BCL11A enhancer haplotypes and fetal hemoglobin in sickle cell anemia.

BACKGROUND: Fetal hemoglobin (HbF) levels in sickle cell anemia patients vary. We genotyped polymorphisms in the erythroid-specific enhancer of BCL11A to see if they might account for the very high HbF associated with the Arab-Indian (AI) haplotype and Benin haplotype of sickle cell anemia. METHODS AND RESULTS: Six BCL112A enhancer SNPs and their haplotypes were studied in Saudi Arabs from the Eastern Province and Indian patients with AI haplotype (HbF ~20%), African Americans (HbF ~7%), and Saudi Arabs from the Southwestern Province (HbF ~12%). Four SNPs (rs1427407, rs6706648, rs6738440, and rs7606173) and their haplotypes were consistently associated with HbF levels. The distributions of haplotypes differ in the 3 cohorts but not their genetic effects: the haplotype TCAG was associated with the lowest HbF level and the haplotype GTAC was associated with the highest HbF level and differences in HbF levels between carriers of these haplotypes in all cohorts were approximately 6%. CONCLUSIONS: Common HbF BCL11A enhancer haplotypes in patients with African origin and AI sickle cell anemia have similar effects on HbF but they do not explain their differences in HbF.

Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

Background: Emerging evidence suggests that a number of factors can influence blood-based biomarker levels for Alzheimer's disease (AD) and Alzheimer's related dementias (ADRD). We examined the associations that demographic and clinical characteristics have with AD/ADRD blood-based biomarker levels in an observational continuation of a clinical trial cohort of older individuals with type 2 diabetes and overweight or obesity. Methods: Participants aged 45-76 years were randomized to a 10-year Intensive Lifestyle Intervention (ILI) or a diabetes support and education (DSE) condition. Stored baseline and end of intervention (8-13 years later) plasma samples were analyzed with the Quanterix Simoa HD-X Analyzer. Changes in Aß42, Aß40, Aß42/Aß40, ptau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were evaluated in relation to randomization status, demographic, and clinical characteristics. Results: In a sample of 779 participants from the Look AHEAD cohort, we found significant associations between blood-based biomarkers for AD/ADRD and 15 of 18 demographic (age, gender, race and ethnicity, education) and clinical characteristics (APOE, depression, alcohol use, smoking, body mass index, HbA1c, diabetes duration, diabetes treatment, estimated glomerular filtration rate, hypertension, and history of cardiovascular disease) . Conclusions: Blood-based biomarkers of AD/ADRD are influenced by common demographic and clinical characteristics. These factors should be considered carefully when interpreting these AD/ADRD blood biomarker values for clinical or research purposes.

Erratum to: Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

[This corrects the article DOI: 10.14283/jarlife.2024.1.].

What would you do? Specialists' perspectives on cancer genetic testing, prophylactic surgery, and insurance discrimination.

PURPOSE: To examine what cancer genetics specialists predict they would do personally if they were at 50% risk of carrying a mutation that predisposes to hereditary breast/ovarian cancer (BRCA1/BRCA2) and hereditary nonpolyposis colon cancer (HNPCC). METHODS: Questionnaire survey of the membership of the National Society of Genetic Counselors (NSGC) Special Interest Group (SIG) in Cancer. RESULTS: Of the 296 active members of the NSGC Cancer-SIG surveyed, 163 (55%) responded. Eighty-five percent predicted that if they had a 50% risk of carrying a BRCA1/BRCA2 mutation, they would pursue genetic testing. If they tested positive for a mutation at age 35, 25% predicted they would pursue prophylactic bilateral mastectomies and 68%, prophylactic oophorectomy. Ninety-one percent of respondents believe they would pursue genetic testing for HNPCC, and 17% would elect prophylactic colectomy; 54%, prophylactic hysterectomy; and 52%, prophylactic oophorectomy if they tested positive for a mutation. The majority (68%) would not bill their insurance companies for genetic testing because of fear of discrimination, and 26% would use an alias when undergoing testing. Fifty-seven percent of counselors would seek professional psychologic support to help them cope with the results of testing. CONCLUSION: A large percentage of cancer genetic counseling providers predicted they would opt for prophylactic surgery at a young age if they carried a BRCA or HNPCC mutation, and most would seek professional psychologic assistance when undergoing testing. More than half of respondents would not bill their insurance companies for genetic testing, largely because of fear of genetic discrimination. The vast majority of those providers most familiar with cancer genetic testing and its associated medical, psychologic, and legal implications would still pursue genetic testing.

Writing Effective Insurance Justification Letters for Cancer Genetic Testing: A Streamlined Approach.

The topic of insurance coverage and justification letters for cancer predisposition testing has been the subject of much discussion on the National Society of Genetic Counselors Cancer Special Interest Group (NSGC Cancer-SIG) listserv. Some counselors have stated that they have had difficulty in obtaining insurance coverage for their patients, while others have indicated that they would appreciate seeing examples of successful letters. The purpose of this paper is to provide practical guidance in writing successful letters of justification and to share insurance success stories in the area of cancer genetic testing.

Enhanced expression of cyclooxygenase-2 in high grade human transitional cell bladder carcinomas.

Studies in human and animal models have shown that cyclooxygenase (COX)-2 is up-regulated in several epithelial carcinomas including colon, breast, and lung. To elucidate the possible involvement of COX-2 in human bladder cancer we examined the expression of COX isoforms in benign tissue and in bladder carcinoma specimens. Paraffin embedded tissues from 75 patients with urothelial carcinomas were immunostained with specific antibodies raised against COX-1 and COX-2. COX-1 expression was detected in smooth muscle cells in both benign and malignant bladders. COX-2 immunoreactivity was absent in benign tissue and in specimens with low-grade urothelial carcinoma (0/23). In contrast, expression of COX-2 was detected in malignant epithelial cells in 38% (17/47) of specimens with high-grade urothelial carcinomas. Expression of COX-2 in high-grade bladder cancer was confirmed by radioactive in situ hybridization using a COX-2-selective riboprobe. Both immunohistochemistry and in situ hybridization showed COX-2 expression in a small subset of malignant cells. COX-2 mRNA was also expressed in three out of seven malignant urothelial cell lines. These data demonstrate elevated expression of COX-2 in a high percentage of high-grade bladder carcinomas, suggesting a possible role of COX-2 in the progression of bladder urothelial carcinoma and supporting its potential as a therapeutic target in human bladder carcinoma.