Elevated Serum PSA is Associated With Human Herpesvirus 8 Infection and Increased Circulating Cytokine Levels in Men From Tobago.

BACKGROUND: Serum-prostate specific antigen (PSA) levels have been used for many years as a biomarker for prostate cancer. This usage is under scrutiny due to the fact that elevated PSA levels can be caused by other conditions such as benign prostatic hyperplasia and infections of or injury to the prostate. As a result, the identification of specific pathogens capable of increasing serum levels of PSA is important. A potential candidate responsible for elevated PSA is human herpesvirus 8 (HHV-8). We have reported previously that HHV-8 is capable of infecting and establishing a latent infection in the prostate. In this current study we test the hypothesis that HHV-8 infection is associated with elevated PSA levels. Circulating cytokine levels between men with elevated PSA and controls are also compared. METHODS: HHV-8 serostatus was determined among men with elevated serum PSA (≥4 ng/ml; n = 168, no prostate cancer on biopsy) and age-matched controls (PSA <4 ng/ml; n = 234), Circulating cytokine levels were determined among a subset of each group (116 with elevated PSA and 85 controls). RESULTS: Men with an elevated serum PSA were significantly more likely to be HHV-8 seropositive (42.9%) than the age-matched cancer-free men (22.2%; OR 2.51; 95%CI 1.48-4.29, P = 00001). Comparison of circulating cytokine levels between men with elevated serum PSA and controls indicated that elevated serum PSA is associated with a pro-inflammatory response with a mixed Th1/Th2 response while HHV-8 infection was associated with significantly higher levels of IL12p70, IL-10, and IL-13 indicating a Th2 immune response. CONCLUSIONS: We found a significant association between HHV-8 infection and increased levels of serum PSA. In an age of patient-centered medicine, men with an elevated serum PSA should be considered for HHV-8 serology testing to determine if HHV-8 is responsible for the elevated PSA. Prostate 77: 617-624, 2017. © 2017 Wiley Periodicals, Inc.

Serum carotenoid and retinol levels in African-Caribbean Tobagonian men with high prostate cancer risk in comparison with African-American men.

Black men are known to have a higher risk for prostate cancer (PC). Carotenoids and retinol, linked to PC, have not been compared in different black populations at risk. We examined serum carotenoid and retinol levels between PC-free African-Caribbean (AC) Tobagonian men with a high PC risk (high-grade prostatic intraepithelial neoplasia, atypical foci or repeated abnormal PC screenings) and African-American (AA) men with elevated serum prostate-specific antigen (PSA) levels (≥4 ng/ml). AC men who participated in the 2003 lycopene clinical trial and AA men who participated in the 2001-2006 National Health and Nutrition Examination Survey were compared. Serum specimens were analysed for carotenoid (ß-carotene, α-carotene, ß-cryptoxanthin, lutein/zeaxanthin and lycopene) and retinol levels by isocratic HPLC. Quantile regression was used to examine the association between serum carotenoid and retinol levels and black ethnicity, overall and among men with elevated serum PSA. There were sixty-nine AC men and sixty-five AA men, aged 41-79 years, included. AC men were associated with lower serum lycopene and retinol levels, and higher serum α- and ß-carotenes and lutein/zeaxanthin levels compared with AA men, after adjusting for age, BMI, ever smoked cigarettes, education and hypertension (P≤0·03). Among men with elevated PSA, serum retinol was no longer statistically significant with ethnicity (P=0·06). Possible differences may be attributed to dietary intake, genetics and/or factors that influence bioavailability of these micronutrients. Prospective studies are warranted that investigate whether these differences in micronutrients between AC Tobagonian and AA men influence PC risk.

Human herpesvirus 8 infection contributes to a T helper 2 immune response in men from Tobago with prostate cancer.

OBJECTIVES: To compare the cytokine profile between human herpesvirus 8 seropositive and seronegative men with and without prostate cancer. METHODS: The study sample was obtained from the Tobago Prostate Survey, an ongoing study of prostate cancer in the Caribbean island of Tobago. Participants in the study were recruited mostly by public service announcement and by word of mouth. For analyses of circulating levels of pro-inflammatory cytokines, participants with biopsy-confirmed prostate cancer (n = 79) were compared with control participants (n = 87). RESULTS: Cytokine analyses showed a T helper 2 response with suppressed T helper 1 response in prostate cancer patients, as evidenced by significantly increased levels of interleukin-13 and reduced levels of interleukin-12p70. Herpesvirus 8 seropositive men showed significantly increased levels of interleukin-13 and interleukin-10. At logistic regression analyses, interleukin-12p70 predicted prostate cancer in 94.4% of human herpesvirus 8 seropositive men. CONCLUSIONS: These findings show that prostate cancer elicits an antitumor, T helper 2 response with a suppressed T helper 1 response. Human herpesvirus 8 infection results in a similar immune response supporting the hypothesis that in Tobago, human herpesvirus 8 establishes a chronic infection that can contribute to an immune response favoring the formation and survival of prostate cancer.

Human herpesvirus 8 establishes a latent infection in prostates of Tobago men resulting in increased macrophage infiltration.

BACKGROUND: The Caribbean island of Tobago, which is 97% African ancestry, has one of the highest rates of prostate cancer in the world. We have previously reported that human herpesvirus 8 (HHV-8) infection is significantly associated with prostate cancer in Tobago. In this study, we extend those results testing the hypothesis that HHV-8 seropositive Tobagonian men have a chronic HHV-8 infection in their prostates that is associated with increased inflammation. METHODS: Prostate sections were screened by immunohistochemistry for the expression of HHV-8 proteins K8.1 and LANA-1 and for presence of B cells (CD20) and macrophages (CD68). RESULTS: HHV-8 antigen expression representing lytic and latent infections was seen in 73.9% of prostates from HHV-8 seropositive subjects. Latent infections were seen predominantly in glandular epithelia whereas lytic gene expression was seen mainly in macrophages in prostate stroma. Macrophage infiltrates were significantly increased in sections expressing HHV-8 proteins. CONCLUSION: HHV-8 establishes a chronic latent infection in the prostate, which is associated with an increased macrophage infiltrate.

Greater skeletal muscle fat infiltration is associated with higher all-cause mortality among men of African ancestry.

BACKGROUND: fat infiltration within and around skeletal muscle (i.e. myosteatosis) increases with ageing, is greater in African versus European ancestry men and is associated with poor health. Myosteatosis studies of mortality are lacking, particularly among African ancestry populations. METHODS: in the Tobago Health study, a prospective longitudinal study, we evaluated the association of all-cause mortality with quantitative computed tomography (QCT) measured lower leg myosteatosis (intermuscular fat (IM fat) and muscle density) in 1,652 African ancestry men using Cox proportional hazards models. Date of death was abstracted from death certificates and/or proxy. RESULTS: one hundred and twelve deaths occurred during follow-up (mean 5.9 years). In all men (age range 40-91 years), higher all-cause mortality was associated with greater IM fat (HR (95% CI) per SD: 1.29 (1.06-1.57)) and lower muscle density (HR (95% CI) per SD lower: 1.37 (1.08-1.75)) in fully adjusted models. Similar mortality hazard rates were seen in the subset of elderly men (aged ≥65 years) with greater IM fat (1.40 (1.11-1.78) or lower muscle density (1.66 (1.24-2.21)) in fully adjusted models. CONCLUSIONS: our study identified a novel, independent association between myosteatosis and all-cause mortality in African ancestry men. Further studies are needed to establish whether this association is independent of other ectopic fat depots and to identify possible biological mechanisms underlying this relationship.

Human herpesvirus 8 seroconversion in a population-based cohort of men in Tobago.

Human herpesvirus 8 (HHV-8) is the causal agent of Kaposi's sarcoma (KS). In Tobago, KS is not common; however, HHV-8 seropositivity has been reported to be 39.9% in men with prostate cancer compared to <22.9% in healthier women and men. To understand HHV-8 transmission, we examined HHV-8 seroconversion and seroreversion, and risk factors for these changes in Tobago men. Serum specimens from a sub-cohort of Tobago Prostate Survey men, aged 40-81 years (n = 381/442), were collected at baseline and a subsequent visit between 3 and 9 years and tested for HHV-8 seropositivity using an immunofluorescence assay for antibodies against HHV-8 lytic antigens. Poisson distribution was used to calculate HHV-8 seroconversion and seroreversion rates and their 95% confidence intervals. Differences in baseline characteristics between HHV-seroconverters versus persistent HHV-8 seronegative men and HHV-8 seroreverters versus HHV-8 seropositive men were examined. HHV-8 seropositivity was 12.3% (N = 381) at baseline, with HHV-8 seropositivity significantly higher in increasing age groups, 40-49 (4.0%) to 70-81 (37.5%) years (P-value trend <0.0001). HHV-8 seroconversion and seroreversion rates were 0.23 per 100 person-years (95% C.I., 0.06-0.58) and 2.42 per 100 person-years (95% C.I., 0.89-5.26), respectively. There were significantly more HHV-8 seroconverters who reported "ever smoked cigarettes of >6 months" at baseline compared to HHV-8 persistent seronegative men (P-value = 0.03). Baseline characteristics of HHV-8 seroreverters did not differ from persistent seropositive men. Low HHV-8 seroconversion and seroreversion rates were found. Data suggest that HHV-8 transmission occurred at earlier ages, <40 years, in Tobago men.

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.

Racial/ethnic differences in bone mineral density among older women.

The epidemiologic information regarding international differences in bone mineral density (BMD) in women is currently insufficient. We compared BMD in older women across five racial/ethnic groups in four countries. The femoral neck, total hip, and lumbar spine BMD were measured in women (aged 65-74 years) from the Study of Osteoporotic Fractures (SOF) (5,035 Caucasian women and 256 African American women in the US), the Tobago Women's Health Study (116 Afro-Caribbean women), the Ms Os Hong Kong Study (794 Hong Kong Chinese women) and the Namwon Study (1,377 South Korean women). BMD was corrected according to the cross-site calibration results for all scanners. When compared with US Caucasian women, the age adjusted mean BMD measurements at the hip sites were 21-31 % higher among Tobago Afro-Caribbean women and 13-23 % higher among African American women. The total hip and spine BMD values were 4-5 % lower among Hong Kong Chinese women and 4-7 % lower among South Korean women compared to US Caucasians. The femoral neck BMD was similar in Hong Kong Chinese women, but higher among South Korean women compared to US Caucasians. Current/past estrogen use was a significant contributing factor to the difference in BMD between US versus non-US women. Differences in body weight partially explained the difference in BMD between Asian versus non-Asian women. These findings show substantial racial/ethnic differences in BMD even within African or Asian origin individuals, and highlight the contributing role of body weight and estrogen use to the geographic and racial/ethnic variation in BMD.

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.

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.

Multi-institutional prostate cancer study of genetic susceptibility in populations of African descent.

Prostate cancer disparities have been reported in men of African descent who show the highest incidence, mortality, compared with other ethnic groups. Few studies have explored the genetic and environmental factors for prostate cancer in men of African ancestry. The glutathione-S-transferases family conjugates carcinogens before their excretion and is expressed in prostate tissue. This study addressed the role of GSTM1 and GSTT1 deletions on prostate cancer risk in populations of African descent. This multi-institutional case-control study gathered data from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database, the African-Caribbean Cancer Consortium (AC3) and Men of African Descent and Carcinoma of the Prostate Consortium (MADCaP). The analysis included 10 studies (1715 cases and 2363 controls), five in African-Americans, three in African-Caribbean and two in African men. Both the GSTM1 and the GSTT1 deletions showed significant inverse associations with prostate cancer [odds ratio (OR): 0.90, 95% confidence interval (CI) 0.83-0.97 and OR 0.88, 95% CI: 0.82-0.96, respectively]. The association was restricted to Caribbean and African populations. A significant positive association was observed between GSTM1 deletion and prostate cancer in smokers in African-American studies (OR: 1.28, 95% CI: 1.01-1.56), whereas a reduced risk was observed in never-smokers (OR: 0.66, 95% CI: 0.46-0.95). The risk of prostate cancer increased across quartiles of pack-years among subjects carrying the deletion of GSTM1 but not among subjects carrying a functional GSTM1. Gene-environment interaction between smoking and GSTM1 may be involved in the etiology of prostate cancer in populations of African descent.

Chromosome 8q24 variants are associated with prostate cancer risk in a high risk population of African ancestry.

BACKGROUND: Earlier studies on the role of germline variations in the disproportionate higher burden of prostate cancer in men of African ancestry have been largely unrewarding. However, the successful replication of recent genome-wide association findings implicating some regions of chromosome 8q24 in the disparate prostate cancer susceptibility in men of European and African ancestry have been encouraging. This case-control study was designed to evaluate the association between germline variations in chromosome 8q24 and prostate cancer risk in Afro-Caribbean Tobago men, a population of predominantly West African ancestry. METHODS: High molecular weight genomic DNA was isolated from blood clots using Qiagen kits. Genotyping was performed on genomic DNA using a pre-designed TaqMan SNP assay according to the manufacture's protocol on a 7900HT Fast Real-Time PCR system (Applied Biosystems, Foster City, CA). RESULTS: SNP rs16901979 in region 2 was associated with significantly increased risk of prostate cancer (OR = 1.41, 95% confidence interval [CI] 1.02-1.95, P = 0.04) with the risk stronger in men with early-onset prostate cancer (OR = 2.37, 95% CI 1.40-3.99, P = 0.001). There was a tendency towards significantly increased risk for SNPs rs1447295 and rs6983267 in men with early-onset prostate cancer. CONCLUSIONS: The replication of the association of chromosome 8q24 variants with increased prostate cancer risk in Tobago men and the higher frequency of the risk alleles in controls in populations of African ancestry further strengthens the possible role of this genomic region in the disproportionate higher burden of prostate cancer in men of African ancestry.

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.

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.

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.