changes in bone mineral density (BMD) at different skeletal sites during the first 5 years after menopause and determine if forearm measurements can substitute for dual-energy X-ray absorptiometry (DXA) of the spine and hip. BMD was measured at 0, 1, 2, 3, and 5 years using Hologic 1000/W and 2000 densitometers in 2,016 perimenopausal women participating in a national cohort study. This analysis comprises 1,422 women remaining in the study after 5 years without changes to their initial treatment (hormone-replacement therapy [HRT], n = 497, or none, n = 925). Despite correlated rates of change between forearm and spine (r2 = 0.11; p < 0.01), one-half of those who experienced a significant decrease in spine BMD at 5 years showed no significant fall in forearm BMD (sensitivity, 50%; specificity, 85%; kappa = 0.25). The total hip had significant better agreement with spine (sensitivity, 63%; specificity, 85%; kappa = 0.37; p < 0.01). Analysis of quartiles of change also showed significant better agreement with spine and whole body for the total hip than for the femoral neck or ultradistal (UD) forearm. In a logistic regression analysis for identification of group (HRT or control), the prediction was best for whole body (82.6%) and spine (80.9%), followed by total hip (78.5%) and forearm (74.7%). In conclusion, changes at the commonly measured sites are discordant, and DXA of the forearm is less useful than DXA of the hip or spine in determining the overall skeletal response to therapy or assessing bone loss in untreated women.