Serigne M. Gueye

Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21

In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study, with 1,047,986 SNP markers examined in 3,425 African-Americans with prostate cancer (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations from stage 1 in 1,844 cases and 3,269 controls of African ancestry. We identified a new risk variant on chromosome 17q21 (rs7210100, odds ratio per allele = 1.51, P = 3.4 × 10−13). The frequency of the risk allele is ∼5% in men of African descent, whereas it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting genome-wide association studies in diverse populations.

Ethnic Differences in the Frequency of Prostate Cancer Susceptibility Alleles at SRD5A2 and CYP3A4

Objectives: Ethnic differences in prostate cancer incidence are well documented, with African-Americans having among the highest rates in the world. Ethnic differences in genotypes for genes associated with androgen metabolism including SRD5A2 and CYP3A4 also may exist. The aim of this study was to evaluate differences in these genotypes by ethnicity. Methods: We studied cancer-free controls representative of four groups: 147 African Americans, 410 Caucasian-Americans, 129 Ghanaians, and 178 Senegalese. PCR-based genotype analysis was undertaken to identify two alleles (V89L, A49T) at SRD5A2 and *1B allele at CYP3A4. Results: Differences were observed for V89L (variant frequency of 30% in Caucasians, 27% in African Americans, 19% in Ghanaians, and 18% in Senegalese, p = 0.002) and were observed for CYP3A4*1B (variant frequencies of 8% in Caucasians, 59% in African Americans, 81% in Ghanaians, and 78% in Senegalese, p = 0.0001). Pooled data combining the present data and previously published data from from Asian, Hispanic, and Arab cancer-free controls showed significant ethnic differences for SRD5A2 and CYP3A4 polymorphisms. Overall, Asians were least likely to have alleles associated with increased prostate cancer risk, while Africans were most likely to have those alleles. Conclusions: These results suggest that ethnicity-specific differences in genotype frequencies exist for SRD5A2 and CYP3A4. Africans and African-Americans have the highest frequency of those alleles that have previously been associated with increased prostate cancer risk. Future studies should address whether allele frequency differences in part explain differences in prostate cancer incidence in these populations.

Global Patterns of Prostate Cancer Incidence, Aggressiveness, and Mortality in Men of African Descent

Prostate cancer (CaP) is the leading cancer among men of African descent in the USA, Caribbean, and Sub-Saharan Africa (SSA). The estimated number of CaP deaths in SSA during 2008 was more than five times that among African Americans and is expected to double in Africa by 2030. We summarize publicly available CaP data and collected data from the men of African descent and Carcinoma of the Prostate (MADCaP) Consortium and the African Caribbean Cancer Consortium (AC3) to evaluate CaP incidence and mortality in men of African descent worldwide. CaP incidence and mortality are highest in men of African descent in the USA and the Caribbean. Tumor stage and grade were highest in SSA. We report a higher proportion of T1 stage prostate tumors in countries with greater percent gross domestic product spent on health care and physicians per 100,000 persons. We also observed that regions with a higher proportion of advanced tumors reported lower mortality rates. This finding suggests that CaP is underdiagnosed and/or underreported in SSA men. Nonetheless, CaP incidence and mortality represent a significant public health problem in men of African descent around the world.

Clinical characteristics of prostate cancer in African Americans, American whites, and Senegalese men☆

OBJECTIVES To describe the clinical features of prostate cancer in Senegalese men and compare these features with those found in African-American and white American men. METHODS We identified an unselected series of 121 patients with prostate cancer diagnosed at two hospitals in Dakar, Senegal between 1997 and 2002. Medical record abstractions were undertaken to evaluate the prostate tumor characteristics, patient age at diagnosis, prostate-specific antigen (PSA) levels, and reason for referral. In addition, these characteristics were compared with a sample of 455 U.S. white men and 60 African-American men with prostate cancer who were studied as part of a prostate cancer case-control study. RESULTS Senegalese men had a significantly worse tumor stage than Americans (41.3% versus 18.8%, P <0.001), a significantly worse mean PSA level at diagnosis (mean PSA 72.7 ng/mL versus 9.0 ng/mL in Americans; P <0.001), and were diagnosed at a significantly later age than U.S. men (69 years versus 61 years, P <0.001). U.S. men were most likely to be diagnosed with prostate cancer after an elevated PSA test, and Senegalese men were most often diagnosed after presenting for prostate-related symptoms. CONCLUSIONS These observations are not unexpected given the differences in the patterns of prostate cancer screening and health care in the United States compared with Senegal. However, our data provide descriptive information about the characteristics of prostate cancer diagnosed in Senegal and highlight differences in the characteristics and detection of these tumors across populations with very different healthcare systems.

A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta

Purpose:Deficiency of prolyl 3-hydroxylase 1, encoded by LEPRE1, causes recessive osteogenesis imperfecta (OI). We previously identified a LEPRE1 mutation exclusively in African Americans and contemporary West Africans. We hypothesized that this allele originated in West Africa and was introduced to the Americas with the Atlantic slave trade. We aimed to determine the frequency of carriers for this mutation among African Americans and West Africans, and the mutation origin and age.Methods:Genomic DNA was screened for the mutation using PCR and restriction digestion, and a custom TaqMan genomic single-nucleotide polymorphism assay. The mutation age was estimated using microsatellites and short tandem repeats spanning 4.2 Mb surrounding LEPRE1 in probands and carriers.Results:Approximately 0.4% (95% confidence interval: 0.22–0.68%) of Mid-Atlantic African Americans carry this mutation, estimating recessive OI in 1/260,000 births in this population. In Nigeria and Ghana, 1.48% (95% confidence interval: 0.95–2.30%) of unrelated individuals are heterozygous carriers, predicting that 1/18,260 births will be affected with recessive OI, equal to the incidence of de novo dominant OI. The mutation was not detected in Africans from surrounding countries. All carriers shared a haplotype of 63–770 Kb, consistent with a single founder for this mutation. Using linkage disequilibrium analysis, the mutation was estimated to have originated between 650 and 900 years before present (1100–1350 CE).Conclusion:We identified a West African founder mutation for recessive OI in LEPRE1. Nearly 1.5% of Ghanians and Nigerians are carriers. The estimated age of this allele is consistent with introduction to North America via the Atlantic slave trade (1501–1867 CE).Genet Med 2012:14(5):543–551

Evaluation of Group Genetic Ancestry of Populations from Philadelphia and Dakar in the Context of Sex-Biased Admixture in the Americas

Background Population history can be reflected in group genetic ancestry, where genomic variation captured by the mitochondrial DNA (mtDNA) and non-recombining portion of the Y chromosome (NRY) can separate female- and male-specific admixture processes. Genetic ancestry may influence genetic association studies due to differences in individual admixture within recently admixed populations like African Americans. Principal Findings We evaluated the genetic ancestry of Senegalese as well as European Americans and African Americans from Philadelphia. Senegalese mtDNA consisted of ∼12% U haplotypes (U6 and U5b1b haplotypes, common in North Africa) while the NRY haplotypes belonged solely to haplogroup E. In Philadelphia, we observed varying degrees of admixture. While African Americans have 9–10% mtDNAs and ∼31% NRYs of European origin, these results are not mirrored in the mtDNA/NRY pools of European Americans: they have less than 7% mtDNAs and less than 2% NRYs from non-European sources. Additionally, there is <2% Native American contribution to Philadelphian African American ancestry and the admixture from combined mtDNA/NRY estimates is consistent with the admixture derived from autosomal genetic data. To further dissect these estimates, we have analyzed our samples in the context of different demographic groups in the Americas. Conclusions We found that sex-biased admixture in African-derived populations is present throughout the Americas, with continual influence of European males, while Native American females contribute mainly to populations of the Caribbean and South America. The high non-European female contribution to the pool of European-derived populations is consistently characteristic of Iberian colonization. These data suggest that genomic data correlate well with historical records of colonization in the Americas.

Androgen Metabolism Gene Polymorphisms, Associations with Prostate Cancer Risk and Pathological Characteristics: A Comparative Analysis between South African and Senegalese Men

Prostate cancer is the most common cancer in men in developed countries and the leading cause of mortality in males in less developed countries. African ethnicity is one of the major risk factors for developing prostate cancer. Pathways involved in androgen metabolism have been implicated in the etiology of the disease. Analyses of clinical data and CYP3A4, CYP3A5, and SRD5A2 genotypes were performed in South African White (120 cases; 134 controls), Mixed Ancestry (207 cases; 167 controls), and Black (25 cases; 20 controls) men, as well as in Senegalese men (86 cases; 300 controls). Senegalese men were diagnosed earlier with prostate cancer and had higher median PSA levels compared to South African men. Metastasis occurred more frequently in Senegalese men. Gene polymorphism frequencies differed significantly between South African and Senegalese men. The CYP3A4 rs2740574 polymorphism was associated with prostate cancer risk and tumor aggressiveness in South African men, after correction for population stratification, and the SRD5A2 rs523349 CG genotype was inversely associated with high-stage disease in Senegalese men. These data suggest that variants previously associated with prostate cancer in other populations may also affect prostate cancer risk in African men.

Screening for Prostate Cancer by Digital Rectal Examination and PSA Determination in Senegal

Objectives. The goal of our study was to investigate the prevalence of prostate cancer in an unselected population of Senegalese men. Patients and Methods. We conducted the study over two years (2008 and 2009) on an unselected population of 572 Senegalese men, aged 35 and older. The following parameters have been investigated: the subjects age, the presence or absence of urination disorders, the familys history of prostate cancer or prostate surgery, the aspects of the prostate on digital rectal examination (DRE), the total PSA level, and the outcomes of the prostate biopsies. Data entry was performed with Epi Info 6 software and was analyzed and recorded using Excel software. We performed mean and frequency calculations. Results. The mean age of our patients was 65.5 years, with extremes of 38 and 93 years. Age groups from 50 to 59 and from 60 to 69 were the most represented. DRE was normal in the age group from 35 to 39, and only one patient in the age group from 40 to 49 had a prostate nodule. PSA level was greater than or equal to 4 ng/mL in 66 cases. A total of 5.4% patients had a PSA level greater than or equal to 10 ng/mL. Only two patients in the age group from 40 to 49 had a PSA level greater than 4 ng/mL. Of the 72 biopsies we performed, prostatic adenocarcinoma was found in 30.6% of the cases. It is the only type of prostate cancer we found in our series. The cases of prostate cancer were mostly observed in the age groups from 60 to 69 and from 70 to 79. No cases were detected for ages younger than 50. DRE gave indications of possible adenocarcinoma in 27.30% cases. Its sensitivity was 27%, while its positive predictive value was estimated at 35%. Of all positive biopsies, 4.5% had a PSA level between 0 and 3.9 ng/mL. In this case, the sensitivity of PSA was 95.5%, and the positive predictive value was 31.8%. High-grade intraepithelial neoplasiae were observed in 21 cases. Conclusion. Prostate cancer is frequent in Senegal, and screening remains the best way for early diagnosis.

Dietary intake of Senegalese adults

The aim of this work is to identify major food sources and dietary constituents of Senegalese adults. We conducted a cross-sectional study, using a single 24-hour dietary recall interview. Foods were classified into food groups based on similarities in nutrient content or use. Food groups included foods consumed individually, or as part of food mixtures such as stews, soups, or sandwiches. Median consumption (amount/day) of each food was determined and examined by relevant subgroups. Participants were 50 healthy Senegalese men, aged 20-62 years recruited at the Hôpital Général de Grand Yoff in Dakar, Senegal and from Sendou village, a rural area outside Dakar. A total of 90 foods and beverages were identified and classified into 11 groups. Sixty-five percent of foods identified could be classified as meats, grains, or fruits/vegetables. Fruits and vegetables comprised 42% (38/90) of all foods; meats 12% (11/90); and grains 11% (10/90). Sauces (6%, 5/90), sweets (4%, 4/90), and desserts (4%, 4/90) were also reported. The most common fruits/vegetables reported were potato, carrot, mango, and lettuce; commonly reported grains were bread and rice; and commonly reported meats were fish, beef, and ox. There were no differences in reported daily intake of each food by age, ethnicity, education, or residence. Most foods reported were traditional to the Senegalese diet, despite the increasing availability of Western foods in Senegal.

Premiers résultats de la cœlioscopie gynécologique au Centre hospitalier universitaire (CHU) de Dakar : série prospective de 128 cas

OBJECTIVES To analyze the results of, and to evaluate, gynaecologic laparoscopy in Dakar Teaching Hospital. METHODS This exploratory and descriptive study deals with a continuous series of 128 gynaecologic laparoscopies carried out between January 1, 2006, and December 31, 2009. In each operative case, sociodemographic and clinical parameters,operative data, and outcomes were studied. RESULTS Laparoscopies represented 14.37% of the programmed operative activities. The average age of the patients was 32 years,and the average parity was 1.2. The interventions were most frequently undertaken because of infertility (78.9%). A history of pelvic infections was found in 39.8% of the cases. The most frequent pathologies were tubal anomalies (70% of infertility cases) followed by ovarian cysts (10.1%) and endometriosis. The operative interventions included adhesiolysis in 35.1% of cases,and tubal surgery in 30.4%. A conversion, necessary in 7% of cases, was necessitated by the extent of adhesions (3 cases),the treatment of an associated pathology (4 cases), or a technical difficulty (2 cases).The main complications were vascular wounds and uterine perforations. The average operating times for diagnostic and operative laparoscopies were 56 minutes and 107 minutes,respectively. Outcomes were simple in 91.8% of cases. During the immediate postoperative period, a death occurred due to an acute pneumopathy. The average length of hospital stay was 3 days. We observed a pregnancy rate of 4.6%. Assisted reproduction was indicated in 28.7% of infertility cases. CONCLUSION Given its many advantages, diagnostic and operative laparoscopy must be integrated and developed by gynaecology departments in developing countries. This necessity is emphasized by the prevalence of tubal infertility of infectious origins, which, if diagnosed and treated early by laparoscopy,could have a better prognosis.