ABCA4-related retinopathies in Lebanon.

Variants in ATP-binding cassette transporter type A4 (ABCA4) have been linked to several forms of inherited retinal diseases (IRDs) besides the classically defined Stargardt disease (STGD), known collectively as ABCA4 retinopathies. ABCA4 is a sizable locus harboring 50 exons; thus, its analysis has revealed over 2,400 variants described, of which more than 2,000 are causal. Due to the clinical and genetic heterogeneity, diagnosing ABCA4 retinopathies is challenging. To date, no ABCA4-related retinopathy has been detected in Lebanon. Using next-generation sequencing, we analyzed our IRDs' cohort retrospectively (61 families) and identified five with ABCA4-related retinopathies, making it a relatively abundant cause of IRDs (about 8 %). Three families were diagnosed with rod-cone dystrophy (RCD), two with STGD, and one with cone-rod dystrophy (CRD). In conclusion, our study showed the presence of ABCA4 variants with a high degree of heterogeneity in Lebanon.

Genotype-phenotype associations in CRB1 bi-allelic patients: a novel mutation, a systematic review and meta-analysis.

PURPOSE: The goal of the study was to search for novel bi-allelic CRB1 mutations, and then to analyze the CRB1 literature at the genotypic and phenotypic levels. APPROACH: We screened various variables such as the CRB1 mutation types, domains, exons, and genotypes and their relation with specific ocular phenotypes. An emphasis was given to the bi-allelic missense and nonsense mutations because of their high prevalence compared to other mutation types. Finally, we quantified the effect of various non-modifiable factors over the best-corrected visual acuity oculus uterque (BCVA OU) using multivariate linear regression models and identified genetic interactions. RESULTS: A novel bi-allelic missense in the exon 9 of CRB1; c.2936G > A; p.(Gly979Asp) was found to be associated with rod-cone dystrophy (RCD). CRB1 mutation type, exons, domains, and genotype distribution varied significantly according to fundus characteristics, such as peripheral pigmentation and condition, optic disc, vessels, macular condition, and pigmentation (P < 0.05). Of the 154 articles retrieved from PubMed, 96 studies with 439 bi-allelic CRB1 patients were included. Missense mutations were significantly associated with an absence of macular pigments, pale optic disc, and periphery pigmentation, resulting in a higher risk of RCD (P < 0.05). In contrast, homozygous nonsense mutations were associated with macular pigments, periphery pigments, and a high risk of LCA (P < 0.05) and increased BCVA OU levels. We found that age, mutation types, and inherited retinal diseases were critical determinants of BCVA OU as they significantly increased it by 33% 26%, and 38%, respectively (P < 0.05). Loss of function alleles additively increased the risk of LCA, with nonsense having a more profound effect than indels. Finally, our analysis showed that p.(Cys948Tyr) and p.(Lys801Ter) and p.(Lys801Ter); p.(Cys896Ter) might interact to modify BCVA OU levels. CONCLUSION: This meta-analysis updated the literature and identified genotype-phenotype associations in bi-allelic CRB1 patients.

Variants in UBAP1L lead to autosomal recessive rod-cone and cone-rod dystrophy.

PURPOSE: Progressive inherited retinal degenerations (IRDs) affecting rods and cones are clinically and genetically heterogeneous and can lead to blindness with limited therapeutic options. The major gene defects have been identified in subjects of European and Asian descent with only few reports of North African descent. METHODS: Genome, targeted next-generation, and Sanger sequencing was applied to cohort of ∼4000 IRDs cases. Expression analyses were performed including Chip-seq database analyses, on human-derived retinal organoids (ROs), retinal pigment epithelium cells, and zebrafish. Variants' pathogenicity was accessed using 3D-modeling and/or ROs. RESULTS: Here, we identified a novel gene defect with three distinct pathogenic variants in UBAP1L in 4 independent autosomal recessive IRD cases from Tunisia. UBAP1L is expressed in the retinal pigment epithelium and retina, specifically in rods and cones, in line with the phenotype. It encodes Ubiquitin-associated protein 1-like, containing a solenoid of overlapping ubiquitin-associated domain, predicted to interact with ubiquitin. In silico and in vitro studies, including 3D-modeling and ROs revealed that the solenoid of overlapping ubiquitin-associated domain is truncated and thus ubiquitin binding most likely abolished secondary to all variants identified herein. CONCLUSION: Biallelic UBAP1L variants are a novel cause of IRDs, most likely enriched in the North African population.

Genetics of Inherited Retinal Diseases in Understudied Ethnic Groups in Italian Hospitals.

Purpose: Describing the clinical and genetic features of an ethnically heterogeneous group of (inherited retinal diseases) IRD patients from different underrepresented countries, referring to specialized Italian Hospitals, and expanding the epidemiological spectrum of the IRD in understudied populations. Methods: The patients' phenotypes underwent were characterized by exhaustive ophthalmological examinations, including morpho-functional testing. Genetic testing was performed using next-generation sequencing (NGS) and gene sequencing panels targeting a specific set of genes, Sanger sequencing and-when necessary-multiplex ligation-dependent probe amplification (MLPA) to better identify the genotype. When possible, segregation analysis was performed in order to confirm unsolved cases. Results: The article reports the results of the phenotypes and genotypes of 123 IRD probands, 69 males and 54 females, mean age 41 (IQR, 54-30) years, disease onset at 13 (IQR, 27.25-5) years. Thirty-three patients out of 123 (26.8%) were Africans (North/Northwest Africa), 21 (17.1%) Asians, 19 (15.4%) Americans (South/Central America) and 50 (40.7%) Europeans (Eastern Europe). Retinitis pigmentosa was the most represented phenotype (56%), followed by cone dystrophy (11%) and Leber congenital amaurosis (7%), while ABCA4 was the most frequently mutated gene (18%), followed by USH2A (9%) and RPGR (5%). About ABCA4 variants found in Stargardt disease, macular and cone dystrophies were predominant in Asian (42%) and European (21%) patients. The most represented inheritance pattern was autosomal recessive, while a higher frequency of homozygous patients versus compound heterozygotes as compared to previous studies on Italian IRD patients was evidenced, reflecting a possible higher frequency of inbreeding marriages. Conclusion: Though limited by the relatively low number of patients, the present paper paints a picture of the clinical and genetic features of IRD patients from understudied ethnic groups referred to Italian specialized hospitals and extended the epidemiological studies on underrepresented world regional areas.

Novel Missense and Splice Site Mutations in USH2A, CDH23, PCDH15, and ADGRV1 Are Associated With Usher Syndrome in Lebanon.

The purpose of this study was to expand the mutation spectrum by searching the causative mutations in nine Lebanese families with Usher syndrome (USH) using whole-exome sequencing. The pathogenicity of candidate mutations was first evaluated according to their frequency, conservation, and in silico prediction tools. Then, it was confirmed via Sanger sequencing, followed by segregation analysis. Finally, a meta-analysis was conducted to calculate the prevalence of USH genes in the Lebanese population. Three missense mutations, two splice site mutations, and one insertion/deletion were detected in eight of the families. Four of these variants were novel: c.5535C > A; p.(Asn1845Lys) in exon 41 of CDH23, c.7130G > A; p.(Arg2377Gln) in exon 32 of ADGRV1, c.11390-1G > A in USH2A, and c.3999-6A > G in PCDH15. All the identified mutations were shown to be likely disease-causing through our bioinformatics analysis and co-segregated with the USH phenotype. The mutations were classified according to the ACMG standards. Finally, our meta-analysis showed that the mutations in ADGRV1, USH2A, and CLRN1 are the most prevalent and responsible for approximately 75% of USH cases in Lebanon. Of note, the frequency USH type 3 showed a relatively high incidence (23%) compared to the worldwide prevalence, which is around 2-4%. In conclusion, our study has broadened the mutational spectrum of USH and showed a high heterogeneity of this disease in the Lebanese population.

The research output of rod-cone dystrophy genetics.

Non-syndromic rod-cone dystrophy (RCD) is the most common condition in inherited retinal diseases. The aim of this study was to evaluate the research output and productivity related to RCD genetics per countries as classified by the human development index (HDI), by analyzing publication frequency and citations, the choice of journals and publishers, since 2000 to date. We have also analyzed the use of next-generation sequencing (NGS) in publications originating from countries with different HDIs. One thousand four hundred articles focusing on non-syndromic RCD were downloaded and analyzed. Citations and published articles were adjusted per one million individuals. The research output is significantly higher in very high HDI countries (86% of the total publications and 95% of the citations) than countries with lower HDIs in all aspects. High and medium HDI countries published together 13.6% of the total articles worldwide and received 4.6% of the citations. On the publication level, the USA (26%), United Kingdom (10%), and Japan (7%) were the top 3 among very high HDI countries, while China (6%) and India (2%) ranked first in high and medium HDI countries respectively. On the citation level, similar profiles were found. Following adjustment for population size, Switzerland (~14%), Jordan (~ 1%) and Morocco (<0.2%) showed the highest rates of publications in very high, high and medium HDI countries respectively. Very high HDI countries published 71% of their papers in first quartile journals (first quartile in Scimago journal rank; Q1), and 23% in Q2 journals. High and medium HDI countries showed a similar profile in quartiles with ~ 40% of their papers published in Q1 journals and ~ 30% in Q2 journals. The first publication using NGS was issued in 2009 in very high HDI countries, while it appeared in 2012 in high HDI countries, and in 2017 in medium HDI countries, with a respective lag of 3 to 8 years compared to very high HDI countries. A profound gap exists between very high HDI countries and the rest of the world. To fill it in, we propose implementing NGS, supporting international collaborations, building capacities and infrastructures, improving accessibility of patients to services, and increasing national and international funding.

Vitamin D Related Gene Polymorphisms and Cholesterol Levels in a Mediterranean Population.

In addition to its role in bone health, vitamin D (VitD) has been implicated in several pathological conditions. Specifically, VitD deficiency has been linked to an increased risk of dyslipidemia. Atherogenic dyslipidemia is characterized by increased low-density lipoprotein-cholesterol (LDL-C) and decreased high-density lipoprotein-cholesterol (HDL-C). In this study, we examined the association of six single nucleotide polymorphisms (SNPs) in VitD-related genes with VitD and lipid levels, in a cohort of 460 Lebanese participants free from chronic diseases. Our results showed no association of the examined SNPs with VitD concentrations. However, the presence of the minor allele in rs10741657G>A of CYP2R1 was associated with increased levels in LDL-C (ß = 4.95, p = 0.04)] and decreased levels in HDL-C (ß = −1.76, p = 0.007)]. Interestingly, rs10741657G>A interacted with gender to increase LDL-C levels in females (ß = 6.73 and p = 0.03) and decrease HDL-C levels in males HDL-C (ß = −1.09, p = 0.009). In conclusion, our results suggest that rs10741657 G>A in CYP2R1 is associated with circulating LDL-C and HDL-C levels in a Lebanese cohort. Although this association was gender-specific, where rs10741657G>A was associated with increased LDL in females and decreased HDL in males, the presence of the minor allele A was associated with increased cardiovascular risk in both genders. These findings need to be validated in a larger population. Further investigations are warranted to elucidate the molecular mechanism of VitD polymorphism and dyslipidemia.

The association of vascular endothelial growth factor related SNPs and circulating iron levels might depend on body mass index.

BACKGROUND AND OBJECTIVES: Vascular Endothelial Growth Factor (VEGF) is an essential regulator of vascular biology. In addition to the well-established role in angiogenesis, circulating VEGF levels were found elevated in severely anemic patients, pointing out that anemia might affect the progression of angiogenesis in malignant and benign diseases through the alteration of VEGF levels. Ten single nucleotide polymorphisms (SNPs) in VEGFA and other loci were shown to explain more than 50% of its circulating levels. This study investigated the association of those ten VEGF-related SNPs with serum iron levels in a general Lebanese population free of chronic diseases (N = 460). RESULT: We found that the rs10738760 and the body mass index (BMI) were associated with decreased Iron levels (p = 0.002, and p < 0.001, respectively). When taken together, both variables, rs10738760 and BMI, interacted to reduce iron levels (p < 0.001). According to obesity status, the stratification revealed that the effect of rs10738760 was more pronounced in obese than non-obese individuals (p = 0.025). Conclusion: The intergenic SNP rs10738760 is associated with circulating iron levels, and this association depends on BMI status. Although of interest, these results need replication in larger populations from different ancestries.

Pharmacogenetics in developing countries and low resource environments.

While significant advances have been made in pharmacogenetics (PGx), especially in countries with developed economies, this field remains at its infancy in developing countries and low resource environments. Herein, we provide insights into the gap and challenges of PGx at the research and clinical fronts, and some perspectives to bridge the gap and move forward with PGx in the developing world. We show that developing countries fall behind in PGx research, evidenced by a lower number of researchers, citations, and research output. In addition, the implementation of PGx in the clinic has been progressing at a much slower pace than research, and more so in developing countries. To bridge this gap, we recommend fostering regional and multinational collaborations to secure funds for high-throughput genotyping and local capacity building while preserving individual countries' identity, implementing next-generation sequencing, and organizing specialized training and exchange programs to move PGx research and clinical applications forward in developing countries.

Analysis of rod-cone dystrophy genes reveals unique mutational patterns.

Background: Rod-cone dystrophy (RCD) is the most common inherited retinal disease that is characterised by the progressive degeneration of retinal photoreceptors. RCD genes classification is based exclusively on gene mutations' prevalence and does not consider the implication of the same gene in different phenotypes. Therefore, we first investigated the mutations occurrence in autosomal recessive RCD (arRCD) and non-arRCD conditions. Then, finally, we identified arRCD enriched mutational patterns in specific genes and coding exons. Methods and results: The mutations patterns differed according to arRCD (p=0.001). Specifically, When compared with missense; insertions/deletions (OR=1.2, p=0.007), nonsense (OR=1.2, p=0.014) and splice-site mutations (OR=1.6, p=0.038) increased the OR of arRCD by 20%-60% versus non-arRCD conditions. The gene-based analysis identified that EYS, IMPG2, RP1L1 and USH2A mutations were enriched in arRCD (p<0.05). The exon-based analysis revealed specific mutation patterns in exons of CRB1, RP1L1 and exons 12, 60 and 62 coding for Lamin EGF and FTIII domains of USH2A. Conclusion: The current analysis showed that many aRCD genes have unique mutational patterns.

CHM mutation spectrum and disease: An update at the time of human therapeutic trials.

Choroideremia is an X-linked inherited retinal disorder (IRD) characterized by the degeneration of retinal pigment epithelium, photoreceptors, choriocapillaris and choroid affecting males with variable phenotypes in female carriers. Unlike other IRD, characterized by a large clinical and genetic heterogeneity, choroideremia shows a specific phenotype with causative mutations in only one gene, CHM. Ongoing gene replacement trials raise further interests in this disorder. We describe here the clinical and genetic data from a French cohort of 45 families, 25 of which carry novel variants, in the context of 822 previously reported choroideremia families. Most of the variants represent loss-of-function mutations with eleven families having large (i.e. ≥6 kb) genomic deletions, 18 small insertions, deletions or insertion deletions, six showing nonsense variants, eight splice site variants and two missense variants likely to affect splicing. Similarly, 822 previously published families carry mostly loss-of-function variants. Recurrent variants are observed worldwide, some of which linked to a common ancestor, others arisen independently in specific CHM regions prone to mutations. Since all exons of CHM may harbor variants, Sanger sequencing combined with quantitative polymerase chain reaction or multiplex ligation-dependent probe amplification experiments are efficient to achieve the molecular diagnosis in patients with typical choroideremia features.

rs6837671A>G in FAM13A Is a Trans-Ethnic Genetic Variant Interacting with Vitamin D Levels to Affect Chronic Obstructive Pulmonary Disease.

(1) Background and objectives: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality throughout the world. In addition to genetics, increasing evidence suggests that Vitamin D (VitD) might be involved in different pathogenic mechanisms in COPD. Furthermore, the prevalence of VitD insufficiency is exceptionally high in COPD patients and increases with the severity. Based on the above, we first tested the relation between the top 10 single nucleotide polymorphisms from genome-wide association studies and the risk of COPD. Then, we investigated whether VitD levels might also have a role in COPD. A meta-analysis followed, combining our participants with previously published European and non-European populations (15,716 cases and 48,107 controls). (2) Methods: 631 Lebanese participants were recruited, of which ~28% were affected with COPD. Demographic and clinical data were collected, and DNA was genotyped using Kompetitive allele-specific PCR (KASPTM). Adjusted multiple logistic regression models were used. Bonferroni corrections were also applied. The statistical power was also assessed. (3) Results: Both rs6837671A>G in FAM13A and VitD levels were significantly associated with increased risk of COPD (OR = 1.75, p = 0.01, and OR = 3.10, p < 0.001 respectively). An interaction between rs6837671A>G in FAM13A and VitD levels, which increased COPD risk, was found (OR = 3.35 and p < 0.001). The meta-analysis showed that rs6837671G increases COPD risk in populations from different origins; Europeans, Asians, and now in Middle-Eastern. (4) Conclusions: Our results suggest that rs6837671A>G in FAM13A is a trans-ethnic genetic variant that interact with VitD to affect COPD.

Molecular Epidemiology in 591 Italian Probands With Nonsyndromic Retinitis Pigmentosa and Usher Syndrome.

Purpose: To describe the molecular epidemiology of nonsyndromic retinitis pigmentosa (RP) and Usher syndrome (US) in Italian patients. Methods: A total of 591 probands (315 with family history and 276 sporadics) were analyzed. For 155 of them, we performed a family segregation study, considering a total of 382 relatives. Probands were analyzed by a customized multigene panel approach. Sanger sequencing was used to validate all genetic variants and to perform family segregation studies. Copy number variants of selected genes were analyzed by multiplex ligation-dependent probe amplification. Four patients who tested negative to targeted next-generation sequencing analysis underwent clinical exome sequencing. Results: The mean diagnostic yield of molecular testing among patients with a family history of retinal disorders was 55.2% while the diagnostic yield including sporadic cases was 37.4%. We found 468 potentially pathogenic variants, 147 of which were unpublished, in 308 probands and 66 relatives. Mean ages of onset of the different classes of RP were autosomal dominant RP, 19.3 ± 12.6 years; autosomal recessive RP, 23.2 ± 16.6 years; X-linked RP, 13.9 ± 9.9 years; and Usher syndrome, 18.9 ± 9.5 years. We reported potential new genotype-phenotype correlations in three probands, two revealed by TruSight One testing. All three probands showed isolated RP caused by biallelic variants in genes usually associated with syndromes such as PERCHING and Senior-Loken or with retinal dystrophy, iris coloboma, and comedogenic acne syndrome. Conclusions: This is the largest molecular study of Italian patients with RP in the literature, thus reflecting the epidemiology of the disease in Italy with reasonable accuracy.

Retinal Phenotype of Patients With Isolated Retinal Degeneration Due to CLN3 Pathogenic Variants in a French Retinitis Pigmentosa Cohort.

Importance: Biallelic variants in CLN3 lead to a spectrum of diseases, ranging from severe neurodegeneration with retinal involvement (juvenile neuronal ceroid lipofuscinosis) to retina-restricted conditions. Objective: To provide a detailed description of the retinal phenotype of patients with isolated retinal degeneration harboring biallelic CLN3 pathogenic variants and to attempt a phenotype-genotype correlation associated with this gene defect. Design, Setting, and Participants: This retrospective cohort study included patients carrying biallelic CLN3 variants extracted from a cohort of patients with inherited retinal disorders (IRDs) investigated at the National Reference Center for Rare Ocular Diseases of the Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts from December 2007 to August 2020. Data were analyzed from October 2019 to August 2020. Main Outcome and Measures: Functional (best-corrected visual acuity, visual field, color vision, and full-field electroretinogram), morphological (multimodal retinal imaging), and clinical data from patients were collected and analyzed. Gene defect was identified by either next-generation sequencing or whole-exome sequencing and confirmed by Sanger sequencing, quantitative polymerase chain reaction, and cosegregation analysis. Results: Of 1533 included patients, 843 (55.0%) were women and 690 (45.0%) were men. A total of 15 cases from 11 unrelated families harboring biallelic CLN3 variants were identified. All patients presented with nonsyndromic IRD. Two distinct patterns of retinal disease could be identified: a mild rod-cone degeneration of middle-age onset (n = 6; legal blindness threshold reached by 70s) and a severe retinal degeneration with early macular atrophic changes (n = 9; legal blindness threshold reached by 40s). Eleven distinct pathogenic variants were detected, of which 4 were novel. All but 1, p.(Arg405Trp), CLN3 point variants and their genotypic associations were clearly distinct between juvenile neuronal ceroid lipofuscinosis and retina-restricted disease. Mild and severe forms of retina-restricted CLN3-linked IRDs also had different genetic background. Conclusions and Relevance: These findings suggest CLN3 should be included in next-generation sequencing panels when investigating patients with nonsyndromic rod-cone dystrophy. These results document phenotype-genotype correlations associated with specific variants in CLN3. However, caution seems warranted regarding the potential neurological outcome if a pathogenic variant in CLN3 is detected in a case of presumed isolated IRD for the onset of neurological symptoms could be delayed.

Helicobacter Pylori Interacts with Serum Vitamin D to Influence Hypertension.

BACKGROUND AND OBJECTIVE: Hypertension is a multifactorial disease where numerous constitutive, genetic, and environmental factors interplay. Among the constitutive factors, age is a major determent continuously reported to be associated with a significant increase in the prevalence of hypertension. In addition to age, Helicobacter pylori (H. pylori) infection was also shown to be associated. On the other hand, Vitamin D (Vit D) plays an important role in the development of hypertension. In the current study, it was investigated whether H. pylori interacts with Vit D levels to influence hypertension. ; Methods: This cross-sectional study was conducted on seven hundred and eighty-two "a priori" healthy individuals equally divided according to hypertension status. To study the association between Vit D, H. pylori, and hypertension, a multivariate logistic regression model was used while correcting for different confounding factors. Power analysis was also performed. ; Results: Approximately half of the participants were hypertensive and had Vit D insufficiency and they were also matched for age. Using a multiple logistic regression model, the results showed an inversely proportionate association between H. pylori infection and the risk of hypertension (OR=0.38, P<0.001). On the other hand, a proportionate association between Vit D deficiency and hypertension was observed (OR=2.76, P=0.004). Furthermore, Vit D and H. pylori status interacted to affect the risk of hypertension (OR=0.97, P=0.004). Stratification, according to Vit D status, showed that 59.1% of Vit D deficient participants were infected with H. pylori organisms (P<0.001). When taking hypertension, Vit D, and H. pylori statuses into account, it was found that the prevalence of hypertension was doubled when the participants were negative for H. pylori infection but had Vit D deficiency (P<0.001). ; Conclusion: H. pylori infection and Vit D deficiency could predict hypertension. The odds of hypertension development were double when the participants were negative for H. pylori infection and had vitamin D deficiency.

The genetics of rod-cone dystrophy in Arab countries: a systematic review.

Since a substantial difference in the prevalence of genetic causes of rod-cone dystrophy (RCD) was found among different populations, we conducted a systematic review of the genetic findings associated with RCD in Arab countries. Of the 816 articles retrieved from PubMed, 31 studies conducted on 407 participants from 11 countries were reviewed. Next-generation sequencing (NGS) was the most commonly used technique (68%). Autosomal recessive pattern was the most common pattern of inheritance (97%) and half of the known genes associated with RCD (32/63) were identified. In the Kingdom of Saudi Arabia, in addition to RP1 (20%) and TULP1 (20%), gene defects in EYS (8%) and CRB1 (7%) were also prevalently mutated. In North Africa, the main gene defects were in MERTK (18%) and RLBP1 (18%). Considering all countries, RP1 and TULP1 remained the most prevalently mutated. Variants in TULP1, RP1, EYS, MERTK, and RLBP1 were the most prevalent, possibly because of founder effects. On the other hand, only ten Individuals were found to have dominant or X-linked RCD. This is the first time a catalog of RCD genetic variations has been established in subjects from the Arabi countries. Although the last decade has seen significant interest, expertise, and an increase in RCD scientific publication, much work needs to be conducted.

Is There a Link Between Nutrition, Genetics, and Cardiovascular Disease?

Cardiovascular diseases (CVDs) are a group of disorders that mainly include coronary, cerebrovascular and rheumatic heart diseases [1].[...].

The Association of rs1898830 in Toll-Like Receptor 2 with Lipids and Blood Pressure.

BACKGROUND AND OBJECTIVE: Toll-like receptors (TLRs) are important components of the innate immune system, involved in establishing immunity to infections. Apart from being implicated in immunity, numerous studies have reported that many TLRs, including TLR2, are involved in the pathogenesis of cardiovascular diseases and their risk factors. Since rs1898830 is associated with TLR2-mediated cellular activation, we aimed to study its association with CVD risk factors, such as lipid levels and hypertension. METHODS: A cross-sectional study was conducted on 460 individuals free from chronic diseases. Clinical and biological data were collected and DNA was extracted and genotyped using Kompetitive allele specific PCR (KASP™). Multiple logistic regression models, adjusted for six covariates, were used. A power calculation analysis was also performed. RESULTS: We found that rs1898830 in TLR2 was positively associated with hypertension (OR = 2.18, p = 0.03) and negatively associated with high-density lipoprotein cholesterol (OR = 0.66, p = 0.05). In contrast, no relation was found with total cholesterol and low-density lipoprotein cholesterol. CONCLUSION: The present results provide additional evidence supporting the implication of TLR2 in CVD risk factors.

rs622342 in SLC22A1, CYP2C9*2 and CYP2C9*3 and Glycemic Response in Individuals with Type 2 Diabetes Mellitus Receiving Metformin/Sulfonylurea Combination Therapy: 6-Month Follow-Up Study.

BACKGROUND AND OBJECTIVE: Since the treatment outcome with oral anti-diabetics differs between individuals, the objective of this study is to evaluate the significance of rs622342 in SLC22A1, CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910) with regard to the efficacy of metformin/sulfonylurea combination therapy in individuals with type 2 diabetes mellitus (T2DM). METHODS: Eighty-eight Lebanese individuals with T2DM received metformin/sulfonylurea combination therapy over 3 and 6 months. The clinical and biochemical characteristics were collected. Genotyping of rs622342 in SLC22A1, CYP2C9*2 and CYP2C9*3 was performed using hybridization probes on real-time polymerase chain reaction (PCR) instrument. Statistical analysis was performed using SPSS 22.0. RESULTS: The levels of fasting blood sugar (FBS) and glycated hemoglobin (HbA1c) showed a statistically significant reduction over 3 and 6 months of follow-up (p < 0.001). An interaction between rs622342 in SLC22A1, CYP2C9*2 and CYP2C9*3 (p = 0.035) was found associated with reduced levels of HbA1c levels after 3 and 6 months. A significant difference between the means of HbA1c was observed among the different groups after 3 and 6 months (p = 0.004 and p < 0.001, respectively). The most beneficial group was; AA and AC, *1*3, whereas the individuals that benefited the least were CC, *1*3 at 3 and 6 months. In contrast to HbA1c, no interaction was found between the three polymorphisms to affect FBS (p = 0.581). CONCLUSION: The combination of metformin/sulfonylurea therapy led to the maximum glycemic control in individuals with T2DM carrying AA or AC genotypes in SLC22A1 and *1*3 in CYP2C9.