Ronald T. Acton

Genetic Cancer Risk Assessment and Counseling: Recommendations of the National Society of Genetic Counselors

These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in this document is derived from extensivereview of the current literature on cancer genetic risk assessment and counseling as well as the personal expertise of genetic counselors specializing in cancer genetics. The recommendations are intended to provid information about the process of genetic counseling and risk assessment for hereditary cancer disorders rather than specific information about individual syndromes. Key components include the intake (medical and family histories), psychosocial assessment (assessment of risk perception), cancer risk assessment (determination and communication of risk), molecular testing for hereditary cancer syndromes (regulations, informed consent, and counseling process), and follow-up considerations. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care providers professional judgment based on the clinical circumstances of a client.

Influence of CYP2C9 and VKORC1 1173C/T Genotype on the Risk of Hemorrhagic Complications in African-American and European-American Patients on Warfarin

The association of CYP2C9 and VKORC1 1173C/T genotype and risk of hemorrhage among African Americans and European Americans is presented. This association was evaluated using Cox proportional hazard regression with adjustment for demographics, comorbidity, and time‐varying covariates. Forty‐four major and 203 minor hemorrhages occurred over 555 person‐years among 446 patients (60.6±15.6 years, 50% men, 227 African Americans). The variant CYP2C9 genotype conferred an increased risk for major (hazard ratio (HR) 3.0; 95% confidence interval (CI): 1.1–8.0) but not minor (HR 1.3; 95% CI: 0.8–2.1) hemorrhage. The risk of major hemorrhage was 5.3‐fold (95% CI: 0.4–64.0) higher before stabilization of therapy, 2.2‐fold (95% CI: 0.7–6.5) after stabilization, and 2.4‐fold (95% CI: 0.8–7.4) during all periods when anticoagulation was not stable. The variant VKORC1 1173C/T genotype did not confer a significant increase in risk for major (HR 1.7; 95% CI: 0.7–4.4) or minor (HR 0.8; 95% CI: 0.5–1.3) hemorrhage. The variant CYP2C9 genotype is associated with an increased risk of major hemorrhage, which persists even after stabilization of therapy.

Kidney Function Influences Warfarin Responsiveness and Hemorrhagic Complications

Although management of warfarin is challenging for patients with chronic kidney disease (CKD), no prospective studies have compared response to warfarin among patients with minimal, moderate, and severe CKD. This secondary analysis of a prospective cohort of 578 patients evaluated the influence of kidney function on warfarin dosage, anticoagulation control, and risk for hemorrhagic complications. We adjusted all multivariable regression and proportional hazard analyses for clinical and genetic factors. Patients with severe CKD (estimated GFR <30 ml/min per 1.73 kg/m2) required significantly lower warfarin dosages (P = 0.0002), spent less time with their international normalized ratio within the target range (P = 0.049), and were at a higher risk for overanticoagulation (international normalized ratio >4; P = 0.052), compared with patients with no, mild, or moderate CKD. Patients with severe CKD had a risk for major hemorrhage more than double that of patients with lesser degrees of renal dysfunction (hazard ratio 2.4, 95% confidence interval 1.1 to 5.3). In conclusion, patients with reduced kidney function require lower dosages of warfarin, have poorer control of anticoagulation, and are at a higher risk for major hemorrhage. These observations suggest that warfarin may need to be initiated at a lower dosage and monitored more closely in patients with moderate or severe CKD compared with the general population. Diminished renal function may have implications for a larger proportion of warfarin users than previously estimated.

The role of TNF and its receptors in Alzheimer’s disease

Tumor necrosis factor (TNF) is an important proinflammatory cytokine that is upregulated in Alzheimer disease (AD) patients and involved with AD genes. Several TNF promoter polymorphisms that increase expression are associated with inflammatory and infectious diseases. We previously reported results that detected a AD associated region near the TNF gene. Using family-based association tests we also reported an association between AD and a TNF haplotype in sibling-pair families, and a significant increase in the mean age of onset for a group of African-American AD patients carrying this same haplotype. Previous reports have shown that that the chromosome 1p and chromosome 12p regions are linked to late-onset AD. These two regions harbor TNF receptors (TNFR) 2 and 1, respectively, and binding to them mediates biological effects of TNF. We found a significant asssociation of a TNFR2 exon 6 polymorphism with late-onset AD in families with no individuals possessing the APOE E4E4 genotype under a dominant model. We found no significant association of three polymorphisms in the TNFR1 gene to AD. These results provide further evidence for the involvement of TNF in the pathogenesis of AD.

Influence of CYP2C9 and VKORC1 on warfarin dose, anticoagulation attainment and maintenance among European–Americans and African–Americans

AIMS The influence of CYP2C9 and VKORC1 on warfarin dose, time to target International Normalized Ratio (INR), time to stabilization, and risk of over-anticoagulation (INR: > 4) was assessed after adjustment for clinical factors, intraindividual variation in environmental factors and unobserved heterogeneity. MATERIALS & METHODS Common CYP2C9 and VKORC1 polymorphisms were assessed in 302 European-Americans and 273 African-Americans receiving warfarin. Race-stratified multivariable analyses evaluated the influence of CYP2C9 and VKORC1 on warfarin response. RESULTS & CONCLUSION CYP2C9 and VKORC1 accounted for up to 30% of the variability in warfarin dose among European-Americans and 10% among African-Americans. Neither CYP2C9 nor VKORC1 influenced the time to target INR or stabilization among patients of either race, and neither influenced the risk of over-anticoagulation among African-Americans. The risk of over-anticoagulation was higher among European-Americans with variant VKORC1 1173C/T (p < 0.01) and marginally significant among those with variant CYP2C9 (p = 0.08) genotype. Although CYP2C9 and VKORC1 genotyping can facilitate individualized initiation of warfarin dose in African and European-Americans, the ability to predict the risk of over-anticoagulation is inconsistent across race. Identification of other factors that can predict such risk consistently in a racially diverse group will facilitate individualized maintenance of warfarin therapy.

Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: The NIMH Alzheimer disease genetics initiative

Tumor necrosis factor (TNF), a proinflammatory cytokine, may be involved in the pathogenesis of Alzheimer disease (AD) based on observations that senile plaques have been found to upregulate proinflammatory cytokines. Additionally, nonsteroidal anti-inflammatory drugs have been found to delay and prevent the onset of AD. A collaborative genome-wide scan for AD genes in 266 late-onset families implicated a 20 centimorgan region at chromosome 6p21.3 that includes the TNF gene. Three TNF polymorphisms, a -308 TNF promoter polymorphism, whose TNF2 allele is associated with autoimmune inflammatory diseases and strong transcriptional activity, the -238 TNF promoter polymorphism, and the microsatellite TNFa, whose 2 allele is associated with a high TNF secretion, were typed in 145 families consisting of 562 affected and unaffected siblings. These polymorphisms formed a haplotype, 2-1-2, respectively, that was significantly associated with AD (P = 0.005) using the sibling disequilibrium test. Singly, the TNFa2 allele was also significantly associated (P = 0.04) with AD in these 145 families. This TNF association with AD lends further support for an inflammatory process in the pathogenesis of AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:823-830, 2000.

Hemochromatosis and Iron Overload Screening (HEIRS) study design for an evaluation of 100,000 primary care-based adults.

BackgroundThe HEIRS Study will evaluate the prevalence, genetic and environmental determinants, and potential clinical, personal, and societal impact of hemochromatosis and iron overload in a multiethnic, primary care-based sample of 100,000 adults over a 5-year period. Participants are recruited from 5 Field Centers. Laboratory testing and data management and analysis are performed in a Central Laboratory and Coordinating Center, respectively. MethodsParticipants undergo testing for serum iron measures and common mutations of the hemochromatosis gene (HFE) on chromosome 6p and answer questions on demographics, health, and genetic testing attitudes. Participants with elevated values of transferrin saturation and serum ferritin and/or C282Y homozygosity are invited to undergo a comprehensive clinical examination (CCE), as are frequency-matched control subjects. These examinations provide data on personal and family medical history, lifestyle characteristics, physical examination, genetic counseling, and assessment of ethical, legal, and social implications. Primary and secondary causes of iron overload will be distinguished by clinical criteria. Iron overload will be confirmed by quantification of iron stores. Recruiting family members of cases will permit DNA analysis for additional genetic factors that affect iron overload. ResultsOf the first 50,520 screened, 51% are white, 24% are African American, 11% are Asian, 11% are Hispanic, and 3% are of other, mixed, or unidentified race; 63% are female and 37% are male. ConclusionsInformation from the HEIRS Study will inform policy regarding the feasibility, optimal approach, and potential individual and public health benefits and risks of primary care-based screening for iron overload and hemochromatosis.

VKORC1 polymorphisms, haplotypes and haplotype groups on warfarin dose among African–Americans and European–Americans

BACKGROUND Although the influence of VKORC1 and CYP2C9 polymorphisms on warfarin response has been studied, variability in dose explained by CYP2C9 and VKORC1 is lower among African-Americans compared with European-Americans. This has lead investigators to hypothesize that assessment of VKORC1 haplotypes may help capture a greater proportion of the variability in dose for this under-represented group. However, the inadequate representation of African-Americans and the assessment of a few VKORC1 polymorphisms have hindered this effort. METHODS To determine if VKORC1 haplotypes or haplotype groups explain a higher variability in warfarin dose, we comprehensively assessed VKORC1 polymorphisms in 273 African-Americans and 302 European-Americans. The influence of VKORC1 polymorphisms, race-specific haplotypes and haplotype groups on warfarin dose was evaluated in race-stratified multivariable analyses after accounting for CYP2C9 (*2, *3, *5, *6 and *11) and clinical covariates. RESULTS VKORC1 explained 18% (30% with CYP2C9) variability in warfarin dose among European-Americans and 5% (8% with CYP2C9) among African-Americans. Four common haplotypes in European-Americans and twelve in African-Americans were identified. In each race VKORC1 haplotypes emerged into two groups: low-dose (Group A) and high-dose (Group B). African-Americans had a lower frequency of Group A haplotype (10.6%) compared with European-Americans (35%, p < 0.0001).The variability in dose explained by VKORC1 haplotype or haplotype groups was similar to that of a single informative polymorphism. CONCLUSIONS Our findings support the use of CYP2C9, VKORC1 polymorphisms (rs9934438 or rs9923231) and clinical covariates to predict warfarin dose in both African- and European-Americans. A uniform set of common polymorphisms in CYP2C9 and VKORC1, and limited clinical covariates can be used to improve warfarin dose prediction for a racially diverse population.

Genetic Association of 11β-Hydroxysteroid Dehydrogenase Type 2 (HSD11B2) Flanking Microsatellites With Essential Hypertension in Blacks

11 beta-Hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) specifically modulates access of the mineralocorticoid aldosterone to the kidney mineralocorticoid type 1 receptors in a physiological environment in which there is a molar excess of cortisol. Cortisol and aldosterone have similar affinities for mineralocorticoid receptors. Mechanistically, 11 beta-HSD2 converts cortisol to cortisone. The other known isoform, 11 beta-HSD1, not only catalyzes the cortisol to cortisone reaction but also the reverse reaction, making it unlikely to play an important role in modulating the access of aldosterone to mineralocorticoid receptors. Mutations in the HSD11B2 gene (both exonic and intronic) have been demonstrated to cause reduced activity of this enzyme in the syndrome of apparent mineralocorticoid excess, a rare autosomal recessive disorder. We hypothesized that this locus is also involved in the etiology of essential hypertension. To test this locus and flanking chromosomal regions for allelic association and genetic linkage to essential hypertension, it is necessary to have informative genetic markers. To this end, we have refined the localization of 11 beta-HSD2 to 16q22.1. We genotyped subjects using the nearest flanking microsatellites (D16S301 and D16S496). We conducted an association study using black subjects with hypertensive end-stage renal disease, black normotensive control subjects, and black and white individuals from the general population. We used chi 2 analysis and Fishers exact test to test for association with these candidate gene markers. No significant association was found between D16S301 and hypertension. However, a positive association with hypertension was found at the D16S496 microsatellite locus (chi 2 = 6.98, df = 1, P < or = .008). Our data suggest that HSD11B2 is associated with hypertension in our black subjects with hypertensive end-stage renal disease. The 16q22.1 chromosome region potentially harbors a candidate gene for essential hypertension. Confirmation of our findings in another independently ascertained group of hypertensive subjects will provide a basis for proceeding with sib-pair linkage analyses.

An Induced Bactericidin in the Spiny Lobster, Panulirus argus

Summary Spiny lobsters, P. argus, immunized with living or killed bacteria, have been shown to synthesize a nondialyzable bactericidin. This substance was present in the hemolymph and was usually detectable within 12 hours. In the primary response, it reached a peak within 24-48 hours. The most effective antigen was a gram-negative bacillus, EMB-1, isolated from the normal intestinal flora of healthy P. argus. Varying results were obtained when specificity was tested with heterologous bacteria, but the bactericidin was less specific than mammalian antibody. Heating at 65°C for 20 min was required for complete inactivation. EDTA, dialysis, carrageenin, and freezing failed to inactivate this substance. It could be adsorbed by homologous and heterologous bacteria.