Victor W. Wheeler

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.

Genetic and Environmental Determinants of Volumetric and Areal BMD in Multi-Generational Families of African Ancestry: The Tobago Family Health Study

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.

Greater adipose tissue infiltration in skeletal muscle among older men of African ancestry

CONTEXT There is substantial variability across ethnic groups in the predisposition to obesity and associated metabolic abnormalities. Skeletal muscle fat has been identified as an important depot that increases with aging and may contribute to the development of diabetes. OBJECTIVE We tested whether men of African ancestry have greater calf intermuscular adipose tissue (IMAT), compared to Caucasian men, and whether IMAT is associated with type 2 diabetes (T2D). DESIGN We measured fasting serum glucose, body mass index, total body fat by dual-energy x-ray absorptiometry, and calf skeletal muscle composition by quantitative computed tomography in 1105 Caucasian and 518 Afro-Caribbean men aged 65+. RESULTS Compared to Caucasian men, we found greater IMAT and lower sc adipose tissue in Afro-Caribbean men at all levels of total adiposity (P < 0.0001), including the subset of men matched on age and dual-energy x-ray absorptiometry total body fat percentage (P < 0.001). In addition, IMAT was 29 and 23% greater, whereas sc adipose tissue was 6 and 8% lower among Caucasian and Afro-Caribbean men with T2D, respectively, compared to men without T2D (P < 0.01). Observed differences in intermuscular and sc fat, both ethnic and between men with and without T2D, were independent of age, height, calf skeletal muscle and total adipose tissue, and lifestyle factors. CONCLUSIONS Our analyses suggest that despite lower total adiposity, skeletal muscle fat infiltration is greater among African than among Caucasian ancestry men and is associated with T2D in both ethnic groups. Additional studies are needed to determine the mechanisms contributing to ethnic differences in skeletal muscle adiposity and to define the metabolic and health implications of this fat depot.

Fat Infiltration in Muscle: New Evidence for Familial Clustering and Associations With Diabetes

Objective: Increased fat infiltration in skeletal muscle has been associated with diabetes. Quantitative computed tomography (QCT) can be used to measure muscle density, which reflects the lipid content of skeletal muscle such that greater fat infiltration in skeletal muscle is associated with lower muscle density. The relative contribution of genetic and environmental factors to fat infiltration in skeletal muscle has not been assessed. Therefore, our aim is to determine genetic and environmental contributions to measures of skeletal muscle composition, and describe their associations with type 2 diabetes in multigenerational families of African ancestry.

Association Analysis of WNT10B With Bone Mass and Structure Among Individuals of African Ancestry

Wnts comprise a family of secreted growth factors that regulate the development and maintenance of many organs. Recently, Wnt10b was shown to stimulate osteoblastogenesis and bone formation in mice. To evaluate further the role of Wnt10b in bone health in humans, we performed bidirectional sequencing of ∼8 kb of the WNT10B gene region in 192 individuals (96 African, 96 white) to identify single nucleotide polymorphisms (SNPs). We identified 19 SNPs with minor allele frequency (MAF) ≥0.01. Ten of these SNPs were not present in the NCBI dbSNP database (build 127), whereas 10 of the 20 SNPs (50%) reported in dbSNP were not verified. We initially genotyped seven tagging SNPs that captured common (MAF ≥ 0.05) variation in the region with r2 > 0.80 and a potentially functional SNP in exon 5 in 1035 Afro‐Caribbean men ≥40 yr of age. Association analysis showed three SNPs in a 3′ region of linkage disequilibrium that were associated with DXA measures of hip BMD. Associations between two of these three SNPs (rs1051886, rs3741627) with hip BMD were replicated in an additional 980 Afro‐Caribbean men (p < 0.05), in the combined sample of 2015 men (p ≤ 0.006), and in 416 individuals ≥18 yr of age (mean, 44 yr) belonging to eight extended, multigenerational Afro‐Caribbean families with mean family size >50 (3535 relative pairs; p < 0.05). Further analysis showed that rs1051886 and rs3741627 were associated with cortical cross‐sectional area, periosteal circumference, and BMC in the radius, such that individuals with the minor alleles had lower biomechanical indices of long‐bone bending strength. This analysis implicates the WNT10B locus as a genetic element in the regulation of bone mass and structural geometry.

Distinct distribution of HPV types among cancer-free Afro-Caribbean women from Tobago

Abstract Human papillomavirus (HPV), a sexually transmitted virus causes cervical carcinomas, and is associated with ∼36% of oropharyngeal tumours where HPV16 is the predominant genotype. The cervical cancer incidence rate in Trinidad and Tobago is about two times higher than the worldwide rate. We have for the first time determined the prevalence and type distribution of cervical HPV infections among cancer-free Afro-Caribbean women from Tobago, and compared it with the HPV subtypes observed in their oral cavity. Thirty-five per cent of the women were cervical HPV positive. The most common high-risk type detected in the cervix was HPV45 rather than HPV16 and 18. The prevalence of HPV infection in the oral mucosa was 6.6%. The distribution of HPV genotypes in healthy Tobagonian women is different from that reported in studies conducted in European and North American populations. This may have important implications for vaccine introduction in this and other Afro-Caribbean countries.

Association of body composition and physical activity with proximal femur geometry in middle-aged and elderly afro-caribbean men: The tobago bone health study

Osteoporotic fractures are less prevalent in African Americans than in caucasians, possibly because of differences in bone structural strength. Bone structural adaptation can be attributed to changes in load, crudely measured as lean and fat mass throughout life. The purpose of this analysis was to describe the associations of leg lean mass, total body fat mass, and hours walked per week with femoral bone mineral density (BMD) and bone geometry in a cross-sectional sample of 1,748 men of African descent between the ages of 40 and 79 years. BMD, section modulus (Z), cross-sectional area (CSA), and subperiosteal width were measured from dual energy X-ray absortiometry (DXA) scans using the hip structural analysis (HSA) program. Multiple linear regression models explained 35% to 48% of the variance in bending (Z) and axial (CSA) strength at the femoral neck and shaft. Independent of all covariates including total body fat mass, one standard deviation increase in leg lean mass was significantly associated with a 5% to 8% higher Z, CSA, and BMD (P < 0.010) at the neck and shaft. The number of hours walked per week was not a strong or consistent independent predictor of bone geometry or BMD. We have shown that weight is the strongest independent predictor of femur BMD and geometric strength although the effect appears to be mediated by lean mass since leg lean mass fraction and total body fat mass fraction had significant and opposing effects at the narrow neck and shaft in this group of middle aged and elderly men.

Comparisons of high-risk cervical HPV infections in Caribbean and US populations

BackgroundDisparities in cervical cancer incidence and mortality rates exist among women of African ancestry (African-American, African-Caribbean and African). Persistent cervical infection with Human papillomavirus (HPV) is associated with cervical dysplasia and if untreated, could potentially progress to invasive cervical cancer. Very few studies have been conducted to examine the true prevalence of HPV infection in this population. Comparisons of cervical HPV infection and the type-specific distribution of HPV were performed between cancer-free Caribbean and US women.ResultsThe Caribbean population consisted of 212 women from Tobago and 99 women from Jamaica. The US population tested, consisted of 82 women from Pittsburgh. The majority of the US subjects was Caucasian, 74% (61/82) while 12% (10/82) and 13% (11/82) were African-American or other ethnic groups, respectively. The age-adjusted prevalence of any HPV infection among women from Tobago was 35%, while for Jamaica, it was 81% (p < 0.0001). The age-adjusted prevalence of HPV infection for Caribbean subjects was not statistically significantly different from the US (any HPV: 47% vs. 39%, p > 0.1; high-risk HPVs: 27% vs. 25%, p > 0.1); no difference was observed between US-Blacks and Jamaicans (any HPV: 92% vs. 81%, p > 0.1; high-risk HPV: 50% vs. 53%, p > 0.1). However, US-Whites had a lower age-adjusted prevalence of HPV infections compared to Jamaican subjects (any HPV: 29% vs. 81%, p < 0.0001; high-risk HPV: 20% vs. 53%, p < 0.001). Subjects from Jamaica, Tobago, and US-Blacks had a higher proportion of high-risk HPV infections (Tobago: 20%, Jamaica: 58%, US-Blacks: 40%) compared to US-Whites (15%). Similar observations were made for the presence of infections with multiple high-risk HPV types (Tobago: 12%, Jamaica: 43%, US-Blacks: 30%, US-Whites: 8%). Although we observed similar prevalence of HPV16 infections among Caribbean and US-White women, there was a distinct distribution of high-risk HPV types when comparisons were made between the ethnic groups.ConclusionThe higher prevalence of cervical HPV infections and multiple high-risk infections in Caribbean and US-Black women may contribute to the high incidence and prevalence of cervical cancer in these populations. Evaluation of a larger sample size is currently ongoing to confirm the distinct distribution of HPV types between ethnic groups.

Adipose Tissue and Volumetric Bone Mineral Density of Older Afro-Caribbean Men

Although low body weight is a risk factor for osteoporosis‐related fractures, conflicting data exist for the association between adiposity and bone mineral density (BMD). Studies examining these relationships have measured body fat and BMD with dual‐energy X‐ray absorptiometry (DXA), which cannot distinguish subcutaneous adipose tissue area (SAT) from total adiposity or trabecular from cortical bone. To investigate the relationship between adiposity and BMD further, we analyzed body composition and adipose tissue distribution by quantitative computed tomography (QCT) in 1829 Afro‐Caribbean men aged 40 years and older from a population‐based sample. Cortical volumetric BMD, muscle cross‐sectional area, total adipose tissue area (TAT), and percentage SAT were measured at the proximal tibia. Trabecular volumetric BMD was measured at the distal tibia. We used analysis of covariance to test for associations between quartile of the adipose tissue measures and BMD, adjusting for anthropometric, health, and lifestyle factors. Higher TAT was associated with lower cortical BMD in both unadjusted and adjusted models (p < .001). Men with a higher percentage SAT had greater cortical BMD (p < .001). Similar associations were seen between percent SAT and trabecular BMD at the distal tibia. These results indicate that total adiposity is a potentially important correlate of bone mass in older men and that different fat depots may have opposing associations with bone mass. Additional research is needed to better understand the mechanisms underlying the relationship between body fat distribution and bone mass.

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.