Combination Of Genetic Variants Research Articles

Primary Role of the Kidney in Pathogenesis of Hypertension.

Previous transplantation studies and the concept of 'nephron underdosing' support the idea that the kidney plays a crucial role in the development of essential hypertension. This suggests that there are genetic factors in the kidney that can either elevate or decrease blood pressure. The kidney normally maintains arterial pressure within a narrow range by employing the mechanism of pressure-natriuresis. Hypertension is induced when the pressure-natriuresis mechanism fails due to both subtle and overt kidney abnormalities. The inheritance of hypertension is believed to be polygenic, and essential hypertension may result from a combination of genetic variants that code for renal tubular sodium transporters or proteins involved in regulatory pathways. The renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) are the major regulators of renal sodium reabsorption. Hyperactivity of either the RAAS or SNS leads to a rightward shift in the pressure-natriuresis curve. In other words, hypertension is induced when the activity of RAAS and SNS is not suppressed despite increased salt intake. Sodium overload, caused by increased intake and/or reduced renal excretion, not only leads to an expansion of plasma volume but also to an increase in systemic vascular resistance. Endothelial dysfunction is caused by an increased intracellular Na+ concentration, which inhibits endothelial nitric oxide (NO) synthase and reduces NO production. The stiffness of vascular smooth muscle cells is increased by the accumulation of intracellular Na+ and subsequent elevation of cytoplasmic Ca++ concentration. In contrast to the hemodynamic effects of osmotically active Na+, osmotically inactive Na+ stimulates immune cells and produces proinflammatory cytokines, which contribute to hypertension. When this occurs in the gut, the microbiota may become imbalanced, leading to intestinal inflammation and systemic hypertension. In conclusion, the primary cause of hypertension is sodium overload resulting from kidney dysregulation.

FDA approves first genetic test to help identify risk for OUD

On Dec. 19, 2023, the U.S. Food and Drug Administration approved the first test that uses DNA in assessing whether certain individuals may have an elevated risk of developing opioid use disorder (OUD). As part of a clinical evaluation, the AutoGenomics, Inc. AvertD test is intended to be used prior to first exposure to oral opioid pain medications in patients being considered for a 4–30‐day prescription for the treatment of acute pain, such as in patients scheduled to undergo a planned surgical procedure. “The AvertD test, a prescription‐use only genetic laboratory test for patients 18 years and older, is to be used only with patients who consent to the test and have no prior use of oral opioid analgesics,” said Jeff Shuren, M.D., J.D., director of the FDA's Center for Devices and Radiological Health. “The test is administered by a health care provider by swabbing the cheek of a patient to collect a DNA sample that will be used to determine if a patient has a combination of genetic variants that may be associated with an elevated risk of developing OUD. This information should be used as part of a complete clinical evaluation and risk assessment; it should not be used alone to make treatment decisions. The test is not intended to be used in patients being treated for chronic pain. AvertD may help patients who are concerned about being treated with an opioid for acute pain make better informed decisions.” As part of the approval order, AutoGenomic, Inc. must provide training to health care providers to help ensure appropriate use of the test and conduct a large post‐market study assessing device performance in patients, regularly reporting progress made toward completion of that study to the FDA. The primary risks associated with AvertD are false negative and false positive results.

In cis “benign” SOCS1 variants linked to enhanced interferon signaling and autoimmunity

We aimed to characterize the genetic basis of disease in a family with multiple autoimmune manifestations, including systemic lupus erythematosus (SLE), immune thrombocytopenia, and autoimmune thyroiditis. Whole exome sequencing (WES) was conducted to identify candidate variants, which were analyzed by flow cytometry, immunoblotting, immunoprecipitation, and luciferase reporter assay in transfected 293T cells. Gene expression in peripheral blood mononuclear cells (PBMC) was profiled by bulk RNA sequencing and plasma cytokines were measured by proximity extension assay.In two siblings with early-onset SLE and immune thrombocytopenia, WES identified two maternally inherited in cis variants (p. Pro50Leu and p.Ala76Gly) in Suppressor of cytokine signaling 1 (SOCS1), flanking the kinase inhibitory domain that interacts with Janus kinases (JAK). Both variants were predicted to be benign by most in silico algorithms and neither alone affected the ability of SOCS1 to inhibit JAK-STAT1 signaling by functional studies. When both variants were expressed in cis, the mutant SOCS1 protein displayed decreased binding to JAK1 and reduced capacity to inhibit type I interferon (IFN–I) signaling by ∼20–30% compared to the wildtype protein. PBMC from the probands and their mother showed increased expression of interferon-inducible genes compared to healthy controls, supporting defective regulation of IFN-I signaling. Cells from all three subjects displayed heightened sensitivity to IFN-I stimulation, while response to IFN-γ, IL-4, and IL-6 was comparable to healthy controls.Our work illustrates the critical fine-tuning of IFN-I signaling by SOCS1 to prevent autoimmunity. We show that a combination of genetic variants that are individually benign may have deleterious consequences.

Histone Modifications in Alzheimer's Disease.

Since Late-onset Alzheimer's disease (LOAD) derives from a combination of genetic variants and environmental factors, epigenetic modifications have been predicted to play a role in the etiopathology of LOAD. Along with DNA methylation, histone modifications have been proposed as the main epigenetic modifications that contribute to the pathologic mechanisms of LOAD; however, little is known about how these mechanisms contribute to the disease's onset or progression. In this review, we highlighted the main histone modifications and their functional role, including histone acetylation, histone methylation, and histone phosphorylation, as well as changes in such histone modifications that occur in the aging process and mainly in Alzheimer's disease (AD). Furthermore, we pointed out the main epigenetic drugs tested for AD treatment, such as those based on histone deacetylase (HDAC) inhibitors. Finally, we remarked on the perspectives around the use of such epigenetics drugs for treating AD.

EP193: Co-occurring TCF12 and mosaic NALCN likely pathogenic variants: Case report of novel skeletal findings without craniosynostosis, neurologic dysfunction, and apnea

We report a unique clinical case of an 18-month-old patient with skeletal dysplasia, neurologic dysfunction, and apneic events caused by a novel combination of genetic variants. Whole exome sequencing (WES) identified two likely pathogenic variants, with one being mosaic, which is distinctive given the difficult nature of WES technology. The first variant was a de novo, heterozygous missense variant (c.1882T>C; p.Cys628Arg) in exon 19 of the TCF12 gene. The second is a mosaic single amino acid deletion (c.4299_4301delCAT; p.Ile1434del) in exon 38 of the NALCN gene, which was detected in 30% of the sequencing reads.

Predictive Ability of a Clinical-Genetic Risk Score for Venous Thromboembolism in Northern and Southern European Populations.

Venous thromboembolism (VTE) is a complex, multifactorial problem, the development of which depends on a combination of genetic and acqfiguired risk factors. In a Spanish population, the Thrombo inCode score (or TiC score), which combines clinical and genetic risk components, was recently proven better at determining the risk of VTE than the commonly used model involving the analysis of two genetic variants associated with thrombophilia: the Factor V Leiden (F5 rs6025) and the G20210A prothrombin (F2 rs1799963).The aim of the present case–control study was to validate the VTE risk predictive capacity of the TiC score in a Northern European population (from Sweden).The study included 173 subjects with VTE and 196 controls. All were analyzed for the genetic risk variants included in the TiC gene panel. Standard measures —receiver operating characteristic (ROC) area under the curve (AUC), sensitivity, specificity, and odds ratio (OR)—were calculated.The TiC score returned an AUC value of 0.673, a sensitivity of 72.25%, a specificity of 60.62%, and an OR of 4.11. These AUC, sensitivity, and OR values are all greater than those associated with the currently used combination of genetic variants. A TiC version adjusted for the allelic frequencies of the Swedish population significantly improved its AUC value (0.783).In summary, the TiC score returned more reliable risk estimates for the studied Northern European population than did the analysis of the Factor V Leiden and the G20210A genetic variations in combination. Thus, the TiC score can be reliably used with European populations, despite differences in allelic frequencies.

1548 The Combination of Candidate Genes in the Formation of Endometriosis in Women of Russia's Central Region

Study Objective Study of role of the combination genetic polymorphisms rs7759938, rs7766109 and rs13111134 in formation of endometriosis. Design Prospective cohort study. Setting Perinatal center St. Joasaph Belgorod Regional Clinic Hospital. Patients or Participants The research group consisted of 688 women between 2010 and 2013, of which 252 endometriosis patients and 436 persons of the control group. Main group and control group included Russian women who were native of Central Region of Russia and who were not relatives to each other. Patients with endometriosis were provided with clinical and gynecological examination, ultrasound investigation if pelvic floor, laparoscopic inspection with histologic confirmation after biopsy. Interventions Typing of single nucleotide polymorphism of the following genes was performed for patients with endometriosis women from control group: rs7759938, rs7766109 and rs13111134. Analysis of roles of combinations of genetic variants in occurrence of endometriosis was performed with the help of APSampler software. Measurements and Main Results It has been discovered that combination of genetic variants C rs7759938 with A rs7766109 and A rs13111134 occur in 10.89% of sick women, respectively, which is 1.86 times lower than that occur in control group (20.23%, pbonf=0.03). When there are these combination of polymorphic markers, pathology risk of endometriosis is significantly lower (OR=0.48, CI 0.35-0.66). Conclusion Protective meaning at formation of endometriosis belongs to combination of genetic variants C rs7759938 with A rs7766109 and A rs13111134 (OR=0.48).

Neutrophils: Innate Effectors of TB Resistance?

Certain individuals are able to resist Mycobacterium tuberculosis infection despite persistent and intense exposure. These persons do not exhibit adaptive immune priming as measured by tuberculin skin test (TST) and interferon-γ (IFN-γ) release assay (IGRA) responses, nor do they develop active tuberculosis (TB). Genetic investigation of individuals who are able to resist M. tuberculosis infection shows there are likely a combination of genetic variants that contribute to the phenotype. The contribution of the innate immune system and the exact cells involved in this phenotype remain incompletely elucidated. Neutrophils are prominent candidates for possible involvement as primers for microbial clearance. Significant variability is observed in neutrophil gene expression and DNA methylation. Furthermore, inter-individual variability is seen between the mycobactericidal capacities of donor neutrophils. Clearance of M. tuberculosis infection is favored by the mycobactericidal activity of neutrophils, apoptosis, effective clearance of cells by macrophages, and resolution of inflammation. In this review we will discuss the different mechanisms neutrophils utilize to clear M. tuberculosis infection. We discuss the duality between neutrophils' ability to clear infection and how increasing numbers of neutrophils contribute to active TB severity and mortality. Further investigation into the potential role of neutrophils in innate immune-mediated M. tuberculosis infection resistance is warranted since it may reveal clinically important activities for prevention as well as vaccine and treatment development.

The tyranny of choice: reproductive selection in the future.

This article explores the enormous challenges to reproductive decision making that could result from two emerging technologies: the potential capacity to create vast numbers of embryos for preimplantation genetic diagnosis and the ability to obtain ever more predictive information about the embryo. Together these technologies could change our reproductive experience, exacerbate existing inequities, and profoundly affect reproductive decision making. Simply comprehending the dizzying amounts of predictive information about the health and traits of future children will overwhelm future parents. But trying to choose embryos with the ‘best’ combination of genetic variants could be paralyzing. Nevertheless, numerous pressures will make this technology alluring, compelling providers to develop remedies to assist future parents with these difficult reproductive decisions. The remedies, however, will create their own challenges. Some might test the limits of reproductive autonomy and heighten social inequities. A particularly vexing remedy would be the development of algorithms for embryo selection, which could routinize reproductive decisions, reduce societal diversity, exacerbate ‘choice overload’ effects, challenge professional norms, and raise the specter of eugenics. Ultimately, this article is a cautionary tale urging circumspection as technological advancements seem to propel us inevitably toward a reproductive future that could create a tyranny of choice.

INTERDEPENDENCE OF COMPLEX GENOTYPES OF ALFA-LACTALBUMIN AND BETA-LACTOGLOBULIN WITH COMPOSITION AND TECHNOLOGICAL PROPERTIES OF MILK OF UKRAINIAN BLACK-AND-WHITE DAIRY CATTLE

The objective of this work was to study the effect of phenotypic combination of genetic variants α-LA and β-LG on the content of technologically and nutritionally important components of milk in cows of Ukrainian Black-and-White Dairy breed. Method PCR-RFLP was used to identify cow’s genotypes on the indicated genes. Milk yield was calculated based on the results of monthly control milking. It has been determined such indices of cow’s milk: fat content, protein content, total solids content, milk solids non-fat (MSNF) content, lactose content, casein content, casein number, milk density, milk rennet ability, heat stability (alcohol number) of milk. Statistical analysis was carried out using program Statistica 6.0. The study of genetic structure of the herd of Ukrainian Black-and-White Dairy cattle showed the high level of polymorphism on α-LA and β-LG genes. 6 genotypes were identified. Genetic structure of the herd on two genes simultaneously was determined. 9 complex genotypes were revealed. Phenotypic variants α-LA АВ/β-LG АВ, α-LAАА/β-LG АА and α-LAАВ/β-LG АА had the highest frequency – 26, 21,5and 14 % respectively. Frequencies of remaining genotypes were not higher than 10 %. The highest milk yield (5617 kg) was received from cows with genotype α-LA ВВ/β-LG АА. The percentage of these animals in the herd was only 7,5 %. The lowest milk yield (5367 kg) was fixed for the group of animals with complex genotypeα-LA АА/β-LG ВВ. The frequency of this genotype was 7 %. Three the most distributed complex genotypes (61,5 %) characterized by medium features of milk yield. Cows with genotypes α-LAАВ/β-LGВВ had the highest indices of fat content (3,93 %). The percentage of these animals in the herd was 5 %. The difference between cows’ groups with the highest and the lowest indices of fat content was 0,14% (td=2,5; p<0,05). Cows with genotypes α-LAАВ/β-LG АА had the highest protein content. Their percentage in the herd was 14 %. The difference between cows’ groups with highest and lowest indices of protein content was 0,06 % (td=1,1; p<0,05). The highest indices of casein content and casein number (2,42 % and 78,3 % respectively) were observed in animals with complex genotypes α-LAВВ/β-LG АВ andα-LAВВ/β-LGВВ, their frequency in the studied herd was 11 %. The difference between cows’ groups with highest and lowest above indicators was 0,05 % (td=1,8; p<0,05) and 3 % (td=2,38; p<0,001) respectively. Thus, milk from 11 % of cows of the studied herd of Ukrainian Black-and-White Dairy breed complied with the requirements for cheese manufacture better. Indicator of rennet ability confirmed this. The lowest time of milk coagulation (rennet ability) we observed in milk from cows with complex genotype α-LAВВ/β-LGВВ – 27,7 min. We can assume that expression of alleles B of α-LA and β-LG in this phenotypic combination determines such desirable properties for cheese making. At the same time, milk from cows with complex genotypes α-LAВВ/β-LG АВ and α-LAВВ/β-LGВВ had the worst indices of heat stability, its alcohol number was 2,17 ml. High heat stability of milk was determined by expression of A allele of genes α-LA and β-LG in phenotypic combination α-LA/β-LG. Milk from cows with genotype α-LA АВ/β-LG АВ had the highest lactose content (4,53 %). The difference between cows’ groups with highest and lowest indices of lactose content was 0,06% (td=1,1; p<0,05). Significant differences between the cows of different complex genotypes were not found for the total solids content. At the same time, some differences on MSNF content were observed. The highest indices (8,65 %) were revealed in groups of animals with genotypesα-LAАА/β-LG АА andα-LAВВ/β-LG АА, lowest (8,57 %) – with genotype α-LAАВ/β-LGВВ, but these differences were not statistically significant. The result presented here shows the relationship between the combination of alfa-lactalbumin and beta-lactoglobulin genetic variants in Ukrainian Black-and-White Dairy cattle and the productivity traits of animals, technological properties of their milk.

Investigation of single and synergic effects of NLRC5 and PD-L1 variants on the risk of colorectal cancer.

Constitutive activation of interferon signaling pathways has been reported in colorectal cancer (CRC), leading to a strong CD8+ T cell response through stimulation of NLRC5 expression. Primed CD8+ T cell expansion, however, may be negatively regulated by PD-L1 expression. Additionally, aberrant PD-L1 expression enables cancer cells to escape the immune attack. Our study aimed to select potential regulatory variants in the NLRC5 and PD-L1 genes by using several online in silico tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, microRNA and transcription factor binding site prediction tools and to investigate their influence on CRC risk in a Czech cohort of 1424 CRC patients and 1114 healthy controls. Logistic regression analysis adjusted for age and gender reported a moderate association between rectal cancer risk and two NLRC5 SNPs, rs1684575 T>G (OR: 1.60, 95% CI: 1.13–2.27, recessive model) and rs3751710 (OR: 0.70, 95% CI: 0.51–0.96, dominant model). Given that a combination of genetic variants, rather than a single polymorphism, may explain better the genetic etiology of CRC, we studied the interplay between the variants within NLRC5, PD-L1 and the previously genotyped IFNGR1 and IFNGR2 variants, to evaluate their involvement in the risk of CRC development. Overall we obtained 18 pair-wise interactions within and between the NLRC5 ad PD-L1 genes and 6 more when IFNGR variants were added. Thirteen out of the 24 interactions were below the threshold for the FDR calculated and controlled at an arbitrary level q*<0.10. Furthermore, the interaction IFNGR2 rs1059293 C>T—NLRC5 rs289747 G>A (P<0.0001) remained statistically significant even after Bonferroni correction. Our data suggest that not only a single genetic variant but also an interaction between two or more variants within genes involved in immune regulation may play important roles in the onset of CRC, providing therefore novel biological information, which could eventually improve CRC risk management but also PD-1-based immunotherapy in CRC.

Colorectal cancer risk genes are functionally enriched in regulatory pathways.

Colorectal cancer (CRC) is a common complex disease caused by the combination of genetic variants and environmental factors. Genome-wide association studies (GWAS) have been performed and reported some novel CRC susceptibility variants. However, the potential genetic mechanisms for newly identified CRC susceptibility variants are still unclear. Here, we selected 85 CRC susceptibility variants with suggestive association P < 1.00E-05 from the National Human Genome Research Institute GWAS catalog. To investigate the underlying genetic pathways where these newly identified CRC susceptibility genes are significantly enriched, we conducted a functional annotation. Using two kinds of SNP to gene mapping methods including the nearest upstream and downstream gene method and the ProxyGeneLD, we got 128 unique CRC susceptibility genes. We then conducted a pathway analysis in GO database using the corresponding 128 genes. We identified 44 GO categories, 17 of which are regulatory pathways. We believe that our results may provide further insight into the underlying genetic mechanisms for these newly identified CRC susceptibility variants.

SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival.

In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox' regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P=1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses.

Lycopene bioavailability is associated with a combination of genetic variants

The intake of tomatoes and tomato products, which constitute the main dietary source of the red pigment lycopene (LYC), has been associated with a reduced risk of prostate cancer and cardiovascular disease, suggesting a protective role of this carotenoid. However, LYC bioavailability displays high interindividual variability. This variability may lead to varying biological effects following LYC consumption. Based on recent results obtained with two other carotenoids, we assumed that this variability was due, at least in part, to several single nucleotide polymorphisms (SNPs) in genes involved in LYC and lipid metabolism. Thus, we aimed at identifying a combination of SNPs significantly associated with the variability in LYC bioavailability. In a postprandial study, 33 healthy male volunteers consumed a test meal containing 100g tomato puree, which provided 9.7mg all-trans LYC. LYC concentrations were measured in plasma chylomicrons (CM) isolated at regular time intervals over 8h postprandially. For the study 1885 SNPs in 49 candidate genes, i.e., genes assumed to play a role in LYC bioavailability, were selected. Multivariate statistical analysis (partial least squares regression) was used to identify and validate the combination of SNPs most closely associated with postprandial CM LYC response. The postprandial CM LYC response to the meal was notably variable with a CV of 70%. A significant (P=0.037) and validated partial least squares regression model, which included 28 SNPs in 16 genes, explained 72% of the variance in the postprandial CM LYC response. The postprandial CM LYC response was also positively correlated to fasting plasma LYC concentrations (r=0.37, P<0.05). The ability to respond to LYC is explained, at least partly, by a combination of 28 SNPs in 16 genes. Interindividual variability in bioavailability apparently affects the long-term blood LYC status, which could ultimately modulate the biological response following LYC supplementation.

Analyzing large-scale samples confirms the association between rs16892766 polymorphism and colorectal cancer susceptibility.

Colorectal cancer (CRC) is a common complex disease caused by the combination of genetic variants and environmental factors. Genome-wide association studies (GWAS) have been performed and reported some novel CRC susceptibility variants. The rs16892766 (8q23.3) polymorphism was first identified to be significantly associated with CRC in European ancestry. The following studies investigated this association in Chinese, Japanese, Romanian, Swedish, African American, European American, and Croatian populations. These studies reported consistent and inconsistent results. Here, we reevaluated this association using the relatively large-scale samples from 13 studies (N = 59737, 26237 cases and 33500 controls) using a meta-analysis by searching the PubMed, Google Scholar and CRCgene databases. We observed no significant heterogeneity among the included studies. Our results showed significant association between rs16892766 polymorphism and CRC (P = 1.33E-35, OR = 1.23, 95% CI 1.20-1.27). Collectively, our analysis further supports previous findings that the rs16892766 polymorphism is significantly associated with CRC susceptibility. We believe that our findings will be very useful for future genetic studies on CRC.

Significant association of combination of OCT4, NANOG, and SOX2 gene polymorphisms in susceptibility and response to treatment in North Indian breast cancer patients.

Dysregulations of regulatory genes in embryonic stem cells (ESCs) gene polymorphisms may lead to breast cancer cell growth, differentiation, and tumor metastasis. Polymorphisms in OCT4 (rs3130932), NANOG (rs11055786), LIN28 (rs4274112), and SOX2 (rs11915160) genes were evaluated for susceptibility in 297 breast cancer females and 273 healthy controls from north Indian population. Response to neo-adjuvant chemotherapy was followed in 128 locally advanced breast cancer patients along with clinicopathological features. Genotyping was done using TaqMan allelic discrimination assays. Statistical analysis was performed using SPSS and multifactor dimensionality reduction (MDR). For OCT4 gene polymorphism, protective effect of genotypes AC [P corr = 0.031, OR = 0.63 (0.44-0.91)] and AC+CC [P corr = 0.031, OR = 0.68 (0.48-0.95)] was seen in patients. However, no association of NANOG, LIN28, and SOX2 gene polymorphisms was found with overall breast cancer susceptibility. Further, significant association of AG+GG genotype [P corr = 0.021, OR = 6.08 (1.83-20.15)] and G allele [P corr = 0.021, OR = 3.07 (1.21-7.77)] of rs4274112 polymorphism was seen with positive lymph node. For OCT4, significant association of allele C was seen with patients having negative hormone receptor [P corr = 0.021, OR = 0.51 (0.29-0.90)], but no association of any of the studied polymorphisms individually was found with response to NACT. On MDR analysis, we found combination of SNPs SOX2 rs11915160, OCT4 rs3130932, and NANOG rs11055786 to be the best interaction model for predicting breast cancer risk [p for permutation test <10(-3), OR = 2.04 (1.43-2.910] and response to NACT [p for permutation test = 0.005, OR = 2.09 (1.24-3.52)]. Combination of genetic variants of ESCs gene may have a profound effect in breast cancer risk and response to NACT.

The combination of genetic variants in the FSHR and FSHB genes affect serum FSH in women of reproductive age

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Genetic variations in drug-induced liver injury (DILI): resolving the puzzle

Genetic variations in drug-induced liver injury (DILI): resolving the puzzle

A genome-wide association study identifies novel risk loci for type 2 diabetes

Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing beta-cells, and two linkage disequilibrium blocks that contain genes potentially involved in beta-cell development or function (IDE-KIF11-HHEX and EXT2-ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.