M.C. Leske

Admixture and Population Stratification in African Caribbean Populations

Throughout biomedical research, there is growing interest in the use of ancestry informative markers (AIMs) to deconstruct racial categories into useful variables. Studies on recently admixed populations have shown significant population substructure due to differences in individual ancestry; however, few studies have examined Caribbean populations. Here we used a panel of 28 AIMs to examine the genetic ancestry of 298 individuals of African descent from the Caribbean islands of Jamaica, St. Thomas and Barbados. Differences in global admixture were observed, with Barbados having the highest level of West African ancestry (89.6%± 2.0) and the lowest levels of European (10.2%± 2.2) and Native American ancestry (0.2%± 2.0), while Jamaica possessed the highest levels of European (12.4%± 3.5) and Native American ancestry (3.2%± 3.1). St. Thomas, USVI had ancestry levels quite similar to African Americans in continental U.S. (86.8%± 2.2 West African, 10.6%± 2.3 European, and 2.6%± 2.1 Native American). Significant substructure was observed in the islands of Jamaica and St. Thomas but not Barbados (K=1), indicating that differences in population substructure exist across these three Caribbean islands. These differences likely stem from diverse colonial and historical experiences, and subsequent evolutionary processes. Most importantly, these differences may have significant ramifications for case‐control studies of complex disease in Caribbean populations.

Risk factors for breast cancer in a black population—The Barbados National Cancer Study†‡§¶

The Barbados National Cancer Study (BNCS) is a nationwide case‐control study investigating environmental and genetic factors for breast cancer (BC) in a predominantly African‐origin population with similar ancestry as African‐Americans. This report evaluates associations of incident BC in the BNCS to various factors, including demographic, anthropometric, reproductive and family history variables, not investigated previously in this population. The BNCS included 241 incident BC cases and 481 age‐matched female controls, with mean ages of 57 and 56 years, respectively. In addition to a reported family history of BC in a close relative [odds ratios (OR) = 3.74, 95% CI (1.41, 9.90) in a parent; OR = 3.26 (1.47, 7.21) in a sibling], other factors associated with BC were older age at first full‐term pregnancy [OR = 1.04 (1.00, 1.07)] and having a history of benign breast disease [OR = 1.88 (1.19, 2.99)]. Increased parity reduced the risk of BC [OR = 0.34 (0.15, 0.77) among those with ≥3 children]. The reproductive patterns of African‐Barbadian (AB) women tended to differ from those of African‐American (AA) women (later age of menarche, earlier age at first pregnancy, higher frequency of lactation and infrequent use of exogenous hormones) and could help to explain their considerably lower postmenopausal incidence of BC. The relationship between reported family history and BC, combined with the associations noted for several reproductive and other variables, supports the genetic and environmental contributions to BC, which may vary in populations across the African diaspora. Further investigations of other populations may clarify these issues.

Breast cancer incidence and mortality in a Caribbean population: Comparisons with African-Americans

We describe breast cancer incidence and mortality in the predominantly African‐origin population of Barbados, which shares an ancestral origin with African‐Americans. Age‐standardized incidence rates were calculated from histologically confirmed breast cancer cases identified during a 45‐month period (July 2002–March 2006). Mortality rates were estimated from death registrations over 10‐years starting January 1995. There were 396 incident cases of breast cancer for an incidence rate of 78.1 (95% confidence interval (CI) 70.5–86.3), standardized to the US population. Breast cancer incidence in African‐Americans between 2000 and 2004 was 143.7 (142.0–145.5) per 100,000. Incidence peaked at 226.6 (174.5–289.4) per 100,000 among Barbadian women aged 50–54 years, and declined thereafter, a pattern in marked contrast to trends in African‐American women, whose rates continued to increase to a peak of 483.5 per 100,000 in those aged 75–79 years. Incidence rate ratios comparing Barbadian and African‐American women showed no statistically significant differences among women aged ≥ 55 years (p ≤ 0.001 at all older ages). The age‐standardized mortality rate in Barbados was 32.9 (29.9–36.0) per 100,000; similar to reported US rates. The pattern of diverging breast cancer incidence between Barbadian and African‐American women may suggest a greater contribution from genetic factors in younger women, and from environmental factors in older women. Studies in intermediate risk populations, such as Barbados, may assist the understanding of racial disparities in breast cancer.

Assessing dietary patterns in Barbados highlights the need for nutritional intervention to reduce risk of chronic disease.

BACKGROUND The dietary habits of the Caribbean have been changing to include more fast foods and a less nutrient dense diet. The aims of this study are to examine dietary patterns in Barbados and highlight foods for a nutritional intervention. METHODS Four-day food diaries collected from control participants in the population-based, case-control Barbados National Cancer Study (BNCS). RESULTS Forty-nine adult participants (91% response) completed the diaries providing 191 days of dietary data. Total energy intake was almost identical to data collected 5-years earlier in the Barbados Food Consumption and Anthropometric Survey 2000, but the percent energy derived from fat was from 2.1% to 5.2% higher. Sugar intake exceeded the Caribbean recommendation almost four-fold, while intakes of calcium, iron (women only), zinc and dietary fibre were below recommendations. Fish and chicken dishes were the two largest sources of energy and fat. Sweetened drinks and juices provided over 40% of total sugar intake. CONCLUSIONS These data provide existing dietary patterns and strongly justify a nutritional intervention program to reduce dietary risk factors for chronic disease. The intervention could focus on the specific foods highlighted, both regarding frequency and amount of consumption. Effectiveness can be evaluated pre- and post-intervention using our Food Frequency Questionnaire developed for BNCS.

Fine-mapping of Breast Cancer Genome-wide Association Studies Loci in Women of African Ancestry Identifies Novel Susceptibility Markers

Numerous single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified by genome-wide association studies (GWAS). However, these SNPs were primarily discovered and validated in women of European and Asian ancestry. Because linkage disequilibrium is ancestry-dependent and heterogeneous among racial/ethnic populations, we evaluated common genetic variants at 22 GWAS-identified breast cancer susceptibility loci in a pooled sample of 1502 breast cancer cases and 1378 controls of African ancestry. None of the 22 GWAS index SNPs could be validated, challenging the direct generalizability of breast cancer risk variants identified in Caucasians or Asians to other populations. Novel breast cancer risk variants for women of African ancestry were identified in regions including 5p12 (odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.11-1.76; P = 0.004), 5q11.2 (OR = 1.22, 95% CI = 1.09-1.36; P = 0.00053) and 10p15.1 (OR = 1.22, 95% CI = 1.08-1.38; P = 0.0015). We also found positive association signals in three regions (6q25.1, 10q26.13 and 16q12.1-q12.2) previously confirmed by fine mapping in women of African ancestry. In addition, polygenic model indicated that eight best markers in this study, compared with 22 GWAS-identified SNPs, could better predict breast cancer risk in women of African ancestry (per-allele OR = 1.21, 95% CI = 1.16-1.27; P = 9.7 × 10(-16)). Our results demonstrate that fine mapping is a powerful approach to better characterize the breast cancer risk alleles in diverse populations. Future studies and new GWAS in women of African ancestry hold promise to discover additional variants for breast cancer susceptibility with clinical implications throughout the African diaspora.

Lack of association between common single nucleotide polymorphisms in the TERT-CLPTM1L locus and breast cancer in women of African ancestry.

As one of the most common cancers worldwide, breast cancer places an extraordinary burden on the populations of African ancestry. Common SNPs in the TERT-CLPTM1L locus have been reported to be associated with several types of cancer, including breast cancer. We sought to investigate whether the previously reported common single nucleotide polymorphisms (SNPs) in the TERT-CLPTM1L locus could also contribute to the breast cancer risk in women of African ancestry. We genotyped eleven SNPs in 2,892 women of African descent but were unable to detect any significant association between TERT-CLPTM1L SNPs and their predispositions for breast cancer risk. Given the differences in linkage disequilibrium patterns across populations, our findings suggest that larger independent studies from diverse populations are expected to evaluate the importance of the TERT-CLPTM1L locus in breast cancer.

Abstract B11: Replication of previously identified breast cancer susceptibility loci in a breast cancer case-control study on women of African ancestry

To date, more than 100 single nucleotide polymorphisms (SNPs) have been found to be associated with breast cancer susceptibility in large genome-wide association studies (GWAS) conducted predominantly in women of European and Asian ancestries. To identify breast cancer susceptibility alleles in populations of African ancestry, we performed a GWAS in 3,686 subjects from Nigeria, Barbados and the United States (Baltimore, Chicago, Detroit, Philadelphia and the Southern Community Cohort Study), using the Illumina HumanOmni2.5 array. Using stringent quality control criteria, a total of 1,657 cases (777 with known estrogen receptor [ER] status) and 2,029 controls were successfully genotyped for 2,116,365 SNPs. Subsequently, imputation was conducted using reference panels from The 1000 Genomes Project and logistic regression models controlling age and global ancestry were applied to examine the association of 78 known breast cancer GWAS index SNPs and 44 iCOGS (Illumina iSelect genotyping array for Collaborative Oncological Gene-Environment Study) SNPs with breast cancer risk in our study population. Only 4 SNPs were statistically significant (unadjusted P Citation Format: Yonglan Zheng, Dezheng Huo, Temidayo O. Ogundiran, Adeyinka G. Falusi, Oladosu Ojengbede, Clement Adebamowo, William J. Blot, Wei Zheng, Qiuyin Cai, Lisa B. Signorello, Katherine L. Nathanson, Susan M. Domchek, Timothy R. Rebbeck, Michael S. Simon, Anselm J.M. Hennis, Barbara Nemesure, Suh-Yuh Wu, Maria Cristina Leske, Stefan Ambs, Abayomi Odetunde, Imaria Anetor, Stella Akinleye, Qun Niu, Jing Zhang, Anna Pluzhnikov, Anuar Konkashbaev, Lin Chen, Eric R. Gamazon, Younghee Lee, Nancy J. Cox, Olufunmilayo O. Olopade. Replication of previously identified breast cancer susceptibility loci in a breast cancer case-control study on women of African ancestry. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B11. doi:10.1158/1538-7755.DISP13-B11