Differences In Allele Frequencies Research Articles

The frequency of rs2231142 in ABCG2 among Native Hawaiian and Pacific Islander subgroups: implications for personalized rosuvastatin dosing.

Statins are among the most commonly prescribed medications worldwide. Rosuvastatin is a moderate- to high-intensity statin depending on the prescribed dose. Statin-associated muscle symptoms are the main side effects, contributing to low adherence to statins. The missense variant rs2231142 in ABCG2 affects the functionality of the ABCG2 transporter, altering the pharmacokinetics and pharmacodynamics of rosuvastatin. This special report aims to accentuate the importance of considering the ABCG2 genotype upon prescribing rosuvastatin in high cardiovascular disease risk subgroups, specifically Native Hawaiian and Pacific Islander populations. Based on the reported frequencies of rs2231142 in ABCG2, it may be justifiable to initiate low-dose rosuvastatin in Samoans relative to Marshallese or Native Hawaiians. Interpopulation differences in pharmacogenetic allele frequencies underscore the need to disaggregate broad population categories to achieve health equity in treatment outcomes.

Pharmacogenomic variabilities in geo-ancestral subpopulations and their clinical implications: Results of collaborations with Hmong in the United States.

Underrepresentation of subpopulations within geo-ancestral groups engaged in research can exacerbate health disparities and impair progress toward personalized medicine. This is particularly important when implementing pharmacogenomics which uses genomic-based sources of variability to guide medication selection and dosing. This mini-review focuses on pharmacogenomic findings with Hmong in the United States and their potential clinical implications. By actively engaging Hmong community in pharmacogenomic-based research, several clinically relevant differences in allele frequencies were observed within key pharmacogenes such as CYP2C9 and CYP2C19 in Hmong compared to those in either East Asians or Europeans. Additionally, using state-of-the-art genome sequencing approaches, Hmong appear to possess novel genetic variants within CYP2D6, a critical pharmacogene affecting pharmacokinetics of a broad range of medications. The allele frequency differences and novel alleles in Hmong have translational impact and real-world clinical consequences. For example, Hmong patients exhibited a lower warfarin stable dose requirement compared to East Asian patients. This was predicted based on Hmong's unique genetic and non-genetic factors and confirmed using real-world data from clinical practice settings. By presenting evidence of the genetic uniqueness and its translational impact within subpopulations, such as the Hmong, we hope to inspire greater inclusion of other geo-ancestrally underrepresented subpopulations in pharmacogenomic-based research.

Genomic divergence of hatchery- and natural-origin Chinook salmon (Oncorhynchus tshawytscha) in two supplemented populations

Captive propagation is widely used for the conservation of imperiled populations. There have been concerns about the genetic effects of such propagation, but few studies have measured this directly at a genomic level. Here, we use moderate-coverage (10X) genome sequences from 80 individuals to evaluate the genomic distribution of variation of several paired groups of Chinook salmon (Oncorhynchus tshawytscha). These include (1) captive- and natural-origin fish separated by at least one generation, (2) fish within the same generation having high fitness in captivity compared to those with high fitness in the wild, and (3) fish listed as different Evolutionarily Significant Units (ESUs) under the US Endangered Species Act. The distribution of variation between high-fitness captive and high-fitness natural fish was nearly identical to that expected from random sampling, indicating that differential selection in the two environments did not create large allele frequency differences within a single generation. In contrast, the samples from distinct ESUs were clearly more divergent than expected by chance, including a peak of divergence near the GREB1L gene on chromosome 28, a gene previously associated with variation in time of return to fresh water. Comparison of hatchery- and natural-origin fish within a population fell between these extremes, but the maximum value of FST was similar to the maximum between ESUs, including a peak of divergence on chromosome 8 near the slc7a2 and pdgfrl genes. These results suggest that efforts at limiting genetic divergence between captive and natural fish in these populations have successfully kept the average divergence low across the genome, but at a small portion of their genomes, hatchery and natural salmon were as distinct as individuals from different ESUs.

Association of rs142548867 (EEFSEC) and periodontitis Grade C in a young Brazilian population.

Periodontitis Stage III-IV, Grade C (PerioC) is a severe form of Periodontitis. The individual genetic background has been shown to be an important etiopathogenic factor for the development of this disease in young, systemically healthy, and non-smokers patients. Recently, after exome sequencing of families with a history of the disease, PerioC was associated with three single nucleotide variations (SNVs) - rs142548867 (EEFSEC), rs574301770 (ZNF136), and rs72821893 (KRT25) - which were classified as deleterious or possibly harmful by prediction algorithms. Seeking to validate these findings in a cohort evaluation, this study aims to characterize the allele and genotypic frequency of the SNVs rs142548867, rs574301770, and rs72821893 in the Brazilian population with PerioC and who were periodontally healthy (PH). Thus, epithelial oral cells from 200 PerioC and 196 PH patients were harvested at three distinct centers at the Brazilian Southern region, their DNA were extracted, and the SNVs rs142548867, rs574301770, rs72821893 were genotyped using 5'-nuclease allelic discrimination assay. Differences in allele and genotype frequencies were analyzed using Fisher's Exact Test. Only the SNV rs142548867 (C > T) was associated with PerioC. The CT genotype was detected more frequently in patients with PerioC when compared with PH subjects (6% and 0.5% respectively), being significantly associated with PerioC (odds ratio 11.76, p=0.02). rs142548867 represents a potential risk for the occurrence of this disease in the Brazilian population.

Genetic Variants Associated with High Susceptibility of Premature Ischemic Stroke.

Several polymorphisms had been associated with an increased risk of ischemic stroke, but results are inconclusive. The aim of this study was to examine the association between AGTR1 A1166C and TSP-1 N700S polymorphisms and ischemic stroke in a young Mexican population. In a case-control study, 250 patients ≤ 45 years of age with ischemic stroke and 250 controls matched by age and gender were included. The polymorphisms were determined in all participants by polymerase chain reaction. There were statistical differences in genotype distribution (p = 0.01) and allele frequency (p = 0.001) of AGTR1 A1166C polymorphism. In contrast, there was a similar genotype distribution (p = 0.96) and allele frequency (p = 0.76) of the TSP1 N700S genetic variant between groups. Hypertension (p = 0.03), smoking (p = 0.02), and family history of atherothrombotic disease (p = 0.04) were associated with stroke, but not diabetes (p = 0.30) and dyslipidemia (p = 0.08). This is the first study in Mexican population to explore several genetic variants in young patients with ischemic stroke. Our results suggest that polymorphisms in the renin-angiotensin-aldosterone system could contribute to premature hypertension, endothelial dysfunction, atherothrombosis, vasoconstriction, smooth muscle cell migration, and proliferation. In contrast, polymorphisms in the coagulation factors are not associated with ischemic stroke. Environmental factors such as diabetes and dyslipidemia could be less important in the pathogenesis of ischemic stroke at a young age. We suggest that those polymorphisms should be determined in individuals with a family history of thrombosis to avoid the stroke development. Therefore, genotype-environmental combination could determine several possible phenotypes at different moments in life.

Polymorphism and Association of the E-selectin and ICAM-1-K469E Genes with Sickle Cell Disease in Congo

Introduction: E-selectin and ICAM-1 are cellular adhesion molecules that play important roles in the pathogenesis of Sickle Cell Disease (SCD), especially in the vaso-occlusion process. Numerous studies reported that single nucleotide polymorphisms in E-selectin and ICAM-1 genes may be associated with the clinical expression of several diseases. However, no evidence exists regarding the association with SCD. Objectives: Investigate the association of E-selectins (S128R and S149R) and ICAM-1K469E polymorphisms with SCD in Congolese patients. Methodology: This case-control study included 110 SCD patients in vaso-occlusive pain crisis and 120 controls (healthy non-sickle cell subjects). Polymorphisms were genotyped by PCR-RFLP method. The differences in genotype and allele frequencies between both groups were analyzed with the Fisher’s exact test. A P level of <0.05 was considered significant. Results: The frequency of the ICAM-1-K469E EE genotype was significantly higher in SCD patients compared to controls (8.2% vs 0.8%; P=0.008). The odd ratio value (OR=11.89; 95% CI = 1.48-96.53; P=0.01) indicated a high association with SCD. Furthermore, the E allele was also significantly associated with SCD (OR=1.72; 95% CI=1.10-2.68; P=0.008). By contrast, no statistically significant differences were found between SCD patients and controls regarding the allele and genotype frequencies of E- selectin S128R and S149R polymorphisms. Conclusion: Our findings suggest that the ICAM-1-K469E polymorphism may be associated with SCD among Congolese patients, possibly with the vaso-occlusive crisis. The EE genotype and the E allele may be genetic risk factors. However, because of the small sample size, this report should be considered as exploratory and further studies are required to confirm these genetic associations with SCD.

The impact of QTL sharing and properties on multi-breed GWAS in cattle: a simulation study

Context Genome-wide association studies (GWAS) and meta-analyses can be used to detect variants that affect quantitative traits. Multi-breed GWAS may lead to increased power and precision compared with within-breed GWAS. However, not all causal variants segregate in all breeds, and variants that segregate in multiple breeds may have different allele frequencies in different breeds. It is not known how differences in minor allele frequency (MAF) affect multi-breed GWAS and meta-analyses. Aims Our aim was to study the impact of differences in MAF at causal variants on mapping power and precision. Methods We used real imputed sequence data to simulate quantitative traits in three dairy cattle breeds. Causal variants (QTN) were simulated according to the following three scenarios: variants with a similar MAF in all breeds, variants with a lower MAF in one breed than the other, and variants that each only segregated in one of the breeds. We analysed the simulated quantitative traits with three methods to compare mapping power and precision: within-breed GWAS, multi-breed GWAS and meta-analysis. Key results Our results indicated that the multi-breed analyses (multi-breed GWAS or meta-analysis) detected similar or more QTN than did within-breed GWAS, with improved mapping precision in most scenarios. However, when MAF differed between breeds, or variants were breed specific, the advantage of the multi-breed analyses over within breed GWAS decreased. Regardless of the type of QTN (similar MAF in all breeds, different MAF in different breeds, or only segregating in one breed), multi-breed GWAS and meta-analyses performed similar or better than did within-breed GWAS, demonstrating the benefits of multi-breed GWAS. We did not find large differences between the results obtained with the meta-analysis and multi-breed GWAS, confirming that a meta-analysis can be a suitable approximation of a multi-breed GWAS. Conclusions Our results showed that multi-breed GWAS and meta-analysis generally detect more QTN with improved precision than does within-breed GWAS, and that even with differences in MAF, multi-breed analyses did not perform worse than within-breed GWAS. Implications Our study confirmed the benefits of multi-breed GWAS and meta-analysis.

Comparison of Risk Allele Frequencies of Psoriasis-Associated Single-Nucleotide Polymorphisms in Different Population Groups.

The prevalence of psoriasis differs by population, and it appears to be more common among Europeans than in East Asians. Recent genome-wide association studies (GWAS) have identified alleles that increase the risk of psoriasis, and these alleles may present different frequencies in different geographic regions. We aimed to gain insights into the causes of differences in disease frequencies according to populations and the factors affecting prevalence and pattern differences. We collected a total of 147 psoriasis-associated single-nucleotide polymorphisms (SNPs) from the GWAS catalog and compared the allele frequency differences in 27 populations using public population frequency in the 1000 Genomes Project phase 3 (n=2,504) and the Korean Reference Genome Database (n=1,722). Additionally, we calculated the composited genetic risk scores across the population groups. There were distinct patterns of allele frequencies in different population groups. In many cases, East Asians exhibited allele frequencies opposite to that of Europeans. The genetic risk score was higher in Europeans (average: 0.487) and Americans (average: 0.492) than in East Asians (average: 0.471). The prevalence of psoriasis correlated with the average genetic risk score of the population. We observed a difference in the allele frequencies of psoriasis-associated SNPs between the studied populations. This result suggests that the difference in the prevalence of psoriasis between population groups can be interpreted to some extent by the genotype.

The social stratification of population as a mechanism of downward causation.

This commentary expands on Burt's concept of downward causation to include any association between genomic variants and a given outcome that is forged through social practices rather than biochemical pathways. It proposes the social stratification of population, through which endogamy over a period of generations produces allele frequency differences between socioeconomic strata, as a mechanism of downward causation.

The relationship of E-selectin singlenucleotide polymorphisms with breast cancer in Iraqi Arab women.

Breast cancer (BC) is a significant threat to female health, with both modifiable andnon-modifiable risk factors. It is essential to monitor patients regularly and to raise population awareness. Increasing research also suggests that E-selectin (SELE) may increase tumor angiogenesis and the development of cancer. This study investigated SELE single-nucleotide polymorphisms (SNPs) in the following positions: rs5367T/C, rs5368C/T, rs5362T/G,and rs5362T/C. Using polymerase chain reaction, significant differences in allele and genotype frequencies were found between BC patients and controls. Position rs5368 was associated with an increased risk of BC for the CT and TT genotypes, with odds ratios (ORs) of16.3 and 6.90 (Fisher probability = 0.0001, p = 0.005). Women with the T allele had a 19.3-fold higher incidence of BC, while allele C may be a protective allele against BC (OR, 0.05).Heterozygous genotypes at rs5367, rs5362, and rs5362 were significantly more common inBC patients, with ORs of 5.70, 4.50, and 3.80, respectively. These SNPs may be associatedwith the risk of BC, because the frequency of mutant alleles was significantly higher in patients (OR: 4.26, 3.83, and 4.30, respectively) than in controls (OR: 0.23, 0.30, and 0.20, respectively). These SNPs may be considered a common genotype in the Iraqi population,with the wild-type allele having a protective fraction and the mutant allele having an environmental fraction. The results also revealed a 2-fold increase in gene expression in BCpatients compared to controls, with a significant effect (p = 0.017). This study's findingsconfirm the importance of SELE polymorphisms in cancer risk prediction.

한국인 투척 선수군에서 CKMM 유전자의 rs8111989(NcoI, A/G) 다형성에 대한 분포 양상

In order to explore the useful genetic marker(s) influencing the athletic performance of throwers, we performed a kind of case-control study genetic association study using the rs8111989(NcoI, A/G) polymorphism in the muscle-specific creatine kinase(CKMM) gene as a candidate gene. A total of 160 unrelated subjects including controls(n=70) and thrower (n=90) were recruited in this study, and total genomic DNA isolated from their saliva. The analysis of A/G polymorphisms in CKMM gene from their total genomic DNA was performed by using SNaPshot method in automated machine. By the result of genotype analysis, there was the significant differences in both genotype and allele frequencies of the A/G polymorphism in CKMM gene between controls and throwers, respectively(p.05). Especially, the frequencies of GG genotype and G allele in this genetic polymorphism showed the significantly higher frequencies in throwers than in controls, respectively. Thus, this genetic polymorphism may be one of useful genetic markers influencing the athletic performance in throwers. However, because athletic performance indicate the polygenic and multifactorial trait, the further studies using other genetic polymorphisms in more candidate genes will be required.

Bebeklerde akut bronşiolit ve surfaktan protein B gen lokusu arasındaki ilişki

Purpose: The aim of this study was to investigate whether there is a relationship between surfactant protein B (SFTPB) C1580T polymorphism and acute bronchiolitis.
 Materials and Methods: The study analyzed the allele frequency and genotype distribution for the SFTPB C1580T polymorphism using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique in 103 acute bronchiolitis infants and 102 healthy infants.
 Results: The results showed no association between SFTPB C1580T polymorphism and clinical characteristics of acute bronchiolitis. The distribution of the CT genotype was higher in acute bronchiolitis infants (43%) than in healthy subjects (39%) and distribution of the TT genotype was found lower in acute bronchiolitis infants (38%) than in healthy subjects (41%). No significant differences in genotype distribution and allele frequency for the SFTPB C1580T polymorphism were found between case group and control group
 Conclusion: SFTPB C1580T gene polymorphism plays no important role in susceptibility to acute bronchiolitis. Further work on the relevance of SFTPB C1580T polymorphism in larger cohorts will require validating our results.

Ancestral risk modification for multiple sclerosis susceptibility detected across the Major Histocompatibility Complex in a multi-ethnic population.

The Major Histocompatibility Complex (MHC) makes the largest genetic contribution to multiple sclerosis (MS) susceptibility, with 32 independent effects across the region explaining 20% of the heritability in European populations. Variation is high across populations with allele frequency differences and population-specific risk alleles identified. We sought to identify MHC-specific MS susceptibility variants and assess the effect of ancestral risk modification within 2652 Latinx and Hispanic individuals as well as 2435 Black and African American individuals. We have identified several novel susceptibility alleles which are rare in European populations including HLA-B*53:01, and we have utilized the differing linkage disequilibrium patterns inherent to these populations to identify an independent role for HLA-DRB1*15:01 and HLA-DQB1*06:02 on MS risk. We found a decrease in Native American ancestry in MS cases vs controls across the MHC, peaking near the previously identified MICB locus with a decrease of ~5.5% in Hispanics and ~0.4% in African Americans. We have identified several susceptibility variants, including within the MICB gene region, which show global ancestry risk modification and indicate ancestral differences which may be due in part to correlated environmental factors. We have also identified several susceptibility variants for which MS risk is modified by local ancestry and indicate true ancestral genetic differences; including HLA-DQB1*06:02 for which MS risk for European allele carriers is almost two times the risk for African allele carriers. These results validate the importance of investigating MS susceptibility at an ancestral level and offer insight into the epidemiology of MS phenotypic diversity.

Whole-genome identification of transposable elements reveals the equine repetitive element insertion polymorphism in Chinese horses.

Transposable elements (TEs) are diverse, abundant, and complicated in genomes. They not only can drive the genome evolution process but can also act as special resources for adaptation. However, little is known about the evolutionary processes that shaped horses. In this work, 126 horse assemblages involved in most horse breeds in China were used to investigate the patterns of TE variation for the first time. By using RepeatMasker and melt software, we found that the horse-specific short interspersed repetitive elements family, equine repetitive elements (ERE1), exhibited polymorphisms in horse genomes. Phylogenetic analysis based on these ERE1 loci (minor allele frequency ≥0.05) revealed three major horse groups, namely, those in northern China, southern China, and Qinghai-Tibetan, which mirrors the result determined by SNPs to some extent. The present ERE1 family emerged ~0.26 to 1.77 Mya ago, with an activity peak at ~0.49 Mya, which matches the early stage of the horse lineage and decreases after the divergence of Equus caballus and Equus ferus przewalskii. To detect the functional ERE1(s) associated with adaptation, locus-specific branch length, genome-wide association study, and absolute allele frequency difference analyses were conducted and resulted in two common protein-coding genes annotated by candidate ERE1s. They were clustered into the vascular smooth muscle contraction (p=0.01, EDNRA) and apelin signalling pathways (p = 0.02, NRF1). Notably, ERE1 insertion into the EDNRA gene showed a higher association with adaptation among southern China horses and other horses in 15 populations and 451 individuals (p = 4.55 e-8). Our results provide a comprehensive understanding of TE variations to analyse the phylogenetic relationships and traits relevant to adaptive evolution in horses.

RESISTIN GENE POLYMORPHISM AND NONALCOHOLIC FATTY LIVER DISEASE RISK.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease and one of the main global health issues in which liver fat surpasses 5% of hepatocytes without the secondary causes of lipid accumulation or excessive alcohol consumption. Owing to the link between NAFLD and insulin resistance (IR) and obesity and the role of resistin in theses metabolic disorders, we explored the possible association between resistin gene (RETN) variant and NAFLD. A total of 308 unrelated subjects, including 152 patients with biopsy-proven NAFLD and 156 controls were enrolled and genotyped for the RETN gene rs3745367 variant using PCR-RFLP method. NAFLD patients had higher liver enzymes, systolic blood pressure (SBP), and diastolic blood pressure (DBP) than the controls (P<0.001). However, we observed no significant difference in genotype and allele frequencies between the cases with NAFLD and the controls for the RETN rs3745367 polymorphism either before or after adjustment for confounding factors including age, BMI, sex, smoking status, SBP, and DBP. To our knowledge, this study is the first one that investigated the association between RETN gene rs3745367 variant and biopsy-proven NAFLD. Our findings do not support a role for this gene polymorphism in NAFLD risk in Iranian population; nonetheless, they need to be further investigated in other populations.

Genetic variant in SPAG16 is associated with the susceptibility of ACPA-positive rheumatoid arthritis possibly via regulation of MMP-3

ObjectivesIn two previously published genome-wide association studies, a cluster of variants of sperm-associated antigen16 (SPAG16) were reported to be associated with the radiological progression rate of ACPA-positive rheumatoid arthritis (RA) patients from North American and Southern European ancestry. In this study, we aimed to investigate whether the reported RA-risk loci in SPAG16 are associated with the disease in the Chinese population and to further validate the functional role of the susceptible locus in RA tissues.MethodsA total of 500 ACPA-positive RA patients and 1000 age-matched healthy subjects were recruited. Two SNPs of SPAG16, including rs7607479 (C/T) and rs6435818 (A/C), were genotyped, and the genotyping data were compared with chi-square test. Gene expression analysis was performed in synovial tissues obtained from 40 RA patients and 30 non-RA controls surgically treated for bone fracture. The tissue expression of SPAG16 and matrix metalloproteinase 3 (MMP-3) was compared between the two groups by the Student’s t test. The relationship between serum indexes and mRNA expression of SPAG16 and MMP-3 were evaluated by Spearman’s correlation analysis.ResultFor rs7607479, the frequency of genotype TT was significantly higher in RA patients than in the controls (49.0% vs. 40.4%, p = 0.002). The RA patients were found to have significantly lower frequency of allele C than the controls (30.9% vs. 36.8%, p = 0.001). As for rs6435818, there was no significant difference of genotype or allele frequency between the two groups. The mRNA expression of MMP-3 was 1.63-fold higher in the RA patients than in the controls (p < 0.001). The expression of SPAG16 was comparable between the two groups (p = 0.43). The mRNA expression of MMP-3 was 1.39-fold higher in patients with genotype TT than in the patients with genotype CC (p = 0.006). The mRNA expression level of MMP-3 was significantly correlated with serum rheumatoid factor (r = 0.498, p < 0.001) and C-reactive protein (r = 0.272, p = 0.01), weakly correlated with erythrocyte sedimentation rate (r = 0.236, p = 0.09).ConclusionsWe validated a common genetic risk factor in ACPA-positive patients with RA, which is associated with the tissue production of MMP-3 and disease progression. Further functional analysis into the role of rs7607479 in MMP-3 expression can shed new light on the genetic architecture of ACPA-positive RA.

Association of Single-Nucleotide Polymorphisms in Interleukin Genes with Microbial Keratitis in a South Indian Population

To examine the relationship between single-nucleotide polymorphisms (SNPs) in interleukin (IL) genes and keratitis and its clinical manifestations. SNPs in IL1B, IL6, CXCL8, IL10, and IL12B were analysed. Differences in frequencies of alleles, genotypes and haplotypes between cases and controls as well as associations between SNPs and clinical variables were calculated by χ2 tests with odds ratios. The minor homologous genotype in IL1B rs16944 (p = 0.036; odds ratio (OR) = 2.063, 95% confidence interval (CI): 1.048-4.061) and CXCL8 rs4073 (p = 0.041; OR = 0.463, 95% CI: 0.224-0.956) and the heterologous genotypes in IL6 rs1800795 (p = 0.046; OR = 0.563, 95% CI: 0.326-0.972) and IL12B rs2569254 (p = 0.0446; OR = 0.557, 95% CI: 0.314-0.989) or rs730691 (p = 0.0051; OR = 0.451, 95% CI: 0.260-0.784) were associated with keratitis. The minor genotype of rs16944 was associated with severe infection (p = 0.046). The heterologous genotype in rs2569254 was associated with hospital admission, photophobia, and mode of contact lens wear (p ≤ 0.041). The heterologous genotype in rs730691 was associated with blurred vision, discharge, anterior chamber reaction, and mode of wear (p ≤ 0.047). This study demonstrates that SNPs in IL1B and CXCL8 are associated with risk of developing keratitis. The study also found relationships between SNPs and clinical measures of keratitis. The potential for ethnic differences in frequency of SNPs and their association with keratitis should be followed up using different populations.

Genetics of BAG3: A Paradigm for Developing Precision Therapies for Dilated Cardiomyopathies.

Nonischemic dilated cardiomyopathy is a common form of heart muscle disease in which genetic factors play a critical etiological role. In this regard, both rare disease-causing mutations and common disease-susceptible variants, in the Bcl-2-associated athanogene 3 (BAG3) gene have been reported, highlighting the critical role of BAG3 in cardiomyocytes and in the development of dilated cardiomyopathy. The phenotypic effects of the BAG3 mutations help investigators understand the structure and function of the BAG3 gene. Indeed, we report herein that all of the known pathogenic/likely pathogenic variants affect at least 1 of 3 protein functional domains, ie, the WW domain, the second IPV (Ile-Pro-Val) domain, or the BAG domain, whereas none of the missense nontruncating pathogenic/likely pathogenic variants affect the proline-rich repeat (PXXP) domain. A common variant, p.Cys151Arg, associated with reduced susceptibility to dilated cardiomyopathy demonstrated a significant difference in allele frequencies among diverse human populations, suggesting evolutionary selective pressure. As BAG3-related therapies for heart failure move from the laboratory to the clinic, the ability to provide precision medicine will depend in large part on having a thorough understanding of the potential effects of both common and uncommon genetic variants on these target proteins. The current review article provides a roadmap that investigators can utilize to determine the potential interactions between a patient's genotype, their phenotype, and their response to therapeutic interventions with both gene delivery and small molecules.

COMT rs4818 less common allele is associated with psychological and psychiatric worse indicators in a cohort of individuals born with cleft lip and palate.

Individuals born with cleft lip and palate may face difficulties in speech function, nutrition, facial aesthetics, and long-term care. These difficulties may increase the risk of psychological and psychiatric diseases. This work aimed to test if the variant allele of COMT was carried more frequently among individuals that have psychological and psychiatric outcomes within a cohort of patients born with cleft lip and palate. DNA extraction from saliva of two hundred and fifteen individuals born with cleft lip with and/or palate and genotyping was performed, and the frequency of COMT rs4818 alleles was determined. The domain 'Psychological Function' of Cleft-Q™ was used to generate scores for analysis. The scores were computed, and differences in genotype or allele frequencies between individuals with psychological function scores 60 or above and 59 or below were compared. The history of psychiatric illness (family history of psychiatric disease or self-reported psychiatric illness) was registered. Genotype and allele frequencies were compared between individuals with and without a family history of psychiatric illness. Individuals with lower Psychological Function (Cleft-Q™) scores were more likely to be GG (P=.04) or carriers of allele G (P < .001). The reported psychiatric illness and positive family history of psychiatric illness were compared to COMT rs4818 allele and genotype frequencies of individuals without these indicators, and individuals with psychiatric illness and positive family history of psychiatric illness were more likely to carry allele G (P=.03 and P=.008, respectively). The study confirms previously suggested role of COMT rs4818 in psychiatric and psychological outcomes in a distinct cohort of patients born with cleft lip and palate.

The HLA-DRB1*07 Allele Is Associated with Interstitial Lung Abnormalities (ILA) and Subpleural Location in a Mexican Mestizo Population.

Interstitial lung abnormalities (ILA) are defined as the presence of different patterns of increased lung density, including ground glass attenuation and reticular opacities on chest high-resolution computed tomography (HRCT). In this study, we included 90 subjects with ILA and 189 healthy controls (HC) from our Aging Lung Program. We found that subjects with ILA are older, have a significant smoking history, and have worse pulmonary function than HC (p < 0.05). When we evaluated the allele frequencies of the human leukocyte antigen (HLA) system, we found that HLA-DRB1*07 was associated with a higher risk for ILA (p < 0.05, OR = 1.95, 95% CI = 1.06-3.57). When we compared subjects with subpleural ILA vs. HC, the association with HLA-DRB1*07 became stronger than the whole ILA group (p < 0.05, OR = 2.29, 95% CI = 1.24-4.25). Furthermore, subjects with subpleural ILA and central ILA display differences in allele frequencies with HLA-DRB1*14 (3.33% vs. 13.33%, p < 0.05) and *15 (3.33% vs. 20%, p < 0.05). Our findings indicate that the HLA-DRB1*07 allele contributes to the risk of ILA, especially those of subpleural locations.