Pharmacogenetics of ophthalmic topical β-blockers

Glaucoma is the second leading cause of blindness worldwide. The primary glaucoma risk factor is elevated intraocular pressure. Topical β-blockers are affordable and widely used to lower intraocular pressure. Genetic variability has been postulated to contribute to interpersonal differences in efficacy and safety of topical β-blockers. This review summarizes clinically significant polymorphisms that have been identified in the β-adrenergic receptors (ADRB1, ADRB2 and ADRB3). The implications of polymorphisms in CYP2D6 are also discussed. Although the candidate-gene approach has facilitated significant progress in our understanding of the genetic basis of glaucoma treatment response, most drug responses involve a large number of genes, each containing multiple polymorphisms. Genome-wide association studies may yield a more comprehensive set of polymorphisms associated with glaucoma outcomes. An understanding of the genetic mechanisms associated with variability in individual responses to topical β-blockers may advance individualized treatment at a lower cost

Spreading maps (polymorphisms), symmetries of Poisson processes and matching summation

The matrix of a permutation is a partial case of Markov transition matrices. In the same way, a measure preserving bijection of a space A with finite measure is a partial case of Markov transition operators. A Markov transition operator also can be considered as a map (polymorphism) A to A, which spreads points of A into measures on A. In this paper, we discuss R-polymorphisms and $\vee$-polymorphisms, who are analogues of the Markov transition operators for the groups of bijections A to A leaving the measure quasiinvariant; two types of the polymorphisms correspond to the cases, when A has finite and infinite measure respectively. We construct a functor from $\vee$-polymorphisms to R-polymorphisms, it is described in terms of summation of convolution products of measures over matchings of Poisson configurations.Comment: 16 pages, European school on asymptotic combinatorics (St-Petersburg, July 2001

Insulin gene polymorphisms in type I diabetes, Addison's disease and the polyglandular autoimmune syndrome type II

Background: Polymorphisms within the insulin gene can influence insulin expression in the pancreas and especially in the thymus, where self-antigens are processed, shaping the T cell repertoire into selftolerance, a process that protects from ß-cell autoimmunity. Methods: We investigated the role of the -2221Msp(C/T) and -23HphI(A/T) polymorphisms within the insulin gene in patients with a monoglandular autoimmune endocrine disease [patients with isolated type 1 diabetes (T1D, n = 317), Addison´s disease (AD, n = 107) or Hashimoto´s thyroiditis (HT, n = 61)], those with a polyglandular autoimmune syndrome type II (combination of T1D and/or AD with HT or GD, n = 62) as well as in healthy controls (HC, n = 275). Results: T1D patients carried significantly more often the homozygous genotype "CC" -2221Msp(C/T) and "AA" -23HphI(A/T) polymorphisms than the HC (78.5% vs. 66.2%, p = 0.0027 and 75.4% vs. 52.4%, p = 3.7 × 10-8, respectively). The distribution of insulin gene polymorphisms did not show significant differences between patients with AD, HT, or APS-II and HC. Conclusion: We demonstrate that the allele "C" of the -2221Msp(C/T) and "A" -23HphI(A/T) insulin gene polymorphisms confer susceptibility to T1D but not to isolated AD, HT or as a part of the APS-II

Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.

Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine

Cytokine gene polymorphisms in preterm infants with necrotising enterocolitis: genetic association study

BACKGROUND The inflammatory cytokine cascade is implicated in the pathogenesis of necrotising enterocolitis (NEC). Genetic association studies of cytokine polymorphisms may help to detect molecular mechanisms that are causally related to the disease process. AIM To examine associations between the common genetic variants in candidate inflammatory cytokine genes and NEC in preterm infants. METHODS Multi-centre case-control and genetic association study. DNA samples were collected from 50 preterm infants with NEC and 50 controls matched for gestational age and ethnic group recruited to a multi-centre case-control study. Ten candidate single-nucleotide polymorphisms in cytokines previously associated with infectious or inflammatory diseases were genotyped. The findings were included in random-effects meta-analyses with data from previous genetic association studies. RESULTS All allele distributions were in Hardy-Weinberg equilibrium. None of the studied cytokine polymorphisms was significantly associated with NEC. Four previous genetic association studies of cytokine polymorphisms and NEC in preterm infants were found. Meta-analyses were possible for several single-nucleotide polymorphisms. These increased the precision of the estimates of effect size but did not reveal any significant associations. CONCLUSIONS The available data are not consistent with more than modest associations between these candidate cytokine variant alleles and NEC in preterm infants. Data from future association studies of these polymorphisms may be added to the meta-analyses to obtain more precise estimates of effects sizes.The study was funded by Tenovus (Scotland)

Genetic Polymorphisms of the Glucocorticoid Receptor and Interleukin-8 Receptor Genes are Related to Production Traits and Hair Coat Score in Crossbred Cattle

The objective of this thesis was to identify polymorphisms in the glucocorticoid receptor (GR) and interleukin-8 receptor (CXCR2) genes and to associate genotypes between the above mentioned polymorphisms and production traits in crossbred cattle. The hypothesis was that polymorphisms will exist for GR and CXCR2 genes and will be linked to production traits. Glucocorticoid receptors have been positively associated with higher milk yields, lactose content, feed intake, and feed conversion rates. Interleukin-8 genes are part of the innate immune response and help with many aspects of female reproduction health, such as protecting the embryo from the maternal immune system during pregnancy. Despite these things, very little is known about how GR and CXCR2 gene polymorphisms affect phenotypes in cattle. Blood samples were collected from ninety-four crossbred cattle over a period of three years (2012, 2013, 2014) and the DNA was extracted, amplified, and sent to GeneSeek in Lincoln, Nebraska, to be analyzed and genotyped for single nucleotide polymorphisms (SNP). Phenotypic data was collected from the ninety-four crossbred cattle and analyzed alongside the genotypic results, including: cow pre-breeding BCS and weight, Julian calving date, calf birth weight, cow weaning BCS and weight, calf weaning weight, calf adjusted 205-day weight, cow efficiency, and HCS. Significant relationships were determined using t-tests. It is expected that SNPs will be found for the GR and CXCR2 genes and that these polymorphisms will be significantly related to the production traits in cattle. Scientists and breeders could manipulate these genes to produce cattle that are more efficient and possess more desirable production traits