Heritability and genetics of serum dickkopf 1 levels in African ancestry families.

The aim of the study was to determine the heritability of serum dickkopf-1 (DKK1) and its association with DKK1 polymorphisms in African ancestry subjects. Serum DKK1 was measured in 422 Afro-Caribbean men and women aged 18+ from 7 large, multi-generational families (mean family size: 60; 3,215 relative pairs). Twenty-four common single nucleotide polymorphisms (SNPs) were genotyped within an 80 kilobase-pair region encompassing the DKK1 gene. Heritability was estimated and SNPs were tested for association with serum DKK1 using variance components analysis. DKK1 mRNA expression was tested in peripheral blood of 16 individuals from each of the rs7069912 genotypes. Mean serum DKK1 was 1724.1 pg/mL and was significantly lower in women than men (P = 0.043). Residual genetic heritability of serum DKK1 was 0.4460 (P < 0.0001). Six SNPs reached nominal significance with DKK1, with rs7069912 being significant after adjustment for multiple comparisons. Two of these six SNPs represented independent association signals (rs7069912 and rs16928725), which accounted for 4.6% of the phenotypic variation in DKK1. Additionally, carriers of the rs7069912 variant had significantly greater DKK1 expression than non-carriers (P = 0.036). Serum DKK1 levels are highly heritable in the African ancestry families. Two SNPs within the DKK1 region accounted for nearly 5% of the variation in serum DKK1.

The association between renal function biomarkers and subclinical cardiovascular measures in African Caribbean families.

BACKGROUND: Risk of cardiovascular disease (CVD) and mortality are increased in people with subclinical CVD. The impact of ethnicity and race on subclinical CVD is substantial. Previous studies assessed the heritability of several renal function biomarkers and their relationship with subclinical CVD among populations of European ancestries, but, to our knowledge, no such data are available in African ancestry populations. OBJECTIVE: Our aim was to investigate the relationships between renal function biomarkers and subclinical CVD among Afro-Caribbeans residing on the island of Tobago. DESIGN AND METHODS: 402 participants, aged 18 to 103 years, from seven large, multi-generation pedigrees (average family size: 50; range: 19 to 96; -3500 relative pairs) were included in this study. Subclinical cardiovascular disease (SCVD) was assessed by brachial-ankle pulse wave velocity (baPWV) and carotid intima-media thickness (IMT). Serum cystatin C, creatinine, and eGFR based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation were used to assess kidney function. The variance component approach, implemented in Sequential Oligogenic Linkage Analysis Routines (SOLAR), was used to assess heritability of these traits, and association with SCVD. RESULTS: Heritability of renal function biomarkers ranged from .19-.32 (all P < .001), and was highest for cystatin C (h2 = .32, P < .0001). Serum cystatin C was independently associated with arterial stiffness (P = .04). This association was not found with other renal function biomarkers. No significant association between renal function and IMT was found. CONCLUSION: Our data suggest that cystatin C is significantly heritable and associated with arterial stiffness among Afro-Caribbeans.

Thigh and Calf Myosteatosis are Strongly Associated with Muscle and Physical Function in African Caribbean Men.

BACKGROUND: African Caribbeans have higher levels of myosteatosis than other populations; however, little is known about the impact of myosteatosis on physical function in African Caribbeans. Herein, we examined the association between regional myosteatosis of the calf, thigh, and abdomen versus physical function in 850 African-Ancestry men aged 64.2 ± 8.9 (range 50-95) living on the Caribbean Island of Tobago. METHODS: Myosteatosis was measured using computed tomography and included intermuscular adipose tissue (IMAT) and muscle density levels of the thigh, calf, psoas, and paraspinous muscles. Outcomes included grip strength, time to complete 5 chair-rises, and 4-meter gait speed. Associations were quantified using separate linear models for each myosteatosis depot and were adjusted for age, height, demographics, physical activity, and chronic diseases. Beta coefficients were presented per standard deviation of each myosteatosis depot. RESULTS: Higher thigh IMAT was the only IMAT depot significantly associated with weaker grip strength (ß = -1.3 ± 0.43 kg, p = .003). However, lower muscle density of all 4 muscle groups was associated with weaker grip strength (all p < .05). Calf and thigh myosteatosis (IMAT and muscle density) were significantly associated with both worse chair rise time and gait speed (all p < .05), whereas psoas IMAT and paraspinous muscle density were associated with gait speed. CONCLUSION: Myosteatosis of the calf and thigh-but not the abdomen-were strongly associated with grip strength and performance measures of physical function in African Caribbean men. However, posterior abdominal myosteatosis may have some utility when abdominal images are all that are available.

Genome-wide association and follow-up replication studies identified ADAMTS18 and TGFBR3 as bone mass candidate genes in different ethnic groups.

To identify and validate genes associated with bone mineral density (BMD), which is a prominent osteoporosis risk factor, we tested 379,319 SNPs in 1000 unrelated white U.S. subjects for associations with BMD. For replication, we genotyped the most significant SNPs in 593 white U.S. families (1972 subjects), a Chinese hip fracture (HF) sample (350 cases, 350 controls), a Chinese BMD sample (2955 subjects), and a Tobago cohort of African ancestry (908 males). Publicly available Framingham genome-wide association study (GWAS) data (2953 whites) were also used for in silico replication. The GWAS detected two BMD candidate genes, ADAMTS18 (ADAM metallopeptidase with thrombospondin type 1 motif, 18) and TGFBR3 (transforming growth factor, beta receptor III). Replication studies verified the significant findings by GWAS. We also detected significant associations with hip fracture for ADAMTS18 SNPs in the Chinese HF sample. Meta-analyses supported the significant associations of ADAMTS18 and TGFBR3 with BMD (p values: 2.56 x 10(-5) to 2.13 x 10(-8); total sample size: n = 5925 to 9828). Electrophoretic mobility shift assay suggested that the minor allele of one significant ADAMTS18 SNP might promote binding of the TEL2 factor, which may repress ADAMTS18 expression. The data from NCBI GEO expression profiles also showed that ADAMTS18 and TGFBR3 genes were differentially expressed in subjects with normal skeletal fracture versus subjects with nonunion skeletal fracture. Overall, the evidence supports that ADAMTS18 and TGFBR3 might underlie BMD determination in the major human ethnic groups.

Patterns and correlates of grip strength change with age in Afro-Caribbean men.

BACKGROUND: muscle strength is essential for physical functions and an indicator of morbidity and mortality in older adults. Among the factors associated with muscle strength loss with age, ethnicity has been shown to play an important role. OBJECTIVE: to examine the patterns and correlates of muscle strength change with age in a population-based cohort of middle-aged and older Afro-Caribbean men. METHODS: handgrip strength and body composition were measured in 1,710 Afro-Caribbean men. Data were also collected for demographic variables, medical history and lifestyle behaviours. RESULTS: the age range of the study population was 29-89 years. Grip strength increased below age 50 years, and decreased after age 50 years over 4.5-year follow-up. The average loss in grip strength was 2.2% (0.49% per year) for ages 50 years or older and 3.8% (0.64% per year) for ages 65 years or older. The significant independent predictors of grip strength loss included older age, a greater body mass index, lower initial arm lean mass and greater loss of arm lean mass. CONCLUSION: Afro-Caribbean men experience a significant decline in muscle strength with advanced age. The major independent factors associated with strength loss were similar to other ethnic groups, including age, body weight and lean mass.

Low prevalence of vitamin D deficiency in elderly Afro-Caribbean men.

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-hydroxyvitamin D (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 years 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 = .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.

Association of physical activity with blood pressure in African ancestry men.

This study tested the association of objectively measured physical activity with blood pressure and hypertension in African Caribbean men, an understudied population segment known to be at high-risk for cardiovascular disease (CVD) which has low levels of high-exertion physical activity. Men (N = 310) were from the Tobago Health Study and aged 50-89 years. Systolic (SBP) and diastolic (DBP) blood pressures were measured using an automated device, and hypertension was defined as SBP ≥ 140 mmHg, DBP ≥ 90 mmHg, or current use of antihypertensive medication. Physical activity was measured using the SenseWear Pro armband (SWA) and consisted of daily time engaged in sedentary behavior (SB), light physical activity (LPA), and moderate to vigorous activity (MVPA), as well as daily step count. Multiple regression analyses using the isotemporal substitution framework were used to test for associations between activity and blood pressures. Models were adjusted in stages for SWA wear time, age, antihypertensive medication use, alcohol consumption, smoking, diabetes, CVD, family history of hypertension, salt intake, and adiposity. Replacement of SB with LPA was associated with lower SBP adjusted for wear time (ß = -0.84, p < 0.05), but attenuated after adjustment for age. Replacement of SB with LPA was associated with lower DBP (ß = -0.50) and lower odds of hypertension (OR = 0.88), adjusted for wear time and age (both p < 0.05). All model associations of replacement of SB with LPA were stronger when restricted to men not taking antihypertensive medications, regardless of their hypertension status. These results support the strategy of increasing light physical activity for blood pressure management in high-risk Afro-Caribbean men.

Sarcopenia Characteristics Are Associated with Incident Mobility Limitations in African Caribbean Men: The Tobago Longitudinal Study of Aging.

BACKGROUND: Sarcopenia varies by ethnicity, and has a major impact on health in older adults. However, little is known about sarcopenia characteristics in African ancestry populations outside the United States. We examined sarcopenia characteristics in 2,142 African Caribbean men aged 59.0 ± 10.4 years (range: 40-92 years) in Tobago, and their association with incident mobility limitations in those aged 55+ (n = 738). METHODS: Body mass index (BMI), grip strength, dual-x-ray absorptiometry (DXA) appendicular lean mass (ALM), and self-reported mobility limitations were measured at baseline, and 6 years later. Change in sarcopenia characteristics, including grip strength, grip strength/BMI, ALMBMI, and ALM/ht2, were determined. Foundations for the National Institutes of Health Sarcopenia Project (FNIH) and European Working Group for Sarcopenia in Older People 2 (EWGSOP2) cut-points were also examined. Odds ratios (OR) and 95% confidence intervals (CI) for mobility limitation were calculated using multivariable linear regression models adjusted for covariates. RESULTS: Overall, sarcopenia prevalence was quite low using the FNIH (0.3%) and EWGSOP2 (0.6%) operational cut-points, but was higher in those aged 75+ (2.1% [FNIH] and 3.7% [EWGSOP2]). Prevalence was also higher when based on "weakness", versus "low ALM." When sarcopenia markers were examined separately, baseline levels, but not changes, were associated with incident mobility limitations. Baseline grip strength/BMI was a particularly strong risk factor for incident mobility limitations (OR per SD: 0.50; 95% CI: 0.37-0.68). CONCLUSIONS: Our findings suggest that grip strength normalized to body mass, measured at one time point, may be a particularly useful phenotype for identifying African Caribbean men at risk for future mobility limitations.

Hepatic and Skeletal Muscle Adiposity Are Associated with Diabetes Independent of Visceral Adiposity in Nonobese African-Caribbean Men.

Background: Adipose tissue (AT) around and within non-AT organs (i.e., ectopic adiposity) is emerging as a strong risk factor for type 2 diabetes (T2D). Not known is whether major ectopic adiposity depots, such as hepatic, skeletal muscle, and pericardial adiposity (PAT), are associated with T2D independent of visceral adiposity (VAT). More data are particularly needed among high-risk nonobese minority populations, as the race/ethnic gap in T2D risk is greatest among nonobese. Methods: Thus, we measured several ectopic adiposity depots by computed tomography in 718 (mean age = 64 years) African-Caribbean men on the Island of Tobago overall, and stratified by obesity (obese N = 187 and nonobese N = 532). Results: In age, lifestyle risk factors, health status, lipid-lowering medication intake, body mass index and all other adiposity-adjusted regression analyses, and hepatic and skeletal muscle adiposity were associated with T2D among nonobese men only (all P < 0.05), despite no association between VAT and PAT and T2D. Conclusions: Our results support the "ectopic fat syndrome" theory in the pathogenesis of T2D among nonobese African-Caribbean men. Longitudinal studies are needed to clarify the independent role of ectopic adiposity in T2D, and to identify possible biological mechanisms underlying this relationship, particularly in high-risk African ancestry and other nonwhite populations.

Wnt Pathway Gene Expression Is Associated With Arterial Stiffness.

Background Animal and in vitro experiments implicate the Wnt pathway in cardiac development, fibrosis, vascular calcification, and atherosclerosis, but research in humans is lacking. We examined peripheral blood Wnt pathway gene expression and arterial stiffness in 369 healthy African ancestry men (mean age, 64 years). Methods and Results Gene expression was assessed using a custom Nanostring nCounter gene expression panel (N=43 genes) and normalized to housekeeping genes and background signal. Arterial stiffness was assessed via brachial-ankle pulse-wave velocity. Fourteen Wnt genes showed detectable expression and were tested individually as predictors of pulse-wave velocity using linear regression, adjusting for age, height, weight, blood pressure, medication use, resting heart rate, current smoking, alcohol intake, and sedentary lifestyle. Adenomatous polyposis coli regulator of Wnt signaling pathway (APC), glycogen synthase kinase 3ß (GSK3B), and transcription factor 4 (TCF4) were significantly associated with arterial stiffness (P<0.05 for all). When entered into a single model, APC and TCF4 expression remained independently associated with arterial stiffness (P=0.04 and 0.003, respectively), and each explained ≈3% of the variance in pulse-wave velocity. Conclusions The current study establishes a novel association between in vivo expression of the Wnt pathway genes, APC and TCF4, with arterial stiffness in African ancestry men, a population at high risk of hypertensive vascular disease.

Human herpesvirus 8 seroprevalence among Tobago women and the role of sexual lifestyle behavior.

Human herpesvirus 8 (HHV-8) infection is present in 22.9% of Tobago men. However, seroprevalence and modes of transmission of HHV-8 among Tobago women are not known. HHV-8 seropositivity rates in Tobago women were examined and compared rates to Tobago men of similar ages. To assess possible modes of transmission, sexual behavior among Tobago women was examined to determine its association with HHV-8 seropositivity. A cross-sectional study was conducted in 213 Tobago women, ages 18-65 years, who participated in the Tobago Cervical and Oral Cancer Screening Study. HHV-8 seropositivity was determined by a monoclonal immunofluorescence assay. Age-specific rates were compared to those previously observed in men. Logistic regression analyses were performed to determine the association between HHV-8 seropositivity and sexual behavior among the women. HHV-8 seroprevalence among Tobago women was 14.1% (95% CI, 10-19%), with no significant difference with men of similar age (P-value = 0.741). Age

Molecular variation in neuropeptide Y and bone mineral density among men of African ancestry.

Neuropeptide Y (NPY) is a physiological candidate gene for the regulation of body weight and has more recently been implicated in regulating bone mass. The current study sought to test if inherited variation in NPY might influence BMD in a population of African-ancestry men who have high bone mineral density (BMD). We genotyped 17 tagging single-nucleotide polymorphisms (SNPs) across the NPY gene region in 1,113 randomly selected men of African ancestry aged >or=40 years and tested for association with anthropometric characteristics and proximal femur BMD. The homozygous rare genotype of four SNPs was associated with a 0.92-1.59% decrease in stature (corrected P < 0.05). No SNP was associated with body mass index or body weight. Two SNPs in a 5-kb linkage disequilibrium block encompassing exons 3 and 4 were associated with proximal femur BMD, adjusted for age, body weight, and height (corrected P < 0.05). These results suggest that genetic variation at the NPY locus may contribute to bone density, independently of body weight.

Arterial stiffness and hypertension status in Afro-Caribbean men.

OBJECTIVE: African ancestry individuals are at high risk for hypertensive cardiovascular disease (CVD) and could benefit from early detection of arterial stiffening. We tested the association between the 2017 ACC/AHA hypertension categorizations, which include new blood pressure (BP) cutoffs and a definition for elevated BP, and arterial stiffness in 772 Afro-Caribbean men aged 50+ years (mean 64 years). METHODS: Arterial stiffness was assessed by brachial-ankle pulse-wave velocity (PWV) using a waveform analyzer. Hypertension groups were based on the 2017 ACC/AHA guidelines and by pharmacologic control status. Multiple linear/logistic regression was used to determine the association of PWV with BP and hypertension. RESULTS: Mean (SD) PWV was 1609 (298) cm/s and was independently correlated with age, SBP, pulse, diabetes, height, and alcohol intake (all P < 0.02). After adjusting for these, in men aged at least 65 years, those with stage 1 or uncontrolled stage 2 hypertension had significantly greater PWV than all other groups (all P < 0.05). Men with controlled hypertension had similar PWV to those with elevated BP (P = 0.7); however, this was significantly greater than men with normal BP (all P < 0.05). Patterns were similar, but with smaller effect sizes, in men aged less than 65 years (all P < 0.05 except controlled hypertension versus elevated or normal BP were not significant). CONCLUSION: In these high-risk Afro-Caribbeans: stage 1 hypertension is associated with increased PWV, which supports the new guidelines; and, pharmacologic control appears to partially protect men from increased PWV. Longitudinal studies are needed to determine optimal PWV and timing of antihypertensive treatment for preventing future CVD.

Body Composition Remodeling and Incident Mobility Limitations in African Ancestry Men.

BACKGROUND: Mobility limitations are common, with higher prevalence in African Americans compared with whites, and are associated with disability, institutionalization, and death. Aging is associated with losses of lean mass and a shift to central adiposity, which are more pronounced in African Americans. We aimed to examine the association of body composition remodeling with incident mobility limitations in older men of African ancestry. METHODS: Seven-year changes in body composition were measured using peripheral quantitative computed tomography (pQCT) of the calf and whole-body dual x-ray absorptiometry (DXA) in 505 African ancestry men aged ≥60 years and free of self-reported mobility limitations at baseline. Self-reported incident mobility limitations were assessed at 7-year follow-up. Odds of developing mobility limitations associated with baseline and change in body composition were quantified using separate logistic regression models. RESULTS: Seventy-five men (14.9%) developed incident mobility limitations over 6.2 ± 0.6 years. Baseline body composition was not associated with incident mobility limitations. After adjustment for covariates, gaining total and intermuscular fat were associated with incident mobility limitations (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.21-2.13; OR: 1.51; 95% CI: 1.18-1.94). Changes in DXA lean mass were not related to mobility limitations; however, maintaining pQCT calf muscle area was protective against mobility limitations (OR: 0.65; 95% CI: 0.48-0.87). CONCLUSIONS: Increases in body fat, and particularly intermuscular fat, and decreases in calf skeletal muscle area were associated with a higher risk of developing mobility limitations. Our findings emphasize the importance of body composition remodeling in the development of mobility limitations among African ancestry men.

Correlates of bone mineral density among postmenopausal women of African Caribbean ancestry: Tobago women's health study.

Population dynamics predict a drastic growth in the number of older minority women, and resultant increases in the number of fractures. Low bone mineral density (BMD) is an important risk factor for fracture. Many studies have identified the lifestyle and health-related factors that correlate with BMD in Whites. Few studies have focused on non-Whites. The objective of the current analyses is to examine the lifestyle, anthropometric and health-related factors that are correlated with BMD in a population based cohort of Caribbean women of West African ancestry. We enrolled 340 postmenopausal women residing on the Caribbean Island of Tobago. Participants completed a questionnaire and had anthropometric measures taken. Hip BMD was measured by DXA. We estimated volumetric BMD by calculating bone mineral apparent density (BMAD). BMD was >10% and >25% higher across all age groups in Tobagonian women compared to US non-Hispanic Black and White women, respectively. In multiple linear regression models, 35-36% of the variability in femoral neck and total hip BMD respectively was predicted. Each 16-kg (one standard deviation (SD)) increase in weight was associated with 5% higher BMD; and weight explained over 10% of the variability of BMD. Each 8-year (1 SD) increase in age was associated with 5% lower BMD. Current use of both thiazide diuretics and oral hypoglycemic medication were associated with 4-5% higher BMD. For femoral neck BMAD, 26% of the variability was explained by a multiple linear regression model. Current statin use was associated with 5% higher BMAD and a history of breast feeding or coronary heart disease was associated with 1-1.5% of higher BMAD. In conclusion, African Caribbean women have the highest BMD on a population level reported to date for women. This may reflect low European admixture. Correlates of BMD among Caribbean women of West African ancestry were similar to those reported for U.S. Black and White women.

Sex and genetic effects on upper and lower body fat and associations with diabetes in multigenerational families of African heritage.

Very few studies have comprehensively defined the genetic and environmental influences on body fat storage in the arms and legs and their association with diabetes, especially in families of African heritage. We analyzed body fat distribution by dual-energy x-ray absorptiometry (percentage total fat, percentage trunk fat, percentage arm fat, and percentage leg fat) and fasting serum glucose in 471 individuals (mean age, 43 years) from 8 multigenerational Afro-Caribbean families (mean family size = 51; 3535 relative pairs). Diabetes was inversely associated with percentage leg fat (P = .009) and, to some extent, positively associated with percentage arm fat independent of age, sex, and body size (P = .08), but not with anthropometric or dual-energy x-ray absorptiometric measures of total and central adiposity. Furthermore, percentage leg fat was inversely, whereas percentage arm fat was positively, associated with body mass index, waist circumference, and serum glucose (P < .01). Residual heritability (h2r) for arm and leg fat was significant (P < .01) and high: 62% (for percentage arm fat) and 40% (for percentage leg fat). Moreover, sex-specific h2r for leg fat was considerably higher (P = .02) in women than in men (h2r values, 58% vs 17%, respectively). Genetic correlation (rho(G)) between arm and leg fat was -0.61 (P < .01), suggesting that only 37% of the covariation between these 2 adipose tissue depots may be due to shared genetic influences. This study provides new evidence for a strong genetic and sex contribution to upper and lower body fat, with relatively little covariation between these traits due to shared genes. Our findings also suggest that, in this population, leg fat is associated with diabetes independent of overall adiposity.

Genetic and environmental determinants of volumetric and areal BMD in multi-generational families of African ancestry: the Tobago Family Health Study.

UNLABELLED: BMD is higher and fracture risk is lower among individuals of African versus European descent, but little is known about the genetic architecture of BMD in the former group. Heritabilities of areal and volumetric BMD were moderate in our large families of African descent but differed for trabecular and cortical BMD. INTRODUCTION: Populations of African ancestry have lower osteoporotic fracture risk and higher BMD than other ethnic groups. However, there is a paucity of information regarding the genetic and environmental influences on bone health among populations of African heritage. MATERIALS AND METHODS: We dissected the genetic architecture of areal BMD measured by DXA at the proximal femur, lumbar spine, and whole body and volumetric BMD measured by pQCT at the distal and proximal radius and tibia in 283 women and 188 men > or =18 years of age (mean, 43 years) from eight multigenerational Afro-Caribbean families (mean family size > 50). Using quantitative genetic methods, we estimated the residual heritability and the effects of anthropometric, demographic, lifestyle, and medical variables on areal and volumetric BMD. RESULTS: Compared with U.S. non-Hispanic blacks and whites, areal BMD at the femoral neck was highest in the Afro-Caribbean men and women at all ages. Trabecular volumetric BMD decreased linearly with increasing age, whereas cortical volumetric BMD did not decrease until age 40-49, especially in women. Anthropometric, lifestyle, and medical factors accounted for 12-32% of the variation in areal and volumetric BMD, and residual heritabilities (range, 0.23-0.52) were similar to those reported in other ethnic groups. Heritability of cortical BMD was substantially lower than that of areal or trabecular volumetric BMD, although the measured covariates accounted for a similar proportion of the total phenotypic variation. CONCLUSIONS: Our study is the first comprehensive genetic epidemiologic analysis of volumetric BMD measured by QCT and the first analysis of these traits in extended families of African descent. Genes account for as much or more of the total variation in areal and volumetric BMD than do environmental factors, but these effects seem to differ for trabecular and cortical bone.

Pleiotropy and heterogeneity in the expression of bone strength-related phenotypes in extended pedigrees.

UNLABELLED: Genetic analysis in 3,535 relative pairs from extended multigenerational families of African heritage showed that volumetric BMD is a highly heritable polygenic trait that is under compartment-specific genetic regulation. The majority of the phenotypic variation in bone size and volumetric BMD also seems to be strongly influenced by distinct genes for each trait. INTRODUCTION: BMD and bone size contribute to bone strength and the risk of fracture. Little is known about the genetic architecture of QCT measures of volumetric BMD and bone size. We studied the contribution of genes, shared genes (pleiotropy), and shared environment to cortical and trabecular volumetric BMD and bone size using variance components analysis. MATERIALS AND METHODS: A total of 471 individuals >or=18 yr of age (mean, 43 yr) from eight multigenerational Afro-Caribbean families (mean family size > 50; 3535 relative pairs) underwent a peripheral QCT scan of the radius and tibia and anthropometry. RESULTS: Strong positive genetic correlations were observed for trabecular or cortical BMD measured at the tibia and radius (rho(G) > 0.82, p < 0.01), but not between trabecular and cortical BMD measured within the same anatomical site. Genetic correlations between volumetric BMD and bone length and circumference were also not statistically significant. CONCLUSIONS: BMD is a highly heritable polygenic trait that is under compartment-specific genetic regulation. The majority of the phenotypic variation in skeletal size and density seems to be strongly influenced by distinct sets of genes for each trait.

Genetic determination of adiponectin and its relationship with body fat topography in multigenerational families of African heritage.

Adiponectin, an adipose-specific protein, is negatively associated with adiposity, insulin sensitivity, and diabetes. Very few studies have examined the role of heredity in the regulation of adiponectin and its association with body fat among individuals of African heritage. Thus, we measured fasting serum adiponectin levels by radioimmunoassay and body composition by dual-energy x-ray absorptiometry (DEXA) in 402 individuals aged 18 to 103 years belonging to 7 multigenerational families of African heritage in the relatively homogeneous island population of Tobago. Heritability of adiponectin was 33.2% (P < .01), and age, sex, and body mass index explained 23.4% of the variance in adiponectin. Sex-specific heritability was significant in men (heritability, 34%; P < .05), but not in women. The inverse associations between body mass index and percentage of body fat and adiponectin, independent of age and height, were much stronger in women (all P values <.001) than in men. However, percentage of trunk fat was consistently strongly associated with adiponectin in both men (r = -0.40, P < .001) and women (r = -0.44, P < .001), independent of age and height. This study suggests that genetic factors are a significant source of interindividual differences in circulating adiponectin among Afro-Caribbeans. Adiponectin may serve as a promising quantitative intermediate trait in studies designed to map the genes underlying diabetes and obesity in this population.