Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

Vascular endothelial function in cyclosporine and tacrolimus treated renal transplant recipients.

BACKGROUND: Endothelial dysfunction is an early key event in the development of arteriosclerotic cardiovascular disease (ASCVD), thus an early marker of subclinical ASCVD. Endothelial function is impaired in renal transplant recipients (RTR) treated with cyclosporine (CyA). Tacrolimus is associated with less hyperlipidemia and hypertension than CyA, however, there are no data on endothelial function in tacrolimus-treated RTR. METHODS: High-resolution brachial ultrasonography was used to assess endothelium-dependent dilatation (EDD), and endothelium-independent dilatation (EID) in 20 stable RTR and a control group of 10 healthy subjects without clinical evidence of ASCVD. The RTR group included patients receiving CyA (n=10) and tacrolimus (n=10). EDD and EID were measured as percent increase in brachial artery diameter in response to reactive hyperemia and nitroglycerin, respectively. RESULTS AND CONCLUSIONS: EDD was significantly lower in RTR versus controls (1.7+/-0.7 vs. 7.3+/-0.7%, P<0.0001), whereas EID was similar in the two groups. No significant differences were found in EDD or in EID between CyA- and tacrolimus-treated RTR. Glomerular filtration rate, plasma homocysteine, blood pressure, and lipid profiles were similar in CyA- and tacrolimus-treated RTR.

Call to action: finding solutions for the drug shortage crisis in the United States.

In their article in this issue of CPT, Woodcock and Wosinska are the first to clearly outline the quality and manufacturing problems causing drug shortages of generic injectables. These authors have focused on the main issue, namely, that manufacturing problems and the lack of incentives for quality products are the primary reasons for most recent shortages of generic injectable drugs.

Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants.

BACKGROUND: Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans. OBJECTIVE: To identify novel genetic variants associated with resting heart rate in African Americans. METHODS: Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P≤2.5×10(-8)). RESULTS: Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98×10(-15)). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans. CONCLUSIONS: An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.

Commentary from Coeur d'Alene: one baby-or two?

PIP: "The Global 2000 Report" predicts a burgeoning world population, a depletion of natural resources, and an ever increasing price to pay for the privilege of living on this planet. It is necessary to consider the probabilities. Assuming, as 1 probability, that in the year 2000 the fields have become less fertile, streams are flowing at a low level, and the cost of raising a family is soaring to an all time high. Obviously, the logical course would be to opt for population control through the limitation of family planning. The question that arises is how would that be accomplished. An instructive example of how to enforce population control is China. Their solution aims at the pocketbooks of the Chinese workers. When a couple marries, a government representative visits and advises that the good of the country lies in the careful limitation of family size. During the 1st pregnancy, all care is free, and the mother is given a generous amount of time off with full pay. If a 2nd pregnancy occurs, an abortion is urged. Should the couple choose to go through with the pregnancy, the reimbursement for maternity care is cut to the minimum, and there is no paid-for postpartum vacation. If a 3rd pregnancy occurs, community pressure is brought to bear and there must be an abortion with a permanent sterilization to follow. This approach can be successful in a communist nation where the government controls the pursestrings and writes the paychecks. In the Philippines the efforts have been directed toward a positive program of conception control. A Barangay Supply Point Officer (BSPO) works as a government agent, dispensing advice and contraceptives. Thailand's vigorous family planning program has reduced the family size number to 3. The exemplary success has been accomplished largely through education. To attain improved educational levels, the government launched a 3-pronged program: education of school children; family planning; and postabortal and postpartum conception control. In the US there seems to be satisfaction with the status quo. In this apathy there seems to be a blindness to the increasingly important roles being played by nonphysicians in the area of population control in this country and to the involvement of governmental and quasi-governmental agencies in fertility control. The younger generation is being conditioned to accept the concept of family planning under the watchful eye of government agencies. These population control programs are being carried out by nonphysicians. It is conceivable that by the year 2000 there will be a further invasion of privacy, further intrusion into family lives.^ieng

Children of homeless families: health status and access to health care.

The parents and children of homeless families are highly vulnerable to illness and the failure to receive timely and continuous health care. Data on health status and health care utilization were collected from 70 homeless families selected for an intensive case management program and compared to data for low-income families. The data suggest that homeless children do not utilize primary care or preventive care on a regular basis in comparison to low income children generally. These results have implications for the delivery of health care services to homeless families in shelters.

Response of gastric lymphoma to chemotherapy: radiographic appearance.

Although the initial radiographic appearance of gastric lymphoma is well described, there are few descriptions of the evolution of these gastric lesions after chemotherapy. Double-contrast upper gastrointestinal examinations were performed in four patients with gastric lymphoma before and after chemotherapy. The following responses were observed: (1) complete resolution without scarring, (2) resolution to a benign-appearing ulcer, (3) ulceration within a plaque associated with a decrease in tumor mass, and (4) ulceration, perforation, and healing to a benign-appearing ulcer scar. Ulceration of gastric lesions after chemotherapy, observed in two cases, was associated with occult gastrointestinal bleeding. These tumors may regress in response to chemotherapy, leaving a benign-appearing ulcer or ulcer scar as the only radiographic evidence of a lymphomatous gastric lesion.

Neonatal alloimmune thrombocytopenia associated with maternal anti-HLA antibody: a case report.

PURPOSE: Although neonatal alloimmune thrombocytopenia (NAIT) due to maternal sensitization to human platelet antigens is well described, the role of maternal anti-human lymphocyte antigen (HLA) antibodies in NAIT is not yet firmly established. PATIENT: A 31-week-old girl born prematurely to a G2POA1 mother was noted to have thrombocytopenia which lasted 18 days without any evidence of infection. MATERIALS AND METHODS: Platelet-associated IgG, anti-platelet antibody, and platelet PL(A1) antigen typing were determined using a commercial solid-phase red cell adherent test. Antibodies to platelet glycoproteins human platelet antigen (HPA) 1 to 5 were determined using a commercial ELISA. Anti-HLA antibodies were assayed using a standard lymphocytotoxicity test. Activities and IgG subclass of anti-HLA antibodies in plasma of the mother and other postpartum mothers were measured using purified HLA antigens in an enzyme linked immunoassay. RESULTS: Both mother and infant were positive for HPA-1 (PL(A1)) antigens. The mother's HLA phenotype was A3, A31, B7, B27. The level of platelet-associated IgG was not increased on maternal platelets; however, increased platelet-associated IgG was detected on the infant's platelets. Antibodies to platelet glycoproteins HPA1 to 5 were not detectable in the maternal plasma. Maternal serum was positive for anti-HLA antibodies, which reacted to 23 of 27 panel cells. The presence of HLA antibodies was confirmed by enzyme-linked immunoassay. Of note, the maternal antibodies reacted positively to the infant's platelets and anti-IgG anti-HLA antibodies were detected in the serum sample from the infant collected at birth. When the activity and IgG subclass of the maternal anti-HLA antibodies were compared with those of other mothers known to have high anti-HLA antibody activity, no differences were noted. CONCLUSION: This report documents a patient with neonatal thrombocytopenia induced by maternal IgG anti-HLA antibody. Neither activity nor IgG subclass could explain the occurrence of NAIT. The factors that contribute to NAIT induced by maternal anti-HLA antibodies remain to be identified.