28 Apr

AFRICAN-AMERICAN HEREDITY PROSTATE CANCER STUDY: A MODEL FOR GENETIC RESEARCH

genetic1Investigators from the National Human Genome Research Institute (NHGRI) and Johns Hopkins University reported the results of a genome-wide scan on 91 high-risk prostate cancer families in North America and Sweden; two of these families were African American. Of the 91 families studied, approximately one-third showed linkage to an area on Chromosome lq (HPC1), including both of the African-American families. In an independent set of 20 families fulfilling the criteria for HPC, Cooney et al. confirmed that Chromosome lq 24-25 is likely to contain a prostate cancer susceptibility gene. The six African-American families in their study contributed disproportionately to the observation of link¬age. Although the majority of affected subjects studied have not been African Americans, the available data suggest that Hereditary Prostate Cancer (HPC) in some African Americans is linked to a locus on Chromosome l. canadian pharmacy

The results of a genome-wide scan using high-risk families from France and Germany suggested the existence of a second autosomal prostate cancer susceptibility locus at lq42 prostate cancer predisposing (PCAP). Additionally, Xu et al. published linkage of prostate cancer to Xq28 in a subset of families, including some families from the original genome-wide scan reported by Smith et al. With this in mind, HPC1 (lq24), HPCX (Xq28), and PCAP (lq42) are the genomic regions of focus for our initial DNA analysis. canadian health viagra

In 1997, investigators at the NHGRI in collaboration with Howard University and a predominantly African-American group of urologists involved in prostate cancer research established the African American Hereditary Prostate Cancer (AAHPC) Study Network. This Network of Collaborative Recruitment Centers (CRCs) in seven major metropolitan areas was formed primarily to increase the number of AAHPC families for genetic studies designed to confirm the suggested linkage of HPC in African Americans with a gene on chromosome 1 and to conduct a genome-wide search for other loci associated with HPC in African American men. Within two years of being established, the AAHPC Study Network has substantially increased the number of AAHPC families reported in previous genetic linkage studies. The AAHPC collection of more than 40 families with at least four first-degree relatives diagnosed with prostate cancer is an invaluable resource not only for assessing population-based differences in the prevalence of linkage to putative HPC genes lq24-25, lq42 and HPC x, but also for mapping other yet undefined genetic predispositions to prostate cancer and for evaluating the association of different clinical phenotypes with genetic variations. canadian pharmacy levitra

METHODS
Study Organization and Design

This is a national cooperative study composed of CRCs geographically located in areas highly populated with African-American families, including Atlanta, GA; Chicago, IL; Detroit, MI; Houston, TX; New York, NY and Columbia, SC. Provision for the recruitment of African-American families from other geographical locations is made through a national referral strategy. In addition to the focus on increasing the number of African-American families in genome studies, the AAHPC Study Network involves the largest group of African-American biomedical scientists collaborating on a genetic study of a common, complex disease in African Americans. Over 90% of the CRC directors and study coordinators are African Americans with a demonstrated ability to recruit African Americans for other studies. African American investigators at the Coordinating Center have successfully recruited African-American families for other genome studies. The molecular geneticist conducting the genotyping and genetic sequence analyses at the NHGRI, NIH, is also African American. Because of the sensitive nature of this study and the need to gain the trust of the African-American community, we felt it was important that African Americans should control not only the ascertainment of families but also the use of the samples, data interpretation and application of resources. This belief stems from the mistrust of the African-American community toward the scientific community due to prior exploitation, as exemplified by the infamous “Tuskegee Study.” cialis professional cheap

The AAHPC Steering Committee is composed of project directors from each CRC; the program director and project coordinator from the Coordinating Center, and the molecular geneticist and other key collaborators from the NHGRI. The Steering Committee provides expertise and guidance in the scientific, clinical and ethical responsibilities of the Study Network; monitors progress of the study, and reviews the results before they are published.

The selection of prospective families begins with the identification of prostate cancer probands or index cases in families with a history of prostate cancer. Families are eligible for the study if they have a minimum of four men clinically diagnosed with prostate cancer and three are alive and available for genetic testing. A diagram of the family pedigree is submitted to the project coordinator at the coordinating center for eligibility approval. The average age of affected men in a family must be 65 years or younger and they must be from one side of the family. Eight family members are required to participate for eligibility of the family. Men and women must be over the age of 18 years. Women are included because they may be carriers of the gene(s). Once a family is approved, an informed consent form is signed, clinical and family history obtained, and blood samples are drawn and sent to the Coordinating Center. Strict confidentiality is maintained, whereby the DNA samples being tested have no personal identifiers. Information remains at the CRC, where the project director and study coordinators keep in under lock and key. DNA is extracted from blood samples at the coordinating center and shipped to the NHGRI where scientists will genotype individual DNA samples with a set of DNA markers whose position in the genome has been mapped. Genotype data are merged with pedigree information so that statistical analysis can be performed to establish potential linkage of a particular marker with the prostate cancer phenotype. Statisticians at the NHGRI will perform the latter studies. cialis professional canada

RESULTS
From March 1, 1998, to July 1, 1999, 3400 people responded to the study. Sixty-three African-American families met the study criteria and 43 families participated. The mean age of men affected with prostate cancer is 60.4. The average number of men affected per family is 5.1 (Table 1). DNA from 221 samples was analyzed for linkage to HPC 1 and HPCX in the first phase of genotyping. canadian pharmacy generic viagra

Table 1. AAHPC Clinical Summary

No. of

Mean age

No.

No. of recruits

men affected

at diagnosis

families

sampled

per family

(yr)

43

221

5.1

60.4

The preliminary results reported in the literature are shown in Table 2. Linkage represents an odds ratio, with the ratio being the probability of two loci being linked versus those same two loci not being linked. The log 10 of this ratio is known as the LOD score. The higher the LOD score, the greater chance of linkage. In general terms, do the affected individuals in a family “share” a similar pattern of genetic markers through a region of the genome that is not “shared” in the unaffected members of that family? Random sharing will occur among nuclear family members because there is a 50/50 chance of inheriting either of two copies of a DNA marker (i.e., allele, gene) from the parents. The power in a linkage study comes from seeing sharing in the same region of the genome across many families. If the same region is shared among af¬fected individuals only, in a large set of families, this usually represents linkage of that region, or locus, to the disease phenotype. Cialis Soft Tabs

Table 2. Genes Linked to PCa (Hereditary PCa)

HPC 1

PCAP

Ethnicity Ц24-25

lq42.2 43

HPx

African American

>50%

co-

0%

White

34%

co-

15%

French

16%

50%

?

DISCUSSION
Preliminary data suggest population-based genetic differences in prevalence of HPC genes. Thus far, the results demonstrate a greater prevalence of linkage among African Americans compared to whites on Chromosome lq24. However, the established linkage to chromosome Xq27 among whites has not been identified among blacks in this preliminary investigation. In addition, European studies of French and German population groups have suggested a prostate cancer susceptibility locus (linkage) at lq42. They were unable to confirm linkage to Chromosome lq24. There was evidence of linkage to lq42 in the initial genome-wide scans at NHGRI, but when more families were analyzed with additional markers, the linkage was no longer found. In addition, linkage to lq42 was also not demonstrated by Gibbs et al. Cialis Super Active

Although linkage of HPC to Chromosome lq24 has been confirmed by three centers in this country, two other centers have not been able to confirm linkage. Our explanation for this difference is based on the hypothesis that the more men affected with PCa in a family, the greater the chance linkage will be found. As shown in Table 2, country of origin and racial group also affect the incidence and extent of linkage of prostate cancer to specific loci.

Heterogeneity within the white population may be just as prevalent as heterogeneity is among African Americans and between blacks and whites. If we continue to find no alteration or linkage to chromosome Xq27 among African Americans, it will strengthen the argument for population-associated genes in common, complex diseases such as prostate cancer. The importance of these findings lays in the future treatment of genetic-based diseases. Viagra 400 mg
The ultimate goal of medical care is prevention.
If common diseases are found to have a genetic basis, it becomes extremely important to identify the specific alterations or mutations in specific populations in order to design effective intervention and prevention strategies. More specifically, the objective will be to block the expression of the gene along its specific pathway from DNA to RNA to protein. There will be no attempt to change the DNA of hereditary diseases for fear that it may have some negative impact on future generations. Cialis Professional online

African-American Resistance to Research Studies
Although we have achieved greater success in recruiting African-American families than other groups, we have nevertheless encountered some resistance to participation in this study. The resistance to participation appears to be greater among northern than southern sites. Also, northern families seem to be more dispersed than southern families. Other barriers include: fear of experimentation; fear of information being used against African Americans; and concerns about other research being performed with tissue without their knowledge. Confidential issues include fear of information being discovered by insurance companies and employers. Finally, some families have expressed a concern about cancer information being disseminated even within the family. This is problematic because obtaining a reliable history of prostate cancer becomes difficult and it also inhibits the dissemination of education about cancer in such families. canadian health care + tramadol

In our study, we have made every attempt to eliminate the above barriers and others that we discover in the process. There is a major attempt to encourage Congress to provide legislative protection for people with hereditary disease predisposition against job and insurance discrimination. However, whether or not such changes occur, strict confidentiality efforts will be maintained. cialis super active

CONCLUSION
Overall, the AAHPC study represents a successful model for recruitment of African Americans to clinical scientific studies and trials. We believe we have also established a model to build trust in the African-American community toward the scientific community. This model can be adopted for other diseases that disproportionately affect African Americans; and we would certainly encourage such an effort. It is time for African-American physicians and scientists to work to¬gether so that we may have a greater impact on the interpretation of data and conclusions that affect the African-American community. The more we become involved in the scientific process and the acquisition of knowledge, the greater the influence we will have on health policy and health care. cheap levitra

We look forward with promise to the wealth of scientific data to be derived from this study. We encourage and challenge other African-American physicians and scientists to form collaborative groups to answer scientific questions, to develop an authoritative knowledge base and become a major factor in health care decision-making. More importantly, we would like to strongly encourage black physicians to help us recruit more families. In order to reach any genetic conclusions about disease and ethnicity links, we need more African-American participation on two levels—patients and investigators. order cialis professional

ACKNOWLEDGMENT
This work was supported by contract HG 75418 from the National Human Genome Research Institute.

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