Functional Deletion/Insertion Promoter Variants in SCARB1 Associated With Increased Susceptibility to Lipid Profile Abnormalities and Coronary Heart Disease

Background: Genetic variants in Scavenger receptor Class B Type 1 (SCARB1) influencing high-density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD) risk were identified by recent genome-wide association studies. Further study of potential functional variants in SCARB1 may provide new ideas of the complicated relationship between HDL-C and CHD.Methods: 2000 bp in SCARB1 promoter region was re-sequenced in 168 participants with extremely high plasma HDL-C and 400 control subjects. Putative risk alleles were identified using bioinformatics analysis and reporter-gene assays. Two indel variants, rs144334493 and rs557348251, respectively, were genotyped in 5,002 CHD patients and 5,175 control subjects. The underlying mechanisms were investigated.Results: Through resequencing, 27 genetic variants were identified. Results of genotyping in 5,002 CHD patients and 5,175 control subjects revealed that rs144334493 and rs557348251 were significantly associated with increased risk of CHD [odds ratio (OR): 1.28, 95% confidence interval (CI): 1.09 to 1.52, p = 0.003; OR: 2.65, 95% CI: 1.66–4.24, p = 4.4 × 10−5). Subsequent mechanism experiments demonstrated that rs144334493 deletion allele attenuated forkhead box A1 (FOXA1) binding to the promoter region of SCARB1, while FOXA1 overexpression reversely increased SR-BI expression.Conclusion: Genetic variants in SCARB1 promoter region significantly associated with the plasma lipid levels by affecting SR-BI expression and contribute to the susceptibility of CHD.

House sparrows do not exhibit a preference for the scent of potential partners with different MHC-I allele numbers and genetic distances

MHC genes play a fundamental role in immune recognition of pathogens and parasites. Therefore, females may increase offspring heterozygosity and genetic diversity by selecting MHC genetically compatible or heterozygous males. In birds, several studies suggest that MHC genes play a role in mate choice, and recent evidence suggest that olfaction may play a role in such discrimination. Previous studies indicated that house sparrow females with low allelic diversity prefer males with higher diversity in MHC-I alleles. Here, we directly explored whether both house sparrow females and males could estimate by scent the number in MHC amino acid and functional variants as well as the level of MHC-I similarity or dissimilarity of potential partners. Our results show that neither females nor males exhibit a preference related to the number of MHC-I amino acid variants or functional variants or in relation to MHC amino acid or functional similarity of potential partners, suggesting that MHC-I is not detected through olfaction. Further studies are needed to understand the mechanisms responsible for MHC-I based mate discrimination in birds.

Analysis of coding variants in the human FTO gene from the gnomAD database

Single nucleotide polymorphisms (SNPs) in the first intron of the FTO gene reported in 2007 continue to be the known variants with the greatest effect on adiposity in different human populations. Coding variants in the FTO gene, on the other hand, have been little explored, although data from complete sequencing of the exomes of various populations are available in public databases and provide an excellent opportunity to investigate potential functional variants in FTO. In this context, this study aimed to track nonsynonymous variants in the exons of the FTO gene in different population groups employing the gnomAD database and analyze the potential functional impact of these variants on the FTO protein using five publicly available pathogenicity prediction programs. The findings revealed 345 rare mutations, of which 321 are missense (93%), 19 are stop gained (5.6%) and five mutations are located in the splice region (1.4%). Of these, 134 (38.8%) were classified as pathogenic, 144 (41.7%) as benign and 67 (19.5%) as unknown. The available data, however, suggest that these variants are probably not associated with BMI and obesity, but instead, with other diseases. Functional studies are, therefore, required to identify the role of these variants in disease genesis.

Association analysis and functional annotation of imputed sequence data within genomic regions influencing resistance to gastro-intestinal parasites detected by an LDLA approach in a nucleus flock of Sarda dairy sheep

Background Gastroinestinal nematodes (GIN) are one of the major health problem in grazing sheep. Although genetic variability of the resistance to GIN has been documented, traditional selection is hampered by the difficulty of recording phenotypes, usually fecal egg count (FEC). To identify causative mutations or markers in linkage disequilibrium (LD) to be used for selection, the detection of quantitative trait loci (QTL) for FEC based on linkage disequilibrium-linkage analysis (LDLA) was performed on 4097 ewes (from 181 sires) all genotyped with the OvineSNP50 Beadchip. Identified QTL regions (QTLR) were imputed from whole-genome sequences of 56 target animals of the population. An association analysis and a functional annotation of imputed polymorphisms in the identified QTLR were performed to pinpoint functional variants with potential impact on candidate genes identified from ontological classification or differentially expressed in previous studies. Results After clustering close significant locations, ten QTLR were defined on nine Ovis aries chromosomes (OAR) by LDLA. The ratio between the ANOVA estimators of the QTL variance and the total phenotypic variance ranged from 0.0087 to 0.0176. QTL on OAR4, 12, 19, and 20 were the most significant. The combination of association analysis and functional annotation of sequence data did not highlight any putative causative mutations. None of the most significant SNPs showed a functional effect on genes’ transcript. However, in the most significant QTLR, we identified genes that contained polymorphisms with a high or moderate impact, were differentially expressed in previous studies, contributed to enrich the most represented GO process (regulation of immune system process, defense response). Among these, the most likely candidate genes were: TNFRSF1B and SELE on OAR12, IL5RA on OAR19, IL17A, IL17F, TRIM26, TRIM38, TNFRSF21, LOC101118999, VEGFA, and TNF on OAR20. Conclusions This study performed on a large experimental population provides a list of candidate genes and polymorphisms which could be used in further validation studies. The expected advancements in the quality of the annotation of the ovine genome and the use of experimental designs based on sequence data and phenotypes from multiple breeds that show different LD extents and gametic phases may help to identify causative mutations.

Association of Serum Bilirubin and Functional Variants of Heme Oxygenase 1 and Bilirubin UDP-Glucuronosyl Transferase Genes in Czech Adult Patients with Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder worldwide. The aim of our study was to assess the role of bilirubin, and the heme oxygenase 1 (HMOX1) and bilirubin UDP-glucuronosyl transferase (UGT1A1) promoter gene variants, which are involved in bilirubin homeostasis, in the NAFLD development in adult patients. The study was performed on 84 patients with NAFLD and 103 age/sex-matched controls. Routine biochemistry, inflammatory markers, adipokines, and the fibrosis/steatohepatitis stage were determined in the NAFLD patients. The (GT)n/(TA)n dinucleotide variations in HMOX1/UGT1A1 gene promoters, respectively, were analyzed by fragment analysis. Compared to controls, serum bilirubin concentrations in NAFLD patients tended to be decreased, while the prevalence of phenotypic Gilbert syndrome was significantly low. Genetic variations in HMOX1 and UGT1A1 gene promoters did not differ between NAFLD patients and controls, and no relationship was found in the NAFLD patients between these gene variants and any of the laboratory or histological parameters. In conclusion, metabolism of bilirubin is dysregulated in NAFLD patients, most likely due to increased oxidative stress, since frequencies of the major functional variants in the HMOX1 or UGT1A1 gene promoters did not have any effect on development of NAFLD in adult patients.

The Teachers' Opinion about Online Learning Process for Children with Special Educational Needs

Communication in the online environment represents a real evolution for the whole society, hence for the educational system but because the whole change took place in a short span of time, the education has faced an unencountered challenge up to now. Component of the informational society, the educational dynamic and open system promotes nowadays ways of achieving the instructional educational process, offering to the teacher a multitude of organisational and functional variants. However, in the case of children with special educational needs, there are many barriers in the way of achieving their right to education in the virtual space. The present study consisted of achieving an inquiry-based questionnaire, applied to the teaching staff who works in inclusive education centres and to those who have students with different deficiencies and special educational needs in their class. The results of the study highlight both the difficulties and the opportunities of achieving a didactic activity in the online environment for students with special educational needs.

Study of association of migraine susceptibility genes with common migraine in 200,000 exome-sequenced UK Biobank participants

BackgroundA number of genes have been implicated in rare familial syndromes which have migraine as part of their phenotype but these genes have not previously been implicated in the common form of migraine.MethodsAmong exome-sequenced participants in the UK Biobank we identified 7,194 migraine cases with the remaining 193,433 participants classified as controls. We investigated ten genes previously reported to be implicated in conditions with migraine as a prominent part of the phenotype and carried out gene and variant based tests for association.ResultsWe found no evidence for association of these genes or variants with the common form of migraine seen in our subjects. In particular, a frameshift variant in KCNK18, F139Wfs*24, which had been shown to segregate with migraine with aura in a multiply affected pedigree was found in 196 (0.10%) controls as well as in 10 (0.14%) cases (χ2 = 0.96, 1 df, p = 0.33).ConclusionsSince there is no other reported evidence to implicate KCNK18, we conclude that this gene and its product, TRESK, should no longer be regarded as being involved in migraine aetiology. Overall, we do not find that rare, functional variants in genes previously implicated to be involved in familial syndromes including migraine as part of the phenotype make a contribution to the commoner forms of migraine observed in this population.

Linkage Guided Sequence Analysis Revealed a Novel Gene PKD1L2 for Adiponectin: The Long Life Family Study (LLFS)

Adiponectin is involved in regulating insulin resistance (IR) and is a potential regulator of healthy aging and lifespan. To identify novel variants associated with adiponectin, we further assessed our previously identified linkage peak on 16q23.2 (LODs=3.8). We used sequence data of 632 participants (age, 24-110 years) from 47 families of European ancestry in the Long Life Family Study, a study with familial clustering of exceptional longevity in the US and Denmark. Adiponectin levels were log-transformed, and adjusted for age, sex, sites, and PCs for ancestry. We found a variant in the PKD1L2 (rs527459046, p=2e-8, MAF=3%, r2=1.5%, accounting for linkage=28%). The PKD1L2, 1.4 Mb upstream of the CDH13 (adiponectin receptor gene) is expressed in heart, liver, and adipocytes, known to function as an ion-channel regulator or a GPCR regulator for aging-related lipolysis, IR, and adiponectin/leptin secretion. Haplotyping, epistatic and bioinformatic analyses will be engaged to capture additional/functional variants and regulatory networks.

Distribution of G6PD deficiency genotypes among Southeast Asian populations

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a group of X-linked, hereditary genetic disorders caused by mutations in the G6PD gene and results in functional variants of about 400 biochemical and clinical phenotypes. Among them, more than 215 genotypes have been identified so far. In this review, specific features of the genotype distribution in different communities and countries are discussed based on multiple reports and our molecular epidemiological studies of Southeast Asian countries. Particularly, in Indonesia, the frequency distribution of G6PD deficiency variants was distinct between western and eastern Indonesian populations, suggesting two different gene flows during Indonesian expansions.

Effects of functional variants of vitamin C transporter genes on apolipoprotein E E4-associated risk of cognitive decline: The Nakajima study

Apolipoprotein E E4 (APOE4) is a risk factor for cognitive decline. A high blood vitamin C (VC) level reduces APOE4-associated risk of developing cognitive decline in women. In the present study, we aimed to examine the effects of functional variants of VC transporter genes expressed in the brain (SLC2A1, SLC2A3, and SLC23A2) on APOE4-associated risk of developing cognitive decline. This case–control study involved 393 Japanese subjects: 252 cognitively normal and 141 cognitively impaired individuals (87 mild cognitive impairment and 54 dementia). Database searches revealed that rs1279683 of SLC23A2, and rs710218 and rs841851 of SLC2A1 are functional variants that are significantly associated with the altered expression of the respective genes and genotyped as three single nucleotide variants (SNVs). When stratified by SNV genotype, we found a significant association between APOE4 and cognitive decline in minor allele carriers of rs1279683 (odds ratio [OR] 2.02, 95% CI, 1.05–3.87, p = 0.035) but not in the homozygote carriers of the major allele. Significant associations between APOE4 and cognitive decline were also observed in participants with major allele homozygotes of rs710218 (OR 2.35, 95% CI, 1.05–5.23, p = 0.037) and rs841851 (OR 3.2, 95% CI, 1.58–6.46, p = 0.0012), but not in minor allele carriers of the respective SNVs. In contrast, the three functional SNVs showed no significant effect on cognitive decline. Our results imply that functional SNVs of VC transporter genes can affect APOE4-associated risk of developing cognitive decline via altered VC levels in the brain.