Mehmet Tevfik Dorak

Kingston University · School of Life Sciences, Pharmacy & Chemistry

Cardiotoxicity induced by anti-cancer treatment has become a significant threat as the number of cardiotoxic anti-cancer agents is growing. Cancer patients are at an increased risk of contracting coronavirus disease 2019 (COVID-19) because of immune suppression caused by anti-cancer drugs and/or supportive treatment. Deterioration in lung functions...

Background: Generalized epileptic convulsions frequently exhibit transient respiratory symptoms and non-infectious leukocytosis. While these peri-ictal effects appear to arise independently from one another, the possibility that they stem from a common ictal pathophysiological response has yet to be explored. We aimed to investigate whether peri-ic...

One of the regulatory elements called X box-like (XL) sequences, XL9, is located between HLA-DRB1 and -DQA1. Multiple enhancers regulating the expression of HLA class II genes map to XL9. XL9 is involved in the formation of long-distance chromatin loops with the promoters of the DRB1 and DQA1 genes. To assess the extent of the involvement of XL9 SN...

South Asians have a greater cardiovascular disease (CVD) and type 2 diabetes (T2D) risk than white Europeans, but the mechanisms are poorly understood. This study examined ethnic differences in free fatty acids (FFAs) metabolic profile (assessed using liquid chromatography-mass spectrometry), appetite-related hormones and traditional CVD and T2D ri...

Objective: To evaluate the frequency of HLA class I and II alleles associated with traditional forms of inflammatory arthritis in patients with immune checkpoint inhibitor (ICI)-induced inflammatory arthritis as compared with population controls. Methods: High-resolution HLA typing was performed on 27 patients with ICI-induced inflammatory arthr...

The HLA region harbours the strongest risk markers for susceptibility to autoimmune disorders (AIDs). Most GWAS top hits, including those for AIDs, are expression quantitative trait loci (eQTL). To systematically examine the direction of the eQTL effects in relation to the direction of AID risk, we screened eQTLs for HLA-DR and -DQ expression in bl...

The extensive linkage disequilibrium (LD) in the extended HLA (xHLA) region is well-known, but there is also data suggesting no difference from the rest of the genome and haplotype-specificity of LD. Current algorithms do not consider LD beyond 500kb. Given that xHLA covers more than 7Mb, we used Haploview to analyse the Immunochip data from 95 HLA...

The extended HLA (xHLA) class I region (6p22.1) has consistently shown linkage and associations with schizophrenia (SCHZ) susceptibility, and in the GWAS era, the strongest hits are also in this region (chr6: 28.165 to 29.151Mb). The latest analysis of xHLA in SCHZ identified rs13194504 as the tagging SNP for a cluster of variants in this region. W...

The HLA region is arguably the most important part of the human genome, but due to its peculiarities and complexities, most researchers are hesitant to work with this region. Recent developments in genome biology equally apply to the HLA region, but the tools may look daunting to non-specialists. To facilitate research in genome biology, especially...

Epidemiological evidence consistently shows that males have a higher susceptibility to non-sex-specific cancers. For some cancers, the sex difference is clearly due to behavioral differences. Differences in morphology, such as greater weight and height, and genetics and physiology also play a role, but exact details are missing. The differences bet...

The major histocompatibility complex (MHC) is located in chromosome 6p21 and contains crucial regulators of immune response, including human leucocyte antigen (HLA) genes, alongside other genes with nonimmunological roles. More recently, a repertoire of noncoding RNA genes, including expressed pseudogenes, has also been identified. The MHC is the m...

We present alternative methods that can unravel the true polygenic background of complex disorders. We re-analysed an already published GWAS study designed to identify genetic markers of gender-specific differences in childhood ”leukaemia” . In genome-wide and candidate gene association studies, Biostatistical methods are used frequently to identif...

Direct-to-Consumer genetic testing services are becoming more ubiquitous. Consumers of such services are sharing their genetic and clinical information with the research community to facilitate the extraction of knowledge about different conditions. In this paper, we build on these services to analyse the genetic data of people with different BMI l...

The immune system is believed to be involved in the control of cancer as the cancer immunoediting concept outlines. As a direct application, cancer immunotherapy has evolved to a powerful treatment option. The evidence for cancer immunoprevention also exists, but relies on increased cancer incidence among immunosuppressed or immunodeficient people,...

Single-nucleotide polymorphisms (SNPs) across the HLA region are often significant in genome-wide association studies (GWAS), but most of these associated SNPs do not correspond to classical HLA alleles, even in immune-mediated disorders. Another level of functional HLA region variation (epitopes/supertypes) is relevant in disease associations, but...

We explored the unique genomic features of the extended HLA (xHLA) region (chr6: 25,726,131 to 33,400,601bp) in the latest genome assembly (GRCh38) to gain insight into the gene content. xHLA makes up 0.24% of the genome, and contains 674 genes (1.1% of total genes) of which 453 are proteincoding genes (2.3% of total). The protein-coding gene propo...

The power of cancer immune surveillance has been documented beyond doubt, and the successful exploitation of immune response to cancer has started a new era in the war against cancer. Cancer biologists have recognized immunoevasion as an emerging hallmark in addition to the six hallmarks of cancer. Besides the natural connection between the immune...

Childhood acute lymphoblastic leukemia (ALL) occurs more frequently in males. Reasons behind sex differences in childhood ALL risk are unknown. In the present genome-wide association study (GWAS), we explored the genetic basis of sex differences by comparing genotype frequencies between male and female cases in a case-only study to assess effect-mo...

Genetic Association Studies is designed for students of public health, epidemiology, and the health sciences, covering the main principles of molecular genetics, population genetics, medical genetics, epidemiology and statistics. It presents a balanced view of genetic associations with coverage of candidate gene studies as well as genome-wide assoc...

Besides environmental risk factors, genetic risk markers can also be used to gain insight into aetiology and disease biology. Childhood acute lymphoblastic leukaemia (ALL) has been repeatedly examined for genetic risk markers and very consistent results have been reported. We also did our own genome-wide association study (GWAS) designed to unravel...

Having recently reported replications of our previously reported associations of the extended HLA region polymorphisms (HLA-DRB9 rs2395185, HFE rs1800562, rs9366637 and rs807212), and the transferrin receptor gene (TFRC) polymorphism (rs3817672) with birth weight and childhood acute lymphoblastic leukaemia (ALL) risk, we have now revisited these st...

Besides environmental risk factors, genetic risk markers can also be used to gain insight into aetiology and disease biology. Childhood acute lymphoblastic leukaemia (ALL) has been repeatedly examined for genetic risk markers and very consistent results have been reported. We also did our own genome-wide association study (GWAS) designed to unravel...

Aim Genetic susceptibility and EBV infection have been reported as co-factors responsible for the risk of developing NPC. The incidence of NPC has a marked geographic variation, though rare in the west; it is high in countries such as Taiwan and China. While Human Leukocyte Antigen (HLA) have been associated with NPC predisposition in Asians, yet t...

Background Acute lymphocytic leukemia (ALL) is the most common pediatric cancer. The exact cause is not known in most cases, but past epidemiological research has suggested a number of potential risk factors. This study evaluated associations between environmental and parental factors and the risk for ALL in Egyptian children to gain insight into r...

The ancestral HLA haplotype A3-B7-C7-DR15-DQ6 (AH 7.1) harbours loci that confer protection for type 1 diabetes (T1D), and risk for multiple sclerosis (MS). To gain insight into the nature of those loci and to the pathogenesis of these diseases, we compiled common risk markers reported by the WTCCC and International MS Genetics Consortium studies....

A number of polymorphisms in immune system genes show associations with multiple diseases. The mechanisms of those associations are unclear. We have started a systematic study to functionally annotate disease-associated immunogenetic polymorphisms. Here, we report our results on PTPN22 rs2476601 (R620W), CTLA4 rs3087243 (CT60) and rs231775 (+49G>A)...

The HLA complex is the most gene dense and polymorphic part of the genome which also contains the strongest trans-eQTLs in the genome. We noted the presence of multiple trans-eQTLs for the DNA repair gene XRCC6 ( P −9 ) across the HLA region from 29.5 MB to 32.5 MB (chromosome 6) despite the absence of any cis-eQTL for XRCC6 in its vicinity in chro...

Although a number of cancer associations with HLA region SNPs have been reported, there is still no conclusion on whether the HLA complex contains cancer susceptibility genes or if the associations reflect alterations in immune surveillance. To identify the HLA-linked non-HLA genes playing a role in carcinogenesis, we screened germline variants of...

The HLA complex is the most gene dense and polymorphic region in the human genome, and not surprisingly, shows a large number of disease associations. The latest genome assembly contains >250K SNPs in the HLA region (chr6:28.5 to 34.5Mb). The emphasis in disease association studies has been on the HLA gene polymorphisms, despite the fact that non-H...

High birth weight is an established risk factor for childhood acute lymphoblastic leukemia (ALL), especially in children younger than 5 years of age at diagnosis. The goal of this study was to explore the association between being born large for gestational age and the risk for ALL by race/ethnicity to determine if the role of this risk factor diff...

Similar to most cancers, males have a higher risk than females for childhood acute lymphoblastic leukemia (ALL). To gain insight into the genetic basis of this difference, we performed a case-only GWAS to identify gender-specific risk markers among 240 ALL cases recruited at Texas Children’s Cancer Center using the Illumina Infinium HumanCoreExome...

The major histocompatibility complex (MHC) was strongly implicated in the development of lung cancers in animal experiments. Lung cancers show the highest number of cancer associations with human MHC (HLA) region. For a systematic analysis, we extracted 73 SNPs located within chromosome 6: 29 to 33Mb and associated with lung cancer from the GWAS ca...

Birth characteristics such as birth order, birth weight, birth defects, and Down syndrome showed some of the first risk associations with childhood leukemia. Examinations of correlations between birth characteristics and leukemia risk markers have been limited to birth weight-related genetic polymorphisms. We integrated information on nongenetic an...

Other than few inherited syndromes, etiology of childhood acute myeloid leukemia (AML) remains largely unknown. Adult AML risk is associated with an HLA-DR53 epitope, and the only previous study from St Jude revealed an HLA-B62 risk association in childhood AML. HLA typing was performed on 130 childhood (≤18yr) AML cases and their parents in Tissue...

The HLA region has the highest gene density and polymorphic content in the human genome resulting in a large number of disease associations. Childhood acute lymphoblastic leukaemia (ALL) shows gender-specific associations with HLA region variants. We conducted a pilot GWAS using Illumina Infinium 610-quad BeadChip on 117 male and 94 female childhoo...

Serotonin reuptake variation is linked to a functional polymorphism in the promoter region of the SLC6A4 gene on chromosome 17. It is plausible that variations in genetically determined SLC6A4 activity may modify the risk for alcohol dependence. To determine whether this allele is associated with alcohol dependence, the authors conducted a systemat...

The aim of this study was to assess the differences in correlation of PPARGC1A polymorphisms with type 2 diabetes (T2D) risk in adults of African origins: African Americans and Haitian Americans. The case-control study consisted of >30 years old, self-identified Haitian Americans ( cases and controls) and African Americans ( cases and controls) liv...

Serotonin reuptake variation is linked to a functional polymorphism in the promoter region of the SLC6A4 gene on chromosome 17. It is plausible that variations in genetically determined SLC6A4 activity may modify the risk for alcohol dependence. To determine whether this allele is associated with alcohol dependence, the authors conducted a systemat...

Hereditary hemochromatosis (HFE) variants correlating with body iron levels have shown associations with cancer risk, including childhood acute lymphoblastic leukemia (ALL). Using a multi-ethnic sample of cases and controls from Houston, TX, we examined two HFE variants (rs1800562 and rs1799945), one transferrin receptor gene (TFRC) variant (rs3817...

Rheumatoid arthritis (RA) is a common autoimmune disorder which shows clinical heterogeneity. It has multiple treatment options, and there is individual variation in response to treatment. These features make RA an ideal condition to develop biomarkers for its preclinical detection, diagnosis, subtyping, prognostic stratification, and selection of...

HLA region is the most gene-dense and polymorphic region, showing the highest number of disease associations in the genome either by HLA typing or by SNP typing. The strongest trans-eQTL effects have also been observed for SNPs from the HLA region. Although the mechanism of most associations are yet to be clarified, given the non-HLA gene content o...

The role played by the HLA complex in the development of childhood acute lymphoblastic leukaemia (ALL) has been controversial. The lack of top hit associations with individual HLA region SNPs in genome-wide association studies may have even generated some pessimism for any role. In the initial phase of an ongoing study of a family-based HLA associa...

Abstract Genome-wide association studies have identified multiple risk loci for childhood acute lymphoblastic leukemia (ALL), but mostly in European/White populations despite Hispanics having a greater risk. We re-examined SNPs of known associations with childhood ALL and known HLA region lymphoma risk markers in a multi-ethnic population. Signific...

Genome-wide association studies (GWAS) have identified multiple lung cancer associations within HLA region, BAG6 rs3117582 being the strongest. Other cancer associations nearby have also been reported (CCHCR1 rs130067 and MDC1 rs28986317/prostate cancer; MICB rs3130922/glioma; HSPA1B rs2763979/poor survival in lung cancer). BAG6 is heat shock-induc...

Aim GWAS reported associations between HLA region SNPs and multiple cancers whose mechanisms remain unexplored. In most cases, whether the associated SNP represents a proxy for an already known HLA association, and if so, whether it is a non-functional proxy or possibly the causal SNP underlying the HLA association, is unknown. Methods To gain mech...

The purpose of this research was to analyze gene x environment (G x E) interactions in lung adenocarcinoma. Based on Oncomine microarray database analysis we showed a higher expression of collagen Type XI Alpha 1 (COL11A1) and reduced expression of Fasciculation and Elongation Protein Zeta 1 (FEZ1) in different stages of lung adenocarcinoma. Using...

Type 2 Diabetes (T2D) has grown to be a major public health issue worldwide. The fundamental clinical characteristic of T2D is high blood glucose levels which may be caused by anomalies in one or more different molecular pathways regulated by certain genes. The Gly482Ser polymorphism in human peroxisome proliferator-activated receptor gamma coactiv...

Type 2 Diabetes (T2D) has grown to be a major public health issue worldwide. The fundamental clinical characteristic of T2D is high blood glucose levels which may be caused by anomalies in one or more different molecular pathways regulated by certain genes. The Gly482Ser polymorphism in human peroxisome proliferator‐activated receptor gamma coactiv...

The gender difference in cancer susceptibility is one of the most consistent findings in cancer epidemiology. Hematologic malignancies are generally more common in males and this can be generalized to most other cancers. Similar gender differences in non-malignant diseases including autoimmunity, are attributed to hormonal or behavioral differences...

The HLA class II gene BCL2-associated athanogene 6 (BAG6, previously BAT3) is induced by heat shock. Its product is a ligand for NKp30 receptor of NK cells, and is also involved in apoptotic pathways through interactions with caspase and P53. Its SNP rs3117582 is associated with lung cancer risk. Our previous work showed that it is exclusively pres...

The strongest susceptibility markers for lymphomas map to the HLA class II region and mark ancestral lineages: rs2395185 (Hodgkin lymphoma, protection, DRB4 lineage); rs10484561 (follicular lymphoma, risk, DR1/DR10 lineage) and rs2647012 (follicular lymphoma, protection, DRB3/DRB5 lineages). Childhood acute lymphoblastic leukemia (ALL) also shows a...

Gene expression levels are regulated by genetic variants and environmental exposures. Unlike many other genes, HLA gene expression levels have not been analyzed using modern tools. We aimed to initiate a series of experiments to assess the degree of variation and its determinants in classic HLA genes. On 16 IHWG cell lines representing common CEHs,...

NOTCH proteins are highly relevant in oncogenesis. Four NOTCH genes are present: NOTCH4 in the HLA complex and others in paralogous regions. Different NOTCH variants show associations with diseases including NOTCH2 and breast cancer (BC). In this stage I study for a BC project, we adopted a combined approach of bioinformatics and genetics to identi...

MICA and MICB loci are relevant in transplantation and tumor immunology. Their polymorphisms show numerous disease associations, but no systematic analysis has been performed to see whether they are expression QTLs or just proxies for HLA alleles. Using TaqMan assays, we genotyped six polymorphisms (MICA rs1051792, rs2596542; MICB rs2248462, rs3132...

Aim Despite the biological plausibility as suggested by animal experiments and HLA associations, genome-wide association studies (GWAS) in breast cancer (BC) have not reported any top hits from the HLA region. We revisited the results of the NIH CGEMS study to seek evidence for the involvement of the HLA region in the development of BC. Methods We...

The study aimed to compare the overall detection rate of Trichomonas vaginalis to Chlamydia trachomatis and Neiserria gonorrhea and report detection rates by age groups. Real-time polymerase chain reaction was used to detect the presence of T. vaginalis, C. trachomatis, and N. gonorrhea in cervical samples obtained from patients during gynecologica...

Journal of Human Genetics, official journal of the Japan Society of Human Genetics, publishes original articles and reviews on all aspects of human genetics, including medical genetics and genomics

The ABO blood group gene located on chromosome 9q34.2 encodes glycosyltransferase that determines the blood groups discovered more than a century ago. DNA sequence variation encoding A and B alleles modify the glycosyltransferase activity that convert the H antigen into the A or B antigen. A frameshift variant changes the protein sequence to blood...

Aim NOTCH proteins are highly relevant in oncogenesis. Four NOTCH genes are present: NOTCH4 in the HLA complex and others in paralogous regions. Different NOTCH variants show associations with diseases including NOTCH2 and breast cancer (BC). In this stage I study for a BC project, we adopted a combined approach of bioinformatics and genetics to id...

HLA region associations reported in genome-wide association studies (GWAS) may simply reflect previously known HLA associations or represent new, independent associations. This distinction is important to proceed to functional validation studies. We examined HLA region SNP associations in published reports and created a catalog. Using 104 IHWG refe...

Previous epidemiologic studies showed four times increased risk of acute lymphoblastic leukemia (ALL) in children of women with multiple sclerosis (MS). MS shows a risk association with Human leukocyte antigens (HLA)-DRA single nucleotide polymorphism (SNP) rs3135388, which is a proxy marker for DRB1*1501. We examined the relevance of rs3135388 in...

Success rate in human pregnancies is believed to be very low and sex-specific mechanisms may operate in prenatal loss. Assuming a sex-differential in prenatal loss exists, we examined genetic markers in biologically plausible targets in the HLA complex, other immune system-related and iron-regulatory genes in 388 healthy newborns from Wales (UK) us...

Childhood cancers make up 1% of the total cancer burden. Despite their rarity, they cause highest disease mortality in childhood. Research on the etiology of childhood cancers has been hampered by small sample sizes, lack of appropriate controls, reliance on case-control studies and difficulties with the definition of environment and measurement of...

In the last two decades, strong observational and experimental evidence has been presented for the role of iron excess in cancer development. The hereditary hemochromatosis gene HFE variants that increase body iron levels are associated with increased cancer risk. The first such association was reported by us in childhood acute lymphoblastic leukem...

The interferon regulatory factor (IRF) family of DNA-binding proteins regulates expression of interferon-inducible genes with roles in the immune response and carcinogenesis. IRF4 is involved in the differentiation of B and T cells and is overexpressed in B-cell malignancies as a result of c-REL (NF-κB) hyperactivation. IRF4 polymorphisms are assoc...

Cancer is a complex disease. Only 5-10% of human cancers are hereditary in nature. Many of us think of environmental agents when we think of carcinogens. The environment includes all that surrounds us, and environmental influences include not only chemical, physical and biological toxicants, but also diet and lifestyle. In this broadest sense, the...

Our original studies reported an association between the iron-metabolism gene HFE and risk of childhood acute lymphoblastic leukemia (ALL), and a birth weight association in ALL. Through its effect on cell proliferation, iron is involved in both fetal development and cancer. We hypothesize that HFE links higher infant birth weight with leukemia ris...

Three heat shock protein 70 (HSP70) genes, HSPA1L, HSPA1A, and HSPA1B, are located within the human leukocyte antigen (HLA) class III region. HSPs act as stress signals and regulate natural killer cell response to cancer. HSP70 gene polymorphisms show disease associations partly due to their linkage disequilibrium with HLA alleles. To systematicall...

Genomic and immunologic surveillance mechanisms are crucial in protection from cancer. The tumor suppressor protein p53, encoded by TP53, is a major regulator of genome surveillance. Among the natural sequence variants of TP53, rs1042522 (R72P) modifies the risk for solid tumors. To investigate its relevance in childhood acute lymphoblastic leukemi...