Identification of a de novo, Novel Pathogenic Variant in the Splice Region of the SOX10 Gene in an Iranian Azeri Turkish Family with Waardenburg Syndrome.

Background: Waardenburg syndrome (WS) is an inherited heterogeneous auditory pigmentary syndrome, divided into at least four types and characterized by iris heterochromia, white forelock, prominent nasal root, dystopia canthorum, middle eyebrow hypertrichosis, and deafness. Pathogenic variants in the SOX10 gene have been reported to be involved in WS disease. Methods: Whole exome sequencing (WES) was conducted on a 24-year-old male, who originated from Iranian Azeri Turkish ethnic group, with symptoms of deafness and blue eyes from brown-eyed parents. Web-based tools including Mutation Taster, VarSome, SIFT, Human Splicing Finder (HSF), and I-TASSER, were used for bioinformatics analysis. To verify the WES findings, DNAs taken from the blood samples of all family members were subjected to PCR-Sanger sequencing. Results: A novel heterozygous pathogenic variant, NC_000022.11 (NM_006941):c.428+1G>T, located in the second intron of the SOX10 gene and disrupting the splicing site, was identified in the proband. Sanger sequencing was applied on the proband and his parents. The results showed that the variant was a de novo pathogenic variant with an autosomal dominant inheritance pattern. Conclusions: Identification of a novel de novo pathogenic variant, NC_000022.11 (NM_006941):c.428+1G>T, in the second intron of the SOX10 gene with autosomal dominant inheritance pattern.

A novel loss of function mutation in the PHD domain of the RAG2 gene, affecting zinc-binding affinity.

BACKGROUND: Severe combined immune deficiencies (SCIDs) are genetically heterogeneous disorders that lead to the absence or malfunction of adaptive immune cells, including T- and B-cells. Pathogenic variants in the RAG2 gene are associated with this disease. METHODS: A couple with consanguineous marriage from the Iranian-Azeri-Turkish ethnic group was referred to the genetic lab. Two children of this family died due to SCID disease with symptoms of skin granulomas, lack of developed T- and B-cells, and intact NK cells. To infer their genotypes, DNA samples obtained from the parents were subjected to whole-exome sequencing (WES). RESULTS: WES data analysis revealed that both parents were carriers of a pathogenic variant, NC_000011.10 (NM_000536.4):c.1268G > C, in the RAG2 gene. This variant was absent in our cohort of 400 healthy individuals from the same ethnic group. To gain insight into the consequence of the variant on the protein function, further analysis was performed by applying bioinformatics tools. This study revealed that the replacement of cysteine with serine at the zinc-binding domain diminished the domain's affinity to zinc ion, resulting in the loss of the mutant protein's ability to bind to the recombination signal sequence (RSS). The formation of the RAG2-RSS complex is vital for T- and B-cell development. CONCLUSION: The identification of a novel pathogenic variant, c.1268G > C, revealed that this variant in the zinc-binding domain diminished the affinity of the zinc ion to the mutant protein and consequently led to the loss of its ability to bind to the RSS.

Identification of a novel mutation in the HACD1 gene in an Iranian family with autosomal recessive congenital myopathy, with fibre-type disproportion.

Congenital fibre-type disproportion (CFTD) with myopathy, is a genetically heterogeneous disease in which there is relative hypotrophy of type-1-muscle-fibres compared to type-2-fibres on skeletal muscle biopsy. The classical characteristics of CFTD are infantile hypotonia and nonprogressive muscle weakness with a broad range of clinical manifestations. Pathogenic mutations in the HACD1 gene encoding 3-hydroxyacyl-CoA-dehydratase-1 have recently been reported to be associated with this disease. Whole-exome sequencing (WES) was conducted in a 12-year-old girl born to consanguineous parents from the Iranian-Azeri-Turkish population. She was diagnosed with congenital myopathy at the age of 4-month-old due to hypotonia and abnormal electromyography. DNAs were extracted from the blood samples of the proband and her parents, and subjected to PCR-Sanger-sequencing to confirm the WES result. WES data analysis identified a homozygous single nucleotide change (A>T) at position c.785-2 located in intron 6 of the HACD1 gene (NC_000010.11(NM_014241.4):c.785-2A>T). This novel mutation located at the splice-acceptor site is disturbing the splicing procedure. The absence of this mutation among our control group (100 normal healthy adults from the same ethnic group) and not being reported in any other population database confirms the pathogenicity of this mutation. Bioinformatics analysis also classified this variant as a pathogenic mutation. PCR-Sanger-sequencing data analysis confirmed the WES result in the proband and showed that the parents were carriers for the mutation. A substitution (NC_000010.11(NM_014241.4):c.785-2A>T) mutation resulted in the removal of the splicing acceptor site at the HACD1 gene. This pathogenic mutation is associated with CFTD disease.

Identification of Two Novel Pathogenic Variants of the ATM Gene in the Iranian-Azeri Turkish Ethnic Group by Applying Whole Exome Sequencing.

Background: The ATM gene encodes a multifunctional kinase involved in important cellular functions, such as checkpoint signaling and apoptosis, in response to DNA damage. Bi-allelic pathogenic variants in this gene cause Ataxia Telangiectasia (AT), while carriers of ATM pathogenic variants are at increased risk of cancer depending on the pathogenicity of the variant they carry. Identifying pathogenic variants can aid in the management of the disease in carriers. Methods: Whole-exome sequencing (WES) was performed on three unrelated patients from the Iranian-Azeri Turkish ethnic group referred to a genetic center for analysis. WES was also conducted on 400 individuals from the same ethnic group to determine the frequencies of all ATM variants. Blood samples were collected from the patients and their family members for DNA extraction, and PCR-Sanger sequencing was performed to confirm the WES results. Results: The first proband with AT disease had two novel compound heterozygote variants (c.2639-2A>T, c.8708delC) in the ATM gene revealed by WES analysis, which was potentially/likely pathogenic. The second proband with bi-lateral breast cancer had a homozygous pathogenic variant (c.6067G>A) in the ATM gene identified by WES analysis. The third case with a family history of cancer had a heterozygous synonymous pathogenic variant (c.7788G>A) in the ATM gene found by WES analysis. Sanger sequencing confirmed the WES results, and bioinformatics analysis of the mutated ATM RNA and protein structure added evidence for the potential pathogenicity of the novel variants. WES analysis of the cohort revealed 38 different variants, including a variant (rs1800057, ATM:c.3161C>G, p.P1054R) associated with prostate cancer that had a higher frequency in our cohort. Conclusion: Genetic analysis of three unrelated families with ATM-related disorders discovered two novel pathogenic variants. A homozygous missense pathogenic variant was identified in a woman with bi-lateral breast cancer, and a synonymous but pathogenic variant was found in a family with a history of different cancers.

Plasma lncRNA profiling identified BC200 and NEAT1 lncRNAs as potential blood-based biomarkers for late-onset Alzheimer's disease.

Long non-coding RNAs (lncRNA) play critical roles in pathogenesis of neurodegenerative diseases. Human plasma carries lncRNAs that are stable in the blood, and their disease-specific profile have made them valuable biomarkers for some diseases. This study reports screening of the plasma levels of 90 lncRNAs in patients with Alzheimer disease (AD) to find out plasma-based AD biomarkers. Total RNA was isolated from plasma samples of 50 AD and 50 matched healthy controls. The plasma samples of 10 advanced AD patients and 10 matched healthy controls were screened for expression levels of 90 lncRNAs using Human LncRNA Profiler qPCR Array Kit (SBI). Based on the profiling results, lncRNAs BC200, NDM29, NEAT1, FAS-AS1 and GAS5-AS1 were selected for further analysis in all samples and their biomarker potency was evaluated by ROC curve analysis. We further surveyed RNAseq data by in silico analysis. We found that the NEAT1 and BC200 levels in the plasma of the AD patients were significantly higher compared with the control group (P=0.0021, p= 0.02, respectively). ROC curve analysis showed that the plasma level of NEAT1 and BC200 discriminated AD patients from healthy controls with sensitivity of 72 % and 60 %, and specificity of 84 % and 91 % respectively. Moreover, NEAT1 discriminated MCI (60 % sensitivity and 91 % specificity) and advanced-AD patients from healthy controls (73 % sensitivity and 71 % specificity). Besides, plasma level of BC200 discriminated the pre-clinical subjects from healthy controls with 83 % sensitivity and 66 % specificity. A positive correlation was also observed between plasma levels of BC200 with the age patients (r = 0.34, p=0.02). In silico RNAseq data analysis showed that a total of 33 lncRNAs were up-regulated but 13 lncRNAs were down-regulated significantly in AD patients compared with the healthy controls. In conclusion, this study elucidated that the plasma levels of lncRNAs NEAT1 and BC200 might be considered as potential blood-based biomarkers for AD development and progression.

Identification of novel cis-mutations in the GJA8 gene in a 3-generation Iranian family with autosomal dominant congenital nuclear cataract.

BACKGROUND: Cataract is mainly due to the presence of high molecular weight protein, which disrupts the normal function of the lens. Pathogenic variants in Gap Junction protein alpha-8 (GJA8) have been associated with autosomal dominant congenital nuclear cataract. In general, mutations in those genes that have important functions in lens development lead to congenital cataract. METHODS: We conducted whole-exome sequencing (WES) in a four-year-old male patient referred to the genetic center for genetic analysis. He had developed cataract at an early age. DNAs were extracted from the blood samples of all family members and subjected to PCR-Sanger sequencing to confirm the WES results. RESULTS: WES analysis on the proband revealed two mutations in the GJA8 gene (c.G12C, c.G58A). His mother, alongside several other members of the third-generation family, had developed cataract. Sanger sequencing of the interested regions showed that these two mutations were co-segregated in all affected members. However, none of the healthy individuals carried these mutations confirming that these two mutations are located in the same allele (complex allele). Bioinformatics analysis of the mutated GJA8 RNA and protein structure confirmed the pathogenicity of the cis-mutations. CONCLUSIONS: Genetic segregation analysis in a three-generation family and also bioinformatics analysis showed that the complex-allele containing c.G12C+c.G58A mutations in the GJA8 gene is a pathogenic variant that causes autosomal-dominant congenital nuclear cataract.

Role of CFH Y402H and ARMS2 A69S polymorphisms in susceptibility to post rhegmatogenous retinal detachment macular complications.

INTRODUCTION: Rhegmatogenous retinal detachment (RRD) is the most common type of retinal detachment. Purpose of this study is to evaluate the possible association of ARMS2 (age-related macular susceptibility 2) A69S and CFH (complement factor H) Y402H polymorphisms with post-surgical macular complications. MATERIALS AND METHODS: One hundred and two RRD patients with macular involvement and proliferative vitreoretinopathy grade A prospectively were enrolled in the study. All patients were genotyped for two polymorphisms of CFH Y402H and ARMS2 A69S by applying Polymerase Chain Reaction (PCR)-Restriction Fragment Length Polymorphism (RFLP). Scleral buckling or deep vitrectomy performed based on surgeon decision. Optical coherence tomography (OCT) for all patients was performed on three, six, and twelve months after operation. RESULTS: The ARMS2 A69S GT genotype showed significant association with postoperative cystoid macular edema (OR = 3.11, P = 0.039). Logistic regression analysis showed that the effect of ARMS2 GT vs GG genotype remained significant on CME after confounding factors correction. (ARMS2 GT vs GG OR = 4.79, p value = 0.035). No association was observed between studied genotypes and postoperative persistent subfoveal fluid, macular atrophy, and macular epiretinal membrane. CONCLUSIONS: The ARMS2 A69S GT genotype was significantly associated with postoperative cystoid macular edema in RRD cases with macular involvement.

Lack of Association between Monocyte Chemoattractant Protein-1 (MCP-1) Gene Promoter Polymorphism and Behcet's Disease with and without Ocular Involvement in Iranian Population: A Case-Control Study.

PURPOSE: This case-control study aimed to evaluate the possible association of MCP-1 - 2518A/G genetic polymorphism with Behcet's disease (BD) in the Iranian patients. MATERIALS AND METHODS: This study was performed in 135 Behcet's patients (51 ocular and 84 non-ocular) and 79 healthy individuals. Peripheral blood samples were genotyped for MCP-1 - 2518A/G using the PCR-RFLP technique. RESULTS: The statistical analysis of MCP-1 - 2518A/G showed no significant differences in genotype/allele frequencies between Behcet's patients and controls. There was no significant association in genotype/allele frequencies between either ocular or non-ocular BD patients and controls. Also, different genotype/allele frequencies between ocular and non-ocular BD were not statistically significant. CONCLUSIONS: In this study, with a threshold P-value of 0.05 and an estimated power of 0.81 to detect a significant association (odds ratio ≥1.2), we did not observe any association of this variant with Behcet's disease.

Genotypes of ANKK1 and DRD2 genes and risk of metabolic syndrome and its components: A cross-sectional study on Iranian women.

We aimed to investigate the association between polymorphism of DRD2/ANKK1 gene with MetS and its components. Women (n = 531, aged 19-50 years) from the North-west of Iran were included by cluster sampling method. Polymorphisms of ANKK1 and DRD2 genes were defined in the study population. D/D (OR: 3.16; 95%CI: 1.31-7.60) and I/D (OR: 1.76; 95%CI: 1.12-2.78) genotypes of DRD2 (rs1799732) increased risk of MetS compared to I/I genotype. The D/D genotype of DRD2 (rs1799732) increased odds of hypertriglyceridemia in the study population. T/T (OR: 6.72; 95%CI: 1.99-22.71) and C/T (OR: 4.42; 95%CI: 2.79-7.01) genotypes of ANKK1 (rs1800497) increased risk of MetS compared to C/C genotype. Also, C/T genotype increased the odds of HTN, high FBS, high TG and low HDL-C levels compared to C/C genotype. These polymorphisms can affect the MetS components via their relation to the signaling of dopaminergic pathways and eating behaviors.

Role of complement factor B rs4151667 (L9H) polymorphisms and its interactional role with CFH Y402H and C3 rs2230199 (R102G) risk variants in age-related macular degeneration: a case control study.

BACKGROUND: Age-related Macular Degeneration (AMD) is a complex eye disease, which is genetically associated with different susceptibility loci. We planned to investigate the possible association of Complement Factor B (CFB) rs4151667 (L9H) variants and their possible interaction with Complement Factor H (CFH) Y402H and Complement factor 3 (C3) rs2230199 (R102G) in AMD. METHODS: This case-control association study included 216 advanced type AMD patients and 191 healthy individuals for evaluation. Extracted-DNA samples were genotyped for the polymorphic regions of CFB rs4151667 (L9H), CFH Y402H and C3 rs2230199 (R102G). RESULTS: The distribution of CFB rs4151667 (L9H) genotypes was not significantly different in the AMD patients compared to that of controls (P = 0.18). The AT genotype frequencies for CFB was non significantly lower in AMD group (6.5% vs. 13.1%, AOR = 0.49, CI = 0.23-1.04, P = 0.064(. The A allele of CFB rs4151667 (L9H) was found to be non-significantly lower in AMD patients. CFB rs4151667 (L9H) had no protective interactional effect against CFH (Y402H) and C3 (R102G) risk variants. CONCLUSIONS: This study showed that the protective role of CFB rs4151667 (L9H) in AMD is not significant and it has no significant protective interactional effect against CFH (Y402H) and C3 (R102G) risk variants.

Association of Saitohin gene rs62063857 polymorphism with dry type age-related macular degeneration.

PURPOSE: Age-related macular degeneration (AMD) as the leading cause of central visual loss in the developed countries has extensive pathologic similarities with Alzheimer's disease (AD). Saitohin rs62063857 Q7 R polymorphism is associated with increased risk of AD though we decided to evaluate the possible association of this polymorphism with advanced AMD. MATERIALS AND METHODS: 152 advanced AMD patients (134 wet AMD and 18 geographic atrophy) and 75 healthy controls included in this study. Cases and controls went through a standard ophthalmologic examination by a retinal specialist. Saitohin gene rs62063857 polymorphism determined by using PCR technique and restriction enzyme HinFI. To evaluate the differences between groups we used t-test, Chi-Squared and one-tailed Fisher exact test. RESULTS: Distribution of genotypes was not significantly different between total AMD or wet AMD patients compared to that of controls (total AMD RR+QR: OR = 1.51, CI = 0.82-2.79, P = .12; wet AMD RR+QR: OR = 1.39, CI = 0.74-2.59, P = .19). The RR+QR genotypes were significantly higher in dry AMD group compared to that of controls (RR+QR: OR = 2.75, CI = 0.96-7.9, P = .05). CONCLUSION: Our results showed that although STH Q7 R polymorphism was not associated with wet AMD susceptibility it was significantly associated with geographic atrophy.

The Contribution of VKORC1 and CYP2C9 Genetic Polymorphisms and Patients' Demographic Characteristics with Warfarin Maintenance Doses: A Suggested Warfarin Dosing Algorithm.

The requirement of varying doses of warfarin for different individuals can be explained by environmental and genetic factors. We evaluated the frequency of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) variants together with patientdemographic characteristics and investigated their association with warfarin dose requirement with the objective to suggest a warfarin dosing algorithm. In this study, 185 patients with heart valve replacement from West Azerbaijan, Iran were genotyped for VKORC1 (-1639 G>A) and CYP2C9 (*2 and *3 alleles) by PCR-RFLP. Multiple linear regression was performed to create a new warfarin dosing algorithm. The frequency of variants in studied subjects was 12% for CYP2C9 *2, 25.8% for CYP2C9 *3, and 60% for -1639A. The patients who carried the A allele at position -1639 VKORC1 and the variants CYP2C9 *2 and *3 required a significantly lower daily mean warfarin dosage (P = 0.001). Statistical analysis also indicated a significant relationship between the daily maintenance dose of warfarin with age and blood pressure among the studied patients' cohort (P < 0.001). This study showed that in the heart valve replacement patients considering VKORC1 and CYP2C9 polymorphisms beside demographic characteristics such as age will be helpful in pre-treatment dosing of warfarin which in turn reduces the complications associated with inappropriate warfarin dosing.

Beta-Boswellic Acid and Ethanolic Extract of Olibanum Regulating the Expression Levels of CREB-1 and CREB-2 Genes.

Physiological studies confirm improvement of memory by Olibanum, a resin from Boswellia species, while little is known about the molecular mechanism by which it affects memory performance. Two master transcription factors, CREB-1 and CREB-2, regulate downstream memory-related genes expression, leading to the long-term memory potentiation. This study addresses the effects of Beta-boswellic acid (ß-BA), the main ingredient of Olibanum, and ethanolic extract of the resin from Boswellia serrata on the expression of CREB-1 and CREB-2 genes in B65 cell line. B65 cells were treated with ß-BA or ethanolic extract of Olibanum in different doses and time intervals and the cell viability/toxicity was measured by MTT assay. Total RNA was extracted from the treated and untreated control cells and cDNA was synthesized. The expression levels of CREB-1 and CREB-2 genes were quantified by Real-time PCR. MTT assays revealed 50% inhibitory concentrations of 42.05, 29.63, and 21.78 µg/mL for ethanolic extract of Olibanum and 89.54, 44.05, and 21.12 µM for ß-BA at 24, 48, and 72 h time intervals respectively. Both ß-BA and ethanolic extract of Olibanum altered CREB-1 and CREB-2 gene expression levels in time-dependent but not in dose-dependent way. However, ß-BA showed stronger and more stable effects. The expression levels of the both genes followed an alternate upregulation and downregulation pattern, but in opposite directions, in response to the both solutions with the progress of time. These results suggest that Olibanum possibly improves memory performance, at least partially, by regulating the levels of CREB-1 and CREB-2 transcription factors via positive/negative-feedback loops.

Thromboxane A synthase 1 gene expression and promotor haplotypes are associated with risk of large artery-atherosclerosis stroke in Iranian population.

Large artery atherosclerosis (LAA) is known as an important cause of ischemic stroke (IS), which is a multifactorial disorder. Many candidate genes have been proposed for IS like (TBXAS1) that plays a significant role in LAA stroke pathogenesis. This is the first study on the evaluation of the association of the five single-nucleotide polymorphisms (SNPs) in TBXAS1 promoter region and the level of TBXAS1 transcript with large-artery atherosclerosis stroke. Five SNPs in TBXAS1 genes were investigated in 248 patients with large-artery atherosclerosis stroke and 199 healthy controls in Iranian population in this case-control study through using the high-resolution melting assay. In addition, the relationships between the selected SNPs with alteration of TBXAS1 gene expressions were investigated in terms of blood platelets through the reverse transcription-quantitative polymerase chain reaction. Multivariate logistic analysis with adjustments indicated that rs10256282CC, rs10237429CC, and rs4590360GG genotypes were associated with large-artery atherosclerosis stroke (adjusted odds ratio = 2.804, 2.872, and 2.432, respectively; P < 0.05, q < 0.05). Furthermore, the frequency of CACCG haplotype in the patients was greatly higher than that in the controls (OR = 1.424, 95% CI: 1.071-1.893, P = 0.014738). In addition, TBXAS1 expression was higher in patients compared to the controls (P = 0.021), and individuals with the homozygous mutated genotypes of these SNPs showed a higher expression level compared to other genotype (P < 0.05). In total, our findings indicate a significant association of TBXAS1 gene rs10256282CC, rs10237429CC, and rs4590360GG polymorphisms with large-artery atherosclerosis stroke susceptibility and the level of TBXAS1 expression, which was not previously reported in any population.

Survival of familial adenomatous polyposis coexistence colorectal cancer in Iran.

CONTEXT: Familial adenomatous polyposis (FAP) is an autosomal dominant disorder. Colorectal cancer (CRC) has been implicated as the most common cause of death in FAP patients, especially in those with coexisting CRC at initial diagnosis (FAP-CRC). AIM: We aimed to determine the survival rate of FAP-CRC and the factors affecting FAP-CRC survival. SETTING AND DESIGN: This was a retrospective cohort FAP study conducted in northwest Iran. SUBJECTS AND METHODS: From 2006 to 2016, 51 FAP-CRC individuals were selected from among 4588 CRC patients. STATISTICAL ANALYSIS: A Student's t-test, life table method, log-rank tests, a Kaplan-Maier survival curve, and Cox regression analysis were performed and a value of P < 0.05 was set as statistically significant. RESULTS: A total of 51 FAP-CRC patients were selected, (30 males and 21 females), with a mean age of 42.2 years at diagnosis. The most common presenting symptom was abdominal pain and the most common primary tumor site was the rectum. The 1-, 5- and 10-year overall survival rates were 76%, 59%, and 52%, respectively. Factors affecting the FAP-CRC survival rate, namely, sex, age at CRC diagnosis, and extracolonic manifestations showed no significant differences. The difference in 5-year survival rates between patients with colon and rectal cancers was significant (75% vs. 33%, P = 0.02). The survival rate was significantly higher among patients with disease Stages I and II than those in disease Stages III and IV (P = 0.001). 5-year survival rates in patients with ileal pouch-anal anastomosis and ileorectal anastomosis were 71% and 78%, respectively (P = 0.001). There was an interesting difference in survival between FAP and attenuated FAP (P = 0.01). In cox regression analysis, distant metastasis was a significant predictor of survival (P = 0.001). CONCLUSIONS: Long-term survival from FAP-CRC remains poor; therefore, early-stage detection and the choice of an appropriate surgical method can improve survival in such patients.

Comparison of ARMS2/LOC387715 A69S and CFH Y402H risk effect in wet-type age-related macular degeneration: a meta-analysis.

PURPOSE: We designed this meta-analysis to pool studies which have analyzed both CFH (Y402H or I62V) and ARMS2 A69S in the same samples to compare the effect of CFH and ARMS2 in neovascular AMD. METHODS: Relevant studies identified and reviewed separately in order to select those for inclusion. Included studies had genotype data of studied groups for both ARMS2 A69S and CFH. To modify the heterogeneity in the variables, we used random effects model. Meta-analysis was performed using STATA. Funnel plot and Egger's regression test used for evaluation of the possible publication bias. RESULTS: Overall, we included 6676 neovascular AMD cases and 7668 controls. Pooled overall odds ratios (ORs) (95% CI) for neovascular AMD/control were ARMS2 A69S: OR = 2.35 (2.01-2.75) for GT versus GG; OR = 8.57 (6.91-10.64) for TT versus GG; CFH Y402H: OR = 1.94 (1.73-2.18) for CT versus TT; OR = 4.89 (3.96-6.05) for CC versus TT. ARMS2 A69S genotype OR/CFH Y402H genotype OR (homogeneous genotypes): Asia = 2.14, Europe: 1.87, America: 1.82, Middle East: 3.56, pooled: 1.75. ARMS2 A69S genotype OR/CFH Y402H genotype OR (heterogeneous genotypes): Asia = 0.93, Europe: 1.39, America: 2.06, Middle East: 1.20, pooled: 1.21. ARMS2 A69S risk genotypes have stronger predisposing effect on neovascular AMD compared to CFH Y402H risk genotypes. CONCLUSION: Our inclusion criteria to select those studies which have analyzed the effect of these two loci in the same case-control samples showed much stronger effect of ARMS2 A69S in neovascular AMD compared to the CFH Y402H.

Association of polymorphisms of complement factor I rs141853578 (G119R) with age-related macular degeneration in Iranian population.

BACKGROUND: Age-related macular degeneration (AMD) is a complex disease, and recent studies have shown role of complement system genes in its development. Complement factor I regulates the complement pathways, and relationship between CFI polymorphisms and AMD is controversial. We evaluated the possible association of complement factor I rs141853578 (G119R) variation with advanced AMD in Iranian patients. MATERIALS AND METHODS: We included 371 case-control samples consisting of 220 advanced AMD patients and 151 genetically unrelated healthy controls. Extracted DNA samples amplified to obtain fragment including the polymorphic complement factor I rs141853578 (G119R) region. RESULTS: The distribution of the genotypes was significantly different in the AMD patients compared to that of controls (p = 0.035). The TT genotype frequencies for CFI were significantly higher in AMD group (7.7 vs. 2%, OR 4.67, CI 1.33-16.45, p = 0.016). This significant difference was maintained after adjustment for the effects of age and gender (OR 5.09, CI 1.42-18.20, p = 0.012). The minor allele frequency (T allele) was also significantly higher in AMD patients compared to that of controls (29.3 vs. 21.5% OR 1.51, CI 1.07-2.13, p = 0.018). CONCLUSION: Current study showed that CFI rs141853578 (G119R) is a risk factor for developing advanced type AMD. This study also suggests that the frequency of G119R polymorphism in our population is not as rare as reported from other populations.