Rare Haplotypes Research Articles

Clinical relevance of TP53 polymorphic genetic variations in chronic lymphocytic leukemia

ObjectivesTo analyze the distribution of single nucleotide polymorphisms (SNPs) in the TP53 gene in chronic lymphocytic leukemia (CLL) patients and to evaluate their associations with clinical behavior of the disease. MethodsSNPs in exons and parts of adjacent introns of the TP53 gene were analyzed in 235 CLL patients observed during 2005-2012 years. Data on individuals of European descent from the 1000 Genomes Project data set were used as a reference. ResultsIn the recessive model of inheritance, we found borderline associations between CLL risk and C/C genotype of rs1642785 (p=0.048); G/G genotype of rs2909430 (in men only; p=0.036) and Pro72Pro genotype of rs1042522 (in men only; p=0.045). Risk of CLL was increased also in carriers of rare haplotypes (p=0.0049). Besides, genotypes Pro72Pro of rs1042522, C/C of rs1642785, and G/G of rs2909430 were associated with an increased incidence of TP53 mutations. Median of overall survival in rs1800372 carriers was comparable to that of patients with TP53 mutations. Other evaluated SNPs were not associated with survival. ConclusionOur data suggest that some TP53 variants may affect the risk of CLL. rs1800372 polymorphism might be the marker of unfavorable prognosis of the disease.

Novel SNP markers in InvGE and SssI genes are associated with natural variation of sugar contents and frying color in Solanum tuberosum Group Phureja

BackgroundPotato frying color is an agronomic trait influenced by the sugar content of tubers. The candidate gene approach was employed to elucidate the molecular basis of this trait in Solanum tuberosum Group Phureja, which is mainly diploid and represents an important genetic resource for potato breeding. The objective of this research was to identify novel genetic variants related with frying quality in loci with key functions in carbohydrate metabolism, with the purpose of discovering genetic variability useful in breeding programs. Therefore, an association analysis was implemented with 109 SNP markers identified in ten candidate genes.ResultsThe analyses revealed four associations in the locus InvGE coding for an apoplastic invertase and one association in the locus SssI coding for a soluble starch synthase. The SNPs SssI-C45711901T and InvGE-C2475454T were associated with sucrose content and frying color, respectively, and were not found previously in tetraploid genotypes. The rare haplotype InvGE-A2475187C2475295A2475344 was associated with higher fructose contents. Our study allowed a more detailed analysis of the sequence variation of exon 3 from InvGE, which was not possible in previous studies because of the high frequency of insertion-deletion polymorphisms in tetraploid potatoes.ConclusionThe association mapping strategy using a candidate gene approach in Group Phureja allowed the identification of novel SNP markers in InvGE and SssI associated with frying color and the tuber sugar content measured by High Performance Liquid Chromatography (HPLC). These novel associations might be useful in potato breeding programs for improving quality traits and to increase crop genetic variability. The results suggest that some genes involved in the natural variation of tuber sugar content and frying color are conserved in both Phureja and tetraploid germplasm. Nevertheless, the associated variants in both types of germplasm were present in different regions of these genes. This study contributes to the understanding of the genetic architecture of tuber sugar contents and frying color at harvest in Group Phureja.

Association of IL-10 gene (-1082A>G, -819C>T and -592C>A) polymorphism and its serum level with metabolic syndrome of north Indian subjects.

Metabolic syndrome (MetS) is an inflammatory disorder, in which various cytokines play important role in tilting balance towards disease state. Interleukin-10 (IL-10) is an important antiinflammatory cytokine, but its genetic polymorphisms and serum levels in Indian MetS subjects are unknown. Three IL-10 gene polymorphisms (-1082A>G (rs1800896), -819C>T (rs1800872) and -592C>A (rs1800871)) were genotyped with PCR-RFLP in MetS subjects (n = 384) and age/sex matched control subjects (n = 386). Serum IL-10 was measured using enzyme-linked immunosorbent assay. Serum IL-10 level was significantly low in MetS subject and significantly correlated with clinicobiochemical parameters of MetS. Of three investigated promoter polymorphisms, IL-10 -819C> T and -592C>A were significantly associated with risk of MetS. The mutant alleles -819T and -592A of IL-10 gene polymorphism were significantly higher in MetS subjects compared to controls. Of the four different haplotypes obtained, common ACC haplotype and rare GTA haplotype of IL-10 polymorphisms were associated with MetS. The mean of fasting insulin and HOMA-IR were significantly different between the genotypes of both -819 C>T and -592C>A polymorphisms of IL-10 in MetS subjects. These results suggested that polymorphisms in IL-10 gene (-819C>T and -592C>A), haplotypes (ACC and GTA) and serum level are significantly associated with risk of MetS. IL- 10 -819C>T and -592C>A polymorphic variants are also significantly associated with insulin level and homeostasis model assessment-insulin resistance in north Indian MetS subjects.

Phylogeographic Identification of Tench Tinca tinca (L., 1758) (Actinopterygii: Cyprinidae) from the Northern Balkans and Adjacent Regions and its Implications for Conservation.

Jelena Lujić, Klaus Kohlmann, Petra Kersten, Zoran Marinović, Miroslav Ćirković, and Vladica Simić (2017) The tench, Tinca tinca, is an endangered freshwater fish species in the Balkans. However, there are no management and conservation strategies developed for this species so far. In order to be able to develop such strategies, we first determined the phylogeographic identity of 70 tench individuals from four countries (Serbia, FYRO Macedonia, Hungary and Croatia) by PCR-RFLP analyses of two nuclear markers (Act and RpS7) and one mitochondrial marker (Cytb). All makers enabled the identification of two major geographic clades of tench (Western and Eastern), while nuclear markers additionally enabled the identification of hybrids between the two clades. Based on the mitochondrial marker Cytb, tench populations can be separated into two distinct areas: areas north of the Danube River with the dominant Western origin, and areas south of the Danube River with the dominant Eastern origin. Data obtained for the Act gene demonstrated Eastern origin for most individuals (88.23%) while data obtained for the RpS7 gene demonstrated mixed origin with a high percentage of hybrids. The presence of high numbers of individuals with Western alleles for the RpS7 gene in areas south of the Danube may indicate a natural invasion of this phylogroup. According to these results, areas north and south of the Danube are identified as two main management units. Additionally, we identified the rare western haplotype W2 based on the Cytb marker which clearly indicated human-aided dispersals of tench in the investigated region and since some individuals with W2 origin were cultured, attention must be given to the genetic structure and identity of the introduced individuals, whether during introduction or reintroduction since biological and ecological consequences of the hybridization between the two major clades are still unknown. Finally, we propose and discuss management and conservation strategies for tench of both management areas.

BRCA1 p.His1673del is a pathogenic mutation associated with a predominant ovarian cancer phenotype.

We have investigated the clinical significance of the BRCA1 variant p.His1673del in 14 families from the Emilia-Romagna region of Italy, including 20 breast and 23 ovarian cancer cases; four families displayed site-specific ovarian cancer.The variant, absent in human variation databases, has been reported three times in BRCA1 specific databases; all probands shared the same rare haplotype at the BRCA1 locus, consistent with a common ancestor.The multifactorial likelihood method by Goldgar, used to estimate the probability of the variant being causative, gave a ratio of 2,263,474:1 in favor of causality. Moreover, in silico modeling suggested that His1673-lacking BRCA1 protein may have a decreased ability to bind BARD1 and other related proteins. All six ovarian carcinomas and two out of four breast carcinomas available showed a loss of the BRCA1 wild-type allele, which in three out of four ovarian carcinomas analyzed by FISH was associated with duplication of the chromosome 17 containing the variant. Although the pathogenicity of the allele is strongly supported by the multifactorial ratio, we cannot exclude that p.His1673del is not itself deleterious, but is linked to another undetected mutation on the same ancestral allele.

Recombinant Haplotypes Narrow the ARMS2/HTRA1 Association Signal for Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness in ageing societies, triggered by both environmental and genetic factors. The strongest genetic signal for AMD with odds ratios of up to 2.8 per adverse allele was found previously over a chromosomal region in 10q26 harboring two genes, ARMS2 and HTRA1, although with little knowledge as to which gene or genetic variation is functionally relevant to AMD pathology. In this study, we analyzed rare recombinant haplotypes in 16,144 AMD cases and 17,832 controls from the International AMD Genomics Consortium and identified variants in ARMS2 but not HTRA1 to exclusively carry the AMD risk with P-values between 1.0 × 10−773 and 6.7 × 10−5. This now allows prioritization of the gene of interest for subsequent functional studies.

Population Genetic Analysis of Oceanic Paddle Crab (Varuna litterata) in Thailand

Population genetic structure of Varuna litterata living along the coast of Thailand were examined in this study. The samples were collected from 3 coastal regions: The Andaman sea (Satun, Trang, Phang Nga), the lower Gulf of Thailand (Pattani, Songkhla, Nakhon Si Thammarat) and the upper Gulf of Thailand (Petchburi, Samut Songkram, Rayong, Trat). Intraspecific variation was determined based on partial sequences of the cytochrome oxidase subunits I gene. A total of 182 samples were collected but only 32 haplotypes were obtained from these samples. An excess of rare haplotypes indicated that the female effective population size of V. litterata living along the coast of Thailand is large. Estimated values of haplotype diversity and nucleotide diversity were 0.790 and 0.003, respectively. The AMOVA (analysis of molecular variance) and phylogenetic analysis results showed that based on genetic variation, the population of this organism was found to have 2 genetically different populations: The Andaman sea population and the Gulf of Thailand population. Genetic exchange of V. litterata among populations inhabiting along the coast of Thailand could be described by the stepping stone model. The results of neutrality tests, both Tajima’s D and Fu’s Fs statistics, yielded negative values (-1.992 and -26.877, respectively) and statistically significant deviation from the neutrality, indicating that the V. litterata living along the Thailand coast had experienced population expansion. Mismatch distribution analysis indicated that a possible expansion occurred 211,428 years ago during the Pleistocene glaciations period.

ERAP1 association with ankylosing spondylitis is attributable to common genotypes rather than rare haplotype combinations

We investigated the proposal that ankylosing spondylitis (AS) is associated with unusual ERAP1 genotypes. ERAP1 haplotypes were constructed for 213 AS cases and 46 rheumatoid arthritis controls using family data. Haplotypes were generated from five common ERAP1 single nucleotide polymorphisms (SNPs)-rs2287987 (M349V), rs30187 (K528R), rs10050860 (D575N), rs17482078 (R725Q), and rs27044 (Q730E). Haplotype frequencies were compared using Fisher's exact test. ERAP1 haplotypes imputed from the International Genetics of AS Consortium (IGAS) Immunochip study were also studied. In the family study, we identified only four common ERAP1 haplotypes ("VRNQE," "MKDRQ," "MRDRE," and "MKDRE") in both AS cases and controls apart from two rare (<0.5%) previously unreported haplotypes. There were no examples of the unusual ERAP1 haplotype combination ("*001/*005") previously reported by others in 53% of AS cases. As expected, K528-bearing haplotypes were increased in the AS family study (AS 43% vs. control 35%), due particularly to an increase in the MKDRQ haplotype (AS 35% vs. control 25%, P = 0.01). This trend was replicated in the imputed Immunochip data for the two K528-bearing haplotypes MKDRQ (AS 33% vs. controls 27%, P = 1.2 × 10-24) and MKDRE (AS 8% vs. controls 7%, P = 0.004). The ERAP1 association with AS is therefore predominantly attributable to common ERAP1 haplotypes and haplotype combinations.

A New Approach to Mixed Stock Analysis that Informs on the Management and Conservation of Hawksbill in the Wider Caribbean: the Case of the Legal Fishery in Jardines del Rey, Cuba

Researchers have used mixed stock analysis (MSA) to infer the relevance of rookeries in sea turtle aggregations for conservation/management purposes. However, their approaches and assumptions are not always homogeneous or realistic. We assayed new MSAs using the annual haplotype frequencies of aggregations and rookeries of Eretmochelys imbricata in the Wider Caribbean (WC), and the population size was selected according to the sampler year most relevant on the maturity of the aggregation. The MSA results obtained using this approach were compared with MSAs executed with grouped haplotype frequency data as has been the most common practice in the literature. The relationship of Jardines del Rey (JR) legal fishing aggregation (Cuba) to other aggregations and rookeries in the region was analyzed with data collected in 2004 to 2006 and during the 1990s. The JR non-adult fishing ground presented high genetic diversity and Mexican rookery was identified as the primary contributor using haplotypes at the 384 bp length and each MSA approach that was used, congruent with the demographic growth reported for this rookery. Using haplotypes at the 740 bp length, the primary contributor to non-adult turtles at JR differed according to the MSA approach used, alternating between Mona Island and the Mexican rookery. Jardines del Rey is a route usually taken by non-adult hawksbills of diverse origin, reflecting the need to strengthen the sampling and conservation efforts on the WC rookeries with rare or orphan haplotypes, and to warn about the impact of the fishery occurring in similar areas. Likewise, adult turtles from JR were highly diverse and from multiple origins, with this area serving as a migratory corridor for first breeders (females) to many WC breeding grounds. Caution should be employed in any MSA approach due to the influence effect of sequence length, selection of the rookery size and haplotype frequencies, as well as other assumptions that may affect the estimated contributions.

Impact of Model Choice on LR Assessment in Case of Rare Haplotype Match (Frequentist Approach)

AbstractThe likelihood ratio (LR) measures the relative weight of forensic data regarding two hypotheses. Several levels of uncertainty arise if frequentist methods are chosen for its assessment: the assumed population model only approximates the true one, and its parameters are estimated through a limited database. Moreover, it may be wise to discard part of data, especially that only indirectly related to the hypotheses. Different reductions define different LRs. Therefore, it is more sensible to talk about ‘a’ LR instead of ‘the’ LR, and the error involved in the estimation should be quantified. Two frequentist methods are proposed in the light of these points for the ‘rare type match problem’, that is, when a match between the perpetrator's and the suspect's DNA profile, never observed before in the database of reference, is to be evaluated.

Haplotypic variation in the UCP1 gene is associated with milk traits in dairy cows

Uncoupling protein-1 (UCP1) plays a role in the regulation of body temperature, metabolic rate and energy expenditure in animals. While variation in UCP1 and its phenotypic effect has been investigated in humans and sheep, little is known about this gene in cattle. In this study, four regions of bovine UCP1 were investigated in 612 Holstein-Friesian × Jersey (HF × J) dairy cows using polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) analyses. In the four regions of the gene analysed, a total of 13 SNPs were detected. Three sequences (a, b and c) were found in Region-2 and three sequences (A, B and C) were found in Region-4, and these were assembled into three (a-B, b-B and c-A) common and three (b-C, c-B and c-C) rare haplotypes. Of the three common haplotypes, b-B and c-A were associated (P < 0·007 and P < 0·043, respectively) with increased milk yield and tended to be associated (P < 0·085 and P < 0·070, respectively) with decreased fat percentage. Cows with genotype b-B/a-B produced more milk (P < 0·004), but with a lower percentage of fat (P < 0·035) and protein (P < 0·038) than cows with genotype a-B/a-B. Cows of genotype a-B/c-A had milk of low fat percentage (P < 0·017), but tended to produce more milk (P < 0·059) than cows of genotype a-B/a-B. This suggests that UCP1 affects milk yield, milk fat percentage and milk protein percentage.

Association of rare haplotypes on ULK4 and MAP4 genes with hypertension.

Several variants have been implicated earlier on ULK4 and MAP4 genes on chromosome 3 to be associated with hypertension. As a natural follow-up step, we explore association of haplotypes in those genes. We consider the Genetic Analysis Workshop 19 real data on unrelated individuals and analyze haplotype blocks of 5 single-nucleotide polymorphisms through a sliding window approach. We apply 4 haplotype association methods—haplo.score, haplo.glm, hapassoc, and logistic Bayesian LASSO (LBL)—and for comparison, sequence kernel association test (SKAT) and its variants. We find several rare haplotype blocks to be associated. To get an idea about the false-positive proportions, we also analyzed the data after permuting the case-control status of individuals. We found that LBL, unlike the other methods, maintains low false-positive rates in presence of rare haplotypes. Thus, we conclude that the haplotypes found to be associated by LBL are more likely to be true positive. SKAT and its variants did not find significance on either gene.

Purifying Selection, Density Blocking and Unnoticed Mitochondrial DNA Diversity in the Red Deer, Cervus elaphus.

The trajectories of postglacial range expansions, the occurrence of lineage patches and the formation and maintenance of secondary contact between lineages may mostly reflect neutral demographic processes, including density blocking, that may leave long-lasting genetic signatures. However, a few studies have recently shown that climate may also play a role. We used red deer, a large, mobile herbivore that is assumed to be sensitive to climate change, to test hypotheses of possible selection on the mitochondrial DNA cytochrome b gene (mtDNA cytb) and competitive and/or density-blocking (using mtDNA control region). We searched for a possible link between the phylogeographic structure and abiotic climatic variables. Finally, we tested for isolation by distance and isolation by environment and assessed the impact of human-mediated translocations on the genetic structure of red deer. Our analysis of 30 red deer populations in Poland using the mtDNA control region (N = 357) and cytochrome b (N = 50) markers not only confirmed the presence of the Western and South-Eastern lineages of the species but also indicated the presence of a previously unnoticed, rare relic haplotype that grouped together C. e. italicus from Italy (the Mesola deer). No significant signs of positive selection were detected for the mtDNA cytb gene in the studied red deer. However, a significant signal for purifying selection was found in our study that may explain the narrowness of the contact zone because gene flow between the Western and South-Eastern lineages should drive relatively strong mito-nuclear incompatibilities. MtDNA control region differentiation among red deer populations in Poland correlated with different abiotic climatic variables. Strikingly, the southernmost ice sheet limits during the Elsterian was the most important factor, and it explained the largest amount of variation. However, neither isolation by distance (IBD) nor isolation by environment (IBE) were recorded, and a very limited impact of human translocations was evident. The above-mentioned results suggest that in contemporary red deer populations in Poland, the phylogeographic pattern is well preserved, and long-term processes (density and/or competitive blocking) still play a major role.

Rare variant phasing and haplotypic expression from RNA sequencing with phASER.

Haplotype phasing of genetic variants is important for clinical interpretation of the genome, population genetic analysis and functional genomic analysis of allelic activity. Here we present phASER, an accurate approach for phasing variants that are overlapped by sequencing reads, including those from RNA sequencing (RNA-seq), which often span multiple exons due to splicing. Using diverse RNA-seq data we demonstrate that this provides more accurate phasing of rare variants compared with population-based phasing and allows phasing of variants in the same gene up to hundreds of kilobases away that cannot be obtained from DNA sequencing (DNA-seq) reads. We show that in the context of medical genetic studies this improves the resolution of compound heterozygotes. Additionally, phASER provides measures of haplotypic expression that increase power and accuracy in studies of allelic expression. In summary, phasing using RNA-seq and phASER is accurate and improves studies where rare variant haplotypes or allelic expression is needed.

Molecular genetic identification of Japanese sand lances using mitochondrial DNA cytochrome c oxidase subunit 1 restriction fragment length polymorphisms

We developed a novel molecular genetic method using restriction fragment length polymorphisms (RFLPs) to identify the taxonomically debatable Japanese sand lances of the genus Ammodytes. Partial nucleotide sequences of the mitochondrial DNA cytochrome c oxidase subunit 1 (COI) gene of Ammodytes japonicus (n = 405), Ammodytes heian (n = 284), and Ammodytes hexapterus (n = 15) were determined and found to contain species-specific restriction sites for HindIII-HF and RsaI enzymes. The observed RFLP patterns from a combination of two enzymes were specific in each species except for specimens with rare haplotypes of A. japonicus (1.5 %) and A. heian (2.1 %), whereas detailed morphological analysis using 29 characters failed to discriminate the COI-identified specimens of these two species collected from the same locality. The developed molecular method will allow rapid and precise identification of the Japanese sand lances, especially for the sympatric A. japonicus and A. heian, thereby providing a reliable means for ecological research and stock management of these species.

A history of invasion: COI phylogeny of Manila clam Ruditapes philippinarum in Europe

The Manila clam Ruditapes philippinarum – synonym Venerupis philippinarum (Adams and Reeve, 1850) is now one of the top 5 most commercially valuable bivalve species worldwide. Originally from the Indo-Pacific region, it has been introduced in many countries for fisheries and aquaculture, including estuarine environments along Atlantic and Mediterranean European coasts. Yet despite its commercial value and widespread distribution, the precise origins of stocks remain speculative and the genetic diversity of introduced populations is poorly known. Thus, the aim of this work was to collect mtDNA COI (Cytochrome oxidase I) gene sequences from 5 European countries with Manila clam stocks and compare them with native Asian populations to evaluate their genetic diversity and identify possible routes of invasion. The COI gene sequencing supported a strong founder effect in the European populations with 3 main haplotypes occurring at high frequencies, derived from Japan. However, high haplotype diversity was also observed due to the occurrence of 10 rare haplotypes. This supports hypotheses (i) there have been additional, previous unrecorded, introductions as previously hypothesized by analysis of 16S rDNA, and (ii) there has been a limited loss of genetic diversity in introduced populations, as previously suggested by microsatellite data. This is the first genetic comparison of Manila clam populations introduced in to Europe with native clams. Genetic data herein presented are fundamentally important for the traceability of clam products and stock management programmes and will also inform discussion on the potential resilience of exploited Manila clam populations.

Detecting rare and common haplotype-environment interaction under uncertainty of gene-environment independence assumption.

Finding rare variants and gene-environment interactions (GXE) is critical in dissecting complex diseases. We consider the problem of detecting GXE where G is a rare haplotype and E is a nongenetic factor. Such methods typically assume G-E independence, which may not hold in many applications. A pertinent example is lung cancer-there is evidence that variants on Chromosome 15q25.1 interact with smoking to affect the risk. However, these variants are associated with smoking behavior rendering the assumption of G-E independence inappropriate. With the motivation of detecting GXE under G-E dependence, we extend an existing approach, logistic Bayesian LASSO, which assumes G-E independence (LBL-GXE-I) by modeling G-E dependence through a multinomial logistic regression (referred to as LBL-GXE-D). Unlike LBL-GXE-I, LBL-GXE-D controls type I error rates in all situations; however, it has reduced power when G-E independence holds. To control type I error without sacrificing power, we further propose a unified approach, LBL-GXE, to incorporate uncertainty in the G-E independence assumption by employing a reversible jump Markov chain Monte Carlo method. Our simulations show that LBL-GXE has power similar to that of LBL-GXE-I when G-E independence holds, yet has well-controlled type I errors in all situations. To illustrate the utility of LBL-GXE, we analyzed a lung cancer dataset and found several significant interactions in the 15q25.1 region, including one between a specific rare haplotype and smoking.

A soybean quantitative trait locus that promotes flowering under long days is identified as FT5a, a FLOWERING LOCUS T ortholog.

FLOWERING LOCUS T (FT) is an important floral integrator whose functions are conserved across plant species. In soybean, two orthologs, FT2a and FT5a, play a major role in initiating flowering. Their expression in response to different photoperiods is controlled by allelic combinations at the maturity loci E1 to E4, generating variation in flowering time among cultivars. We determined the molecular basis of a quantitative trait locus (QTL) for flowering time in linkage group J (Chromosome 16). Fine-mapping delimited the QTL to a genomic region of 107kb that harbors FT5a We detected 15 DNA polymorphisms between parents with the early-flowering (ef) and late-flowering (lf) alleles in the promoter region, an intron, and the 3' untranslated region of FT5a, although the FT5a coding regions were identical. Transcript abundance of FT5a was higher in near-isogenic lines for ef than in those for lf, suggesting that different transcriptional activities or mRNA stability caused the flowering time difference. Single-nucleotide polymorphism (SNP) calling from re-sequencing data for 439 cultivated and wild soybean accessions indicated that ef is a rare haplotype that is distinct from common haplotypes including lf The ef allele at FT5a may play an adaptive role at latitudes where early flowering is desirable.

Compatibilidad HLA donante-receptor y probabilidades de trasplante renal en una población colombiana

Introduction: In Colombia, despite the fact that kidney transplants are the most common type of transplant surgery, a great number of transplanted patients do not achieve the desired Human Leucocyte Antigen (hla) compatibility. hla compatibility plays an important role in graft survival; patients with matched-hla have a lower chance of graft-versus-host disease and graft ejection. Objective: To determine the probability of finding an hla-matched donor-recipient pairs according to hla−a, −b and −drb1 frequencies in a specific Colombian population. Materials and methods: The study included a total of 484 unrelated individuals (61 donors and 423 recipients) from the hla registry. hla alleles were determined by polymerase chain reaction sequence with specific indicators. Results: hla–A*02, –A*24, –B*35 and –DRB1*04 alleles showed the highest minimum allele frequency (>10%). In addition, hla–A*24–B*35–DRB1*04 was the most frequent extended haplotype in both donors and recipients (7.38 % and 6.76 %, respectively). Our experimental evidence showed that the maximum chance of finding at least one hla allele-matched kidney is 20.3 % for a patient with the most frequent extended haplotype, whereas for patients with rare or non-common haplotypes this probability is rather unlikely. Discussion: In terms of probability, the chance of finding an hla matched kidney donor/recipients in our region is low. This is due, at least in part, to the higher number of alleles and a the lower donation rate. Therefore, to define the hla profile of a population is important for establishing transplantation programs and alternative strategies in the kidney donation and allocation processes.

Chronic Rhinosinusitis Patients Show Accumulation of Genetic Variants in PARS2.

Genetic studies of chronic rhinosinusitis (CRS) have identified a total of 53 CRS-associated SNPs that were subsequently evaluated for their reproducibility in a recent study. The rs2873551 SNP in linkage disequilibrium with PARS2 showed the strongest association signal. The present study aims to comprehensively screen for rare variants in PARS2 and evaluate for accumulation of such variants in CRS-patients. Sanger sequencing and long-range PCR were used to screen for rare variants in the putative promoter region and coding sequence of 310 CRS-patients and a total of 21 variants were detected. The mutation spectrum was then compared with data from European populations of the 1000Genomes project (EUR) and the Exome Aggregation Consortium (ExAC). The CRS population showed a significant surplus of low-frequency variants compared with ExAC data. Haplotype analysis of the region showed a significant excess of rare haplotypes in the CRS population compared to the EUR population. Two missense mutations were also genotyped in the 310 CRS patients and 372 CRS-negative controls, but no associations with the disease were found. This is the first re-sequencing study in CRS research and also the first study to show an association of rare variants with the disease.