Association of <Emphasis Type="Italic">ACYP2</Emphasis> and <Emphasis Type="Italic">TSPYL6</Emphasis> Genetic Polymorphisms with Risk of Ischemic Stroke in Han Chinese Population

The development of ischemic stroke is associated with advanced age. Telomere length, as a marker of biological aging, has been reported to influence the risk of several age-related diseases, including ischemic stroke. Recent studies have identified the genetic variant within ACYP2 and TSPYL6 associated with shorter telomere length. The objective of this study is to investigate the putative association of ischemic stroke with common polymorphisms in ACYP2 and TSPYL6 genes in a Chinese Han population. We found that the risk alleles of six single nucleotide polymorphisms (SNPs), including rs11125529, rs12615793, rs843711, rs11896604, and rs843706 within both ACYP2 and TSPYL6, and rs17045754 in ACYP2 gene, were related with increased risk of ischemic stroke according to both allelic and genotype association analyses. The significant correlations between ACYP2 and TSPYL6 SNPs and ischemic stroke risk were also observed in dominant, recessive, and additive models, respectively. Two blocks in high linkage disequilibrium were identified in this study, and two haplotypes were associated with higher ischemic stroke susceptibility. In conclusion, the genetic polymorphisms of ACYP2 and TSPYL6 are associated with increased risk of developing ischemic stroke. Further studies with larger sample sizes are required to validate our findings.     

A multifaceted computational report on the variants effect on <Emphasis Type="Italic">KIR2DL3</Emphasis> and <Emphasis Type="Italic">IFNL3</Emphasis> candidate gene in HCV clearance

HCV infection causes acute and chronic liver diseases including, cirrhosis and hepatocellular carcinoma. Following HCV infection, spontaneous clearance occurs in approximately 20 % of the population dependant upon HCV genotype. In this study, functional and non-functional variant analysis was executed for the classical and the latest HCV clearance candidate genes namely, KIR2DL3 and IFNL3. Initially, the functional effects of non-synonymous SNPs were assigned on exposing to homology based tools, SIFT, PolyPhen-2 and PROVEAN. Further, UTR and splice sites variants were scanned for the gene expression and regulation changes. Subsequently, the haplotype and CNV were also identified. The mutation H77Y of KIR2DL3 and R157Q, H156Y, S63L, R157W, F179V, H128R, T101M, R180C, and F176I of IFNL3 results in conservation, RMSD, total energy, stability, and secondary structures revealed a negative impact on the structural fitness. UTRscan and the splice site result indicate functional change, which may affect gene regulation and expression. The graphical display of selected population shows alleles like rs270779, rs2296370, rs10423751, rs12982559, rs9797797, and rs35987710 of KIR2DL3 and rs12972991, rs12980275, rs4803217, rs8109886, and rs8099917 of IFNL3 are in high LD with a measure of \({\text{r}}^{2 }\ge 0.8\) broadcasting its protective effect in HCV clearance. Similarly, CNV report suggests major DNA fragment loss that could have a profound impact on the gene expression affecting the overall phenotype. This roundup report specifies the effect of NK cell receptor, KIR2DL3 and IFNL3 variants that can have a better prospect in GWAS and immunogenetic studies leading to better understanding of HCV clearance and progression.     

Role of allelic genes of matrix metalloproteinases and their tissue inhibitors in the risk of peptic ulcer disease development

Peptic ulcer disease is a chronic disease of the gastrointestinal tract, mainly manifesting itself in the formation of the fairly persistent ulcer defect of the mucous membrane of the stomach and/or duodenum. Association analysis of common polymorphisms of matrix metalloproteinases genes MMP-1 (rs1799750, rs494379), MMP-2 (rs2285052), MMP-3 (rs3025058), MMP-9 (rs3918242, rs17576), and MMP-12 (rs2276109) and their tissue inhibitors TIMP-2 (rs8179090) and TIMP-3 (rs9619311) was carried out in 353 patients with a gastric ulcer or duodenal ulcer and in 325 unrelated healthy individuals from the Republic of Bashkortostan. Associations of polymorphic variants rs1799750 and rs494379 of gene MMP-1, rs3025058 of gene MMP-3, rs3918242 and rs17576 of gene MMP-9, and rs9619311 of gene TIMP-3 with the risk of peptic ulcer disease in Russians and Tatars were revealed.     

Field Synopsis and Re-analysis of Systematic Meta-analyses of Genetic Association Studies in Multiple Sclerosis: a Bayesian Approach

To provide an up-to-date summary of multiple sclerosis-susceptible gene variants and assess the noteworthiness in hopes of finding true associations, we investigated the results of 44 meta-analyses on gene variants and multiple sclerosis published through December 2016. Out of 70 statistically significant genotype associations, roughly a fifth (21%) of the comparisons showed noteworthy false-positive rate probability (FPRP) at a statistical power to detect an OR of 1.5 and at a prior probability of 10^?6 assumed for a random single nucleotide polymorphism. These associations (IRF8/rs17445836, STAT3/rs744166, HLA/rs4959093, HLA/rs2647046, HLA/rs7382297, HLA/rs17421624, HLA/rs2517646, HLA/rs9261491, HLA/rs2857439, HLA/rs16896944, HLA/rs3132671, HLA/rs2857435, HLA/rs9261471, HLA/rs2523393, HLA-DRB1/rs3135388, RGS1/rs2760524, PTGER4/rs9292777) also showed a noteworthy Bayesian false discovery probability (BFDP) and one additional association (CD24 rs8734/rs52812045) was also noteworthy via BFDP computation. Herein, we have identified several noteworthy biomarkers of multiple sclerosis susceptibility. We hope these data are used to study multiple sclerosis genetics and inform future screening programs.     

LncRNA <Emphasis Type="Italic">ANRIL</Emphasis> Expression and <Emphasis Type="Italic">ANRIL</Emphasis> Gene Polymorphisms Contribute to the Risk of Ischemic Stroke in the Chinese Han Population

The aim of the present study was to explore the role of lncRNA ANRIL in the pathogenesis of ischemic stroke (IS) and coronary artery disease (CAD) and to determine the association between ANRIL variants and the genetic susceptibility of IS and CAD in the Chinese Han population. A genetic association study including 550 IS patients, 550 CAD patients, and 550 healthy controls was conducted. The expression levels of lncRNA ANRIL, CDKN2A, and CDKN2B were detected using qRT-PCR. Genotyping was performed by Sequenom MassARRAY on an Agena platform. Our study showed that IS patients had an increased lncRNA ANRIL expression (P?=?0.002) and a decreased CDKN2A expression (P?<?0.001) compared with normal controls. A significant difference with regard to the genotype distribution of rs2383207 was found between male IS patients and controls (P?=?0.011). The minor allele of rs2383207 significantly increased the IS risk under a recessive model (OR?=?1.52, 95% CI?=?1.05–2.21, P?=?0.027). The minor allele of rs1333049 was significantly associated with the risk of IS among the male patients under a recessive model (OR?=?1.56, 95% CI?=?1.04–2.35, P?=?0.031). However, no significant association was found between the ANRIL variants and the risk of CAD (all P?>?0.050). In addition, we found a decreased lncRNA ANRIL expression in IS patients who carried the GG genotype of rs1333049 compared with IS patients who carried the CC or CG genotype (P?=?0.041). In summary, we found that IS patients had an increased lncRNA ANRIL expression and a decreased CDKN2A expression compared with the controls, which might play an impellent role in pathological processes of IS. The ANRIL variants rs2383207 and rs1333049 were significantly associated with the risk of IS among males but not females in the Chinese Han population.     

Gemcabene,a first-in-class lipid-lowering agent in late-stage development,down-regulates acute-phase C-reactive protein via C/EBP-δ-mediated transcriptional mechanism

The marked clinical and genetic heterogeneity seen in hypertrophic (HCM) and dilated cardiomyopathies (DCM) suggests involvement of disease modifiers and environmental factors in the pathophysiology of these diseases. In the current study, we examined association of single nucleotide polymorphisms (SNPs) of three candidate genes, ACE2 (rs6632677), TNNI3K (rs49812611) and CALM3 (rs13477425) with clinical phenotypes of HCM and DCM patients of North Indian ethnicity. Prevalence of ACE2 (7160726 C>G) variant genotypes (CG and GG) was significantly higher in DCM subjects as compared to controls. Prevalence of TNNI3K (3784 C>T) and CALM3 (?34T>A) variant homozygous genotype were significantly higher in HCM and DCM subjects as compared to controls. DCM patients with CT genotype showed significant decrease in LVEF as compared to CC genotype (p < 0.03). There was significant gene–gene interaction between these SNPs and three-way SNP combination of ACE2 C>G, TNN13K C>T, CALM3 A>T gene variants and was associated with high risk of HCM and DCM. Presence of ACE2 (7160726 C>G) and CALM3 (?34T>A) variant genotypes in HCM Patients with mutations (sarcomeric or non sarcomeric genes) was associated with increased mean septal thickness, further suggesting a role of these gene variants in modifying disease phenotype. Our results suggest that ACE2, TNNI3K and CALM3 polymorphisms are associated with increased risk of HCM and DCM and may act as disease modifiers of these diseases.     

The analysis of association between type 2 diabetes and polymorphic markers in the <Emphasis Type="Italic">CDKAL1</Emphasis> gene and in the <Emphasis Type="Italic">HHEX/IDE</Emphasis> locus

The increase in diabetes was noted at the turn of the 21st century. Patients with type 2 diabetes (T2DM) make up the majority of patients. Diabetes is a multifactorial disease. It arises from adverse effects of environmental factors on the body of genetically susceptible peoples. According to modern concepts, T2DM is a polygenic disease. Each of the involved genes contributes to the risk of developing of this disease. In our study, the association between polymorphic genetic markers rs7756992, rs9465871, rs7754840, and rs10946398 in the CDKAL1 gene and rs1111875 in the HHEX/IDE locus and T2DM in the Russian population were studied. Four hundred forty patients with type 2 diabetes and 264 healthy individuals without any signs of the disease were examined. The comparative analysis of distribution of genotypes and allele frequencies points to an association between polymorphic genetic markers rs7756992, rs9465871, and rs10946398 in the CDKAL1 gene and this disease. For the other polymorphic genetic markers (rs7754840 in the CDKAL1 gene and rs1111875 in the HHEX/IDE locus), no statistically significant associations are found. On the basis of these data, we can conclude that the CDKAL1 gene is associated with development of T2DM. For the HHEX/IDE locus, such an association is absent.     

Effects of <Emphasis Type="Italic">HLA</Emphasis>-<Emphasis Type="Italic">DRB1</Emphasis>/<Emphasis Type="Italic">DQB1</Emphasis> Genetic Variants on Neuroimaging in Healthy,Mild Cognitive Impairment,and Alzheimer’s Disease Cohorts

Alzheimer’s disease (AD) is the most common form of dementia and exhibits a considerable level of heritability. Previous association studies gave evidence for the associations of HLA-DRB1/DQB1 alleles with AD. However, how and when the gene variants in HLA-DRB1/DQB1 function in AD pathogenesis has yet to be determined. Here, we firstly investigated the association of gene variants in HLA-DRB1/DQB1 alleles and AD related brain structure on magnetic resonance imaging (MRI) in a large sample from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We selected hippocampus, subregion, parahippocampus, posterior cingulate, precuneus, middle temporal, entorhinal cortex, and amygdala as regions of interest (ROIs). Twelve SNPs in HLA-DRB1/DQB1 were identified in the dataset following quality control measures. In the total group hybrid population analysis, our study (rs35445101, rs1130399, and rs28746809) were associated with the smaller baseline volume of the left posterior cingulate and rs2854275 was associated with the larger baseline volume of the left posterior cingulate. Furthermore, we detected the above four associations in mild cognitive impairment (MCI) sub-group analysis, and two risk loci (rs35445101 and rs1130399) were also the smaller baseline volume of the left posterior cingulate in (NC) sub-group analysis. Our study suggested that HLA-DRB1/DQB1 gene variants appeared to modulate the alteration of the left posterior cingulate volume, hence modulating the susceptibility of AD.     

Genetic Association of <Emphasis Type="Italic">HLA</Emphasis> Gene Variants with MRI Brain Structure in Alzheimer’s Disease

There is accumulating evidence that the human leukocyte antigen (HLA) gene variants are associated with Alzheimer’s disease (AD). However, how they affect AD occurrence is still unknown. In this study, we firstly investigated the association of gene variants in HLA gene variants and brain structures on MRI in a large sample from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to explore the effects of HLA on AD pathogenesis. We selected hippocampus, hippocampus CA1 subregion, parahippocampus, posterior cingulate, precuneus, middle temporal, entorhinal cortex, and amygdala as regions of interest (ROIs). According to the previous association studies of HLA variants and AD, 12 SNPs in HLA were identified in the dataset following quality control measures. In total group analysis, our results showed that TNF-α SNPs at rs2534672 and rs2395488 were significantly positively associated with the volume of the left middle temporal lobe (rs2534672: P?=?0.00035, Pc?=?0.004; rs2395488: P?=?0.0038, Pc?=?0.023) at baseline. In the longitudinal study, HFE rs1800562 was remarkably correlated with the lower atrophy rate of right middle temporal lobe (P?=?0.0003, Pc?=?0.003) and RAGE rs2070600 was associated with the atrophy rate of right hippocampus substructure-CA1 over 2 years (P?=?0.003, Pc?=?0.035). Furthermore, we detected the above four associations in mild cognitive impairment (MCI) subgroup analysis, as well as the association of rs2534672 with the baseline volume of the left middle temporal lobe in normal cognition (NC) subgroup analysis. Our study provided preliminary evidences that HLA gene variants might participate in the structural alteration of AD associated brain regions, hence modulating the susceptibility of AD.     

<Emphasis Type="Italic">PPARGC1B</Emphasis> gene is associated with Kashin-Beck disease in Han Chinese

Kashin-Beck disease (KBD) is a chronic osteochondropathy. The genetic basis of KBD remains elusive now. To investigate the relationship between PPARGC1B gene polymorphism and KBD, we conducted a two-stage association study using 2743 unrelated Han Chinese subjects. In the first stage, three SNPs rs1078324, rs4705372, and rs11743128 of PPARGC1B gene were genotyped in 559 KBD patients and 467 health controls using Sequenom MassARRAY platform. In the second stage, the association analysis results of PPARGC1B with KBD were replicated using an independent sample of 1717 subjects. SNP association analysis was conducted by PLINK software. Genotype imputation was conducted by IMPUTE 2.0 against the reference panel of the 1000 genome project. Bonferroni multiple testing correction was performed. We observed a significant association signal at rs4705372 (P?=?0.0160) and a suggestive association signal at rs11743128 (P?=?0.0290). Further replication study confirmed the association signals of rs4705372 (P?=?0.0026) and rs11743128 (P?=?0.0387) in the independent validation sample. Our study results suggest that PPARGC1B is a novel susceptibility gene of KBD.     

Analysis of <Emphasis Type="Italic">H63D</Emphasis> mutation in hemochromatosis (<Emphasis Type="Italic">HFE</Emphasis>) gene in populations of Central Eurasia

An analysis of the frequency of H63D (c.187C>G) mutations in the HFE gene in 19 populations from Central Eurasia demonstrated that the distribution of the mutation in the region of interest was not uniform and that there were the areas of H63D accumulation. The investigation of three polymorphic variants, c.340+4T>C (rs2071303, IVS2(+4)T>C), c.893-44T>C (rs1800708, IVS4(-44)T>C), and c.1007-47G>A (rs1572982, IVS5(-47)A>G), in the HFE gene in individuals homozygous for H63D mutations in the HFE gene revealed the linkage of H63D with three haplotypes, *CTA, *TTG, and *TTA. These findings indicated the partial spread of the mutation in Central Eurasia from Western Europe, as well as the possible repeated appearance of the mutation on the territory on interest.     

Association of <Emphasis Type="Italic">FGFR2</Emphasis> (rs2981579) gene polymorphism with the risk of mesial occlusion

The molecular-genetic testing of the polymorphic rs2981579 (C>T) locus of the FGFR2 gene as the marker of increased predisposition to the development of mesial occlusion was carried out in 110 patients with mesial occlusion and 103 general-population control subjects from Ukraine. It was shown that polymorphism rs2981579 in gene FGFR2 is associated with mesial occlusion (OR = 1.67, 95% CI = 1.14–2.45, p = 0.009). Compared to CC carriers, TT+CT carriers had a 3.21-fold higher risk of mesial occlusion (95% CI = 1.57–6.57, p = 0.001). We found the protective effect of the homozygous allele C on mesial occlusion development (OR = 0.31, p = 0.001). This is the first published data on FGFR2 polymorphisms rs2981579 (C>T) in patients with mesial occlusion.     

Haplotype-specific <Emphasis Type="Italic">MAPT</Emphasis> exon 3 expression regulated by common intronic polymorphisms associated with Parkinsonian disorders

Background

Genome wide association studies have identified microtubule associated protein tau (MAPT) H1 haplotype single nucleotide polymorphisms (SNPs) as leading common risk variants for Parkinson’s disease, progressive supranuclear palsy and corticobasal degeneration. The MAPT risk variants fall within a large 1.8 Mb region of high linkage disequilibrium, making it difficult to discern the functionally important risk variants. Here, we leverage the strong haplotype-specific expression of MAPT exon 3 to investigate the functionality of SNPs that fall within this H1 haplotype region of linkage disequilibrium.

Methods

In this study, we dissect the molecular mechanisms by which haplotype-specific SNPs confer allele-specific effects on the alternative splicing of MAPT exon 3. Firstly, we use haplotype-hybrid whole-locus genomic MAPT vectors studies to identify functional SNPs. Next, we characterise the RNA-protein interactions at two loci by mass spectrometry. Lastly, we knockdown candidate splice factors to determine their effect on MAPT exon 3 using a novel allele-specific qPCR assay.

Results

Using whole-locus genomic DNA expression vectors to express MAPT haplotype variants, we demonstrate that rs17651213 regulates exon 3 inclusion in a haplotype-specific manner. We further investigated the functionality of this region using RNA-electrophoretic mobility shift assays to show differential RNA-protein complex formation at the H1 and H2 sequence variants of SNP rs17651213 and rs1800547 and subsequently identified candidate trans-acting splicing factors interacting with these functional SNPs sequences by RNA-protein pull-down experiment and mass spectrometry. Finally, gene knockdown of candidate splice factors identified by mass spectrometry demonstrate a role for hnRNP F and hnRNP Q in the haplotype-specific regulation of exon 3 inclusion.

Conclusions

We identified common splice factors hnRNP F and hnRNP Q regulating the haplotype-specific splicing of MAPT exon 3 through intronic variants rs1800547 and rs17651213. This work demonstrates an integrated approach to characterise the functionality of risk variants in large regions of linkage disequilibrium.

     

Longitudinal analytical approaches to genetic data

Background

Longitudinal phenotypic data provides a rich potential resource for genetic studies which may allow for greater understanding of variants and their covariates over time. Herein, we review 3 longitudinal analytical approaches from the Genetic Analysis Workshop 19 (GAW19). These contributions investigated both genome-wide association (GWA) and whole genome sequence (WGS) data from odd numbered chromosomes on up to 4 time points for blood pressure–related phenotypes. The statistical models used included generalized estimating equations (GEEs), latent class growth modeling (LCGM), linear mixed-effect (LME), and variance components (VC). The goal of these analyses was to test statistical approaches that use repeat measurements to increase genetic signal for variant identification.

Results

Two analytical methods were applied to the GAW19: GWA using real phenotypic data, and one approach to WGS using 200 simulated replicates. The first GWA approach applied a GEE-based model to identify gene-based associations with 4 derived hypertension phenotypes. This GEE model identified 1 significant locus, GRM7, which passed multiple test corrections for 2 hypertension-derived traits. The second GWA approach employed the LME to estimate genetic associations with systolic blood pressure (SBP) change trajectories identified using LCGM. This LCGM method identified 5 SBP trajectories and association analyses identified a genome-wide significant locus, near ATOX1 (p?=?1.0E^?8). Finally, a third VC-based model using WGS and simulated SBP phenotypes that constrained the β coefficient for a genetic variant across each time point was calculated and compared to an unconstrained approach. This constrained VC approach demonstrated increased power for WGS variants of moderate effect, but when larger genetic effects were present, averaging across time points was as effective.

Conclusion

In this paper, we summarize 3 GAW19 contributions applying novel statistical methods and testing previously proposed techniques under alternative conditions for longitudinal genetic association. We conclude that these approaches when appropriately applied have the potential to: (a) increase statistical power; (b) decrease trait heterogeneity and standard error; (c) decrease computational burden in WGS; and (d) have the potential to identify genetic variants influencing subphenotypes important for understanding disease progression.

     

Association of polymorphic markers of chemokine genes,their receptors,and <Emphasis Type="Italic">CD14</Emphasis> gene with coronary atherosclerosis

Atherosclerosis represents an inflammatory response to the disturbance of the endothelial layer in the arterial bloodstream. In the present study, an analysis of associations of polymorphic markers for the genes controlling synthesis of proteins involved in atherosclerosis pathogenesis in coronary atherosclerosis (CA) patients (217 subjects) and in a control group (250 subjects) was conducted. The following genes were examined: rs991804 (CCL2 gene), rs1126579 (CXCR2 gene), rs4074 (CXCL1 gene), rs4073 (CXCL8 gene), rs333 (CCR5 gene), rs2471859 (CXCR4 gene), rs1801157 (CXCL12 gene), and rs2569190 (CD14 gene). Using the Monte Carlo and Markov chain (APSampler) method, allele/genotype combinations associated with both low and high CA risk were revealed. The most important findings included the following: CXCR4*T/T + CCL2*C + CCR5*I/I (P_perm = 1 × 10^–6, OR = 0.44, 95% CI 0.3–0.63), CXCR2*C + CD14*C + CXCL12*G + CCL2*C + CCR5*D (P_perm = 4 × 10^–6, OR = 5.78, 95% CI 2.34–14.28), CD14*C + CCL2*C/C + CCR5*D (P_perm = 6.3 × 10^–6, OR = 5.81, 95% CI 2.17–15.56), CXCL8*A + CXCR2*C + CD14*T + CXCR4*C (P_perm = 0.01, OR = 3.21, 95% CI 1.63–6.31).     

Association between smoking behaviour and genetic variants of glial cell line-derived neurotrophic factor

Glial cell line-derived neurotrophic factor (GDNF) promotes development and differentiation of dopaminergic neurons, thus it has an important role in dopamine-related neuropsychiatric disorders. Since the role of dopamine system in smoking is well established, we hypothesized that GDNF gene variants may affect smoking behaviour. Self-reported data on smoking behaviour (never smoked, quit, occasional, or regular smokers) and level of nicotine addiction (Hooked on Nicotine Checklist and Fagerstrom Nicotine Addiction Scale), anxiety, as well as buccal samples were obtained from 930 Hungarian young adults (18–35 years). Genetic analysis involved eight GDNF single-nucleotide polymorphisms (SNP) (rs1981844, rs3812047, rs3096140, rs2973041, rs2910702, rs1549250, rs2973050 and rs11111). Allele-wise association analyses of the eight GDNF SNPs provided a significant association between smoking behaviour and rs3096140 (P = 0.0039). The minor allele (C) was more frequent in those groups who smoked in some form (quit, occasional or regular smokers) as compared to those who never smoked (P = 0.0046). This result remained significant after Bonferroni correction for multiple testing. In the ever smoking group, no significant differences were found in the level of nicotine addiction by the alleles of these polymorphisms. Also, no significant interaction of rs3096140 and smoking categories were observed on anxiety mean scores. Although previous data demonstrated an association between GDNF rs2910704 and severity of methamphetamine use to the best of our knowledge, this is the first study on the role of GDNF genetic variations in smoking behaviour. Our results suggest that GDNF rs3096140 might be involved in the genetic background of smoking, independent of anxiety characteristics.     

<Emphasis Type="Italic">SNCA</Emphasis> alleles rs356219 and rs356165 are associated with Parkinson’s disease and increased α-synuclein gene expression in CD45<Superscript>+</Superscript> blood cells

Impaired metabolism of α-synuclein (SNCA) and its aggregation are key molecular events underlying Parkinson’s disease (PD). Emerging data show that there is a connection between PD and the gene locus containing the SNCA gene. Meta-analyses have demonstrated a highly significant PD connection with single nucleotide polymorphisms (SNPs) rs356165 (A/G) and rs356219 (A/G) in the SNCA gene. We conducted SNP genotyping in 260 PD patients (n = 260) and 262 healthy people (n = 262) from northwestern regions of Russia. Linkage disequilibrium was registered between rs356219 and rs356165 alleles (D' = 0.926). It was confirmed that G alleles (rs356165 and rs356219) are associated with increased risk of PD development. For the first time, we have evaluated the relationship between rs356165 and rs356219 and levels of SNCA mRNA and α-synuclein protein in CD45⁺ peripheral blood cells in drug-naïve PD patients (n = 43) and controls (n = 39). Both the level of mRNA SNCA gene and that of α-synuclein protein were increased in carriers of rs356219 and rs356165 compared to carriers with AA genotype in control group (in the group of healthy people) (p = 0.046 and p = 0.039, respectively). Linkage disequilibrium was shown between associated marker alleles. Our data suggest that rs356165 and rs356219 allele variants may affect the PD development by up-regulation of SNCA expression.     

Association of <Emphasis Type="Italic">PALB2</Emphasis> sequence variants with the risk of early-onset breast cancer in patients from Turkey

The PALB2 gene, has been accepted as a moderate-penetrance gene associated with breast cancer susceptibility and this gene product is involved in the DNA damage repair pathway via co-localization with BRCA2. Germline PALB2 mutations are associated with an increased breast cancer risk. However, the prevalence of the diverse types of PALB2 variants depend on the population. Thus, the aim of the present study was to determine, for the first time, the prevalence of PALB2 variants in a Turkish population of BRCA1/BRCA2-negative early-onset patients with breast cancer. In total, 223 Turkish patients with BRCA1/BRCA2 negative early-onset breast cancer and 60 unaffected women were included in the study. All the coding exons and intron/exon boundaries of PALB2 were subjected to mutational analysis by heteroduplex analysis (HDA)and DNA sequencing. Eighteen PALB2 variants were found in breast cancer patients within the Turkish population. Three variants (c.271G>A, c.404C>A and c.2981T>A) have not been previously reported. In addition, nine intronic variants were described, and this study is the first to describe the c.1685-44T>A intronic variant. The prevalence of possible pathogenic PALB2 variants was found to be 4.03 % in BRCA1/2-negative Turkish patients with early-onset breast cancer. Different variants of PALB2 have been reported in the literature, and the prevalence of these variants could different for each population. This is the first study to investigate the prevalence of PALB2 variants in Turkish patients with early-onset breast cancer.     

Targeted imputation of sequence variants and gene expression profiling identifies twelve candidate genes associated with lactation volume,composition and calving interval in dairy cattle

Dairy cattle are an interesting model for gaining insights into the genes responsible for the large variation between and within mammalian species in the protein and fat content of their milk and their milk volume. Large numbers of phenotypes for these traits are available, as well as full genome sequence of key founders of modern dairy cattle populations. In twenty target QTL regions affecting milk production traits, we imputed full genome sequence variant genotypes into a population of 16,721 Holstein and Jersey cattle with excellent phenotypes. Association testing was used to identify variants within each target region, and gene expression data were used to identify possible gene candidates. There was statistical support for imputed sequence variants in or close to BTRC, MGST1, SLC37A1, STAT5A, STAT5B, PAEP, VDR, CSF2RB, MUC1, NCF4, and GHDC associated with milk production, and EPGN for calving interval. Of these candidates, analysis of RNA-Seq data demonstrated that PAEP, VDR, SLC37A1, GHDC, MUC1, CSF2RB, and STAT5A were highly differentially expressed in mammary gland compared to 15 other tissues. For nine of the other target regions, the most significant variants were in non-coding DNA. Genomic predictions in a third dairy breed (Australian Reds) using sequence variants in only these candidate genes were for some traits more accurate than genomic predictions from 632,003 common SNP on the Bovine HD array. The genes identified in this study are interesting candidates for improving milk production in cattle and could be investigated for novel biological mechanisms driving lactation traits in other mammals.