Candidate Gene Polymorphisms Research Articles

Genetic effects on white matter integrity in drug-naive patients with major depressive disorder: a diffusion tensor imaging study of 17 genetic loci associated with depressive symptoms.

BackgroundA genome-wide association study using megadata identified 17 single-nucleotide polymorphisms (SNPs) in candidate genes for major depressive disorder (MDD). These MDD susceptibility polymorphisms may affect white matter (WM) integrity. This study aimed to investigate the relationship between WM alterations and 17 SNPs in candidate genes for MDD in the first depressive episode of drug-naive MDD patients using a tract-based spatial statistics (TBSS) method.MethodsThirty-five drug-naive MDD patients with a first depressive episode and 47 age-and sex-matched healthy subjects underwent diffusion tensor imaging scans and genotyping. The genotype–diagnosis interactions related to WM integrity were evaluated using TBSS for the 17 SNPs.ResultsFor the anterior thalamic radiation, cingulum, corticospinal tract, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, uncinate fasciculus, forceps major, and forceps minor, the genotype effect significantly differed between diagnosis groups (P<0.05, family-wise error corrected) in only one SNP, rs301806, in the arginine–glutamic acid dipeptide (RE) repeats (RERE) gene.ConclusionThe RERE polymorphism was associated with WM alterations in first-episode and drug-naive MDD patients, which may be at least partially related to the manifestation of MDD. Future studies are needed to explore the gene–environment interactions with regard to individual WM integrity.

Exploring polymorphism and effects of candidate genes on milk fat and protein quality in munjal sheep

Exploring polymorphism and effects of candidate genes on milk fat and protein quality in munjal sheep

Identification of selected genetic polymorphisms in polycystic ovary syndrome in Sri Lankan women using low cost genotyping techniques.

BackgroundPolycystic ovary syndrome (PCOS), the commonest endocrine disorder affecting young women, appears to be a multigenic trait with contributing genes being unclear. Hence, analysis of polymorphisms in multiple candidate genes is required. Currently available genotyping methods are expensive, time-consuming with limited analytical sensitivity.Aim(i) Develop and validate high resolution melting (HRM) assay and allele-specific real-time quantitative PCR (AS-qPCR) for genotyping selected SNPs associated with PCOS.(ii) Identify selected SNPs and their association with a Sri Lankan cohort of well-characterized PCOS.MethodsDNA was extracted from women with well-characterized PCOS from adolescence (n = 55) and ethnically matched controls (n = 110). FTO (Fat mass and obesity associated gene; rs9939609), FSHB (Follicle stimulating hormone beta subunit; rs6169), FSHR (Follicle stimulating hormone receptor; rs6165/rs6166), and INSR (Insulin receptor; rs1799817) genes were genotyped using HRM assay. GnRH1 (Gonadotropin releasing hormone; rs6185), LHB (Luteinizing hormone beta subunit; rs1800447/rs34349826) and LHCGR (Luteinizing hormone/choriogonadotropin receptor; rs2293275) genes were genotyped using AS-qPCR method. Genotyping results were validated using Sanger sequencing.ResultsA significant association was observed within FTO gene polymorphism (rs9939609) and PCOS. Genotype frequency of FTO gene (rs9939609)—cases versus controls were TT-36.4% vs.65.4% (p<0.05), AT-23.6% vs.20.9%, AA-40% vs.13.6% (p<0.05). Genotype frequencies of the SNPs GnRH1 (rs6185), FSHB (rs6169), FSHR (rs6165 & rs6166), LHB (rs1800447 & rs34349826), LHCGR (rs2293275) and INSR (rs1799817) were not significantly different between cases and controls (p>0.05). Only the mutant alleles were observed for LHB rs1800447 and rs34349826 SNPs in both groups. The HRM and AS-qPCR assay results had 100% concordance with sequencing results.ConclusionsFTO gene rs9939609 polymorphism is significantly more prevalent among Sri Lankan PCOS subjects while the other selected SNPs of HPG axis genes and INSR gene showed no association. HRM and AS-qPCR assays provide a reliable, fast and user-friendly genotyping method facilitating wider implication in clinical practice.

ANALYSIS OF CANDIDATE POLYMORPHISMS AT EPILEPSY PATIENTS WITHOUT MECHANICAL DISTURBANCES

Thе article presents the results of a molecular-genetics research on patients with diagnosed epilepsy without mechanical disturbance. The aim of this research was the analysis of candidate gene polymorphisms in development of different forms of epilepsy excepting mechanical reasons. 78 patients of V.M. Savinov SVS clinic with different forms of epilepsy were selected for the molecular-genetic analysis. Genotyping on candidate polimorphisms of gene coding the methyl-СрG-binding protein 2 (МЕСР2, 3 polymorphisms), the genes of sodium (SCN1A, 4 polymorphisms) and potassium (KCNT1, 2 polymorphisms) channels was performed by a site-specific PCR-RFLP method. Molecular genetic analysis revealed the presence of normal functioning alleles for 3 investigated candidate polymorphisms (p.Thr158Met, p.Thr197Met, p.Arg306Ter) of 3d exon of МЕСР2 gene at all epilepsy patients. However, 1 case (patient suffering from Dravet syndrome) of de novo mutation was defined for sodium channel gene (SCN1A p.Ala1783Thr) and 3 cases (2 patients suffering from temporal epilepsy and 1 patient with residual encephalopathy) of new mutations in gene responsible for potassium channel (KCNT1 p.Ala934Thr). To determine the inherited SCN1A and KCNT1 mutations, the molecular-genetics analysis was conducted for close relatives of patients. As a result, we conclude that, candidate polymorphisms of SCN1A p.Ala1783Thr and KCNT1 p.Ala934Thr, disrupting the ion channels normal functioning, can be involved in development of non-mechanical forms of epilepsy.

Clinical Implications of Single Nucleotide Polymorphisms in Diagnosis of Asthma and its Subtypes.

For the past three decades, a large number of genetic studies have been performed to examine genetic variants associated with asthma and its subtypes in hopes of gaining better understanding of the mechanisms underlying disease pathology and to identify genetic biomarkers predictive of disease outcomes. Various methods have been used to achieve these objectives, including linkage analysis, candidate gene polymorphism analysis, and genome-wide association studies (GWAS); however, the degree to which genetic variants contribute to asthma pathogenesis has proven to be much less significant than originally expected. Subsequent application of GWAS to well-defined phenotypes, such as occupational asthma and non-steroidal anti-inflammatory drugexacerbated respiratory diseases, has overcome some of these limitations, although with only partial success. Recently, a combinatorial analysis of single nucleotide polymorphisms (SNPs) identified by GWAS has been used to develop sets of genetic markers able to more accurately stratify asthma subtypes. In this review, we discuss the implications of the identified SNPs in diagnosis of asthma and its subtypes and the progress being made in combinatorial analysis of genetic variants.

Single nucleotide polymorphisms in candidate genes associated with milk yield in Argentinean Holstein and Holstein x Jersey cows

BackgroundResearch on loci influencing milk production traits of dairy cattle is one of the main topics of investigation in livestock. Many genomic regions and polymorphisms associated with dairy production have been reported worldwide. In this context, the purpose of this study was to identify candidate loci associated with milk yield in Argentinean dairy cattle. A database of candidate genes and single nucleotide polymorphisms (SNPs) for milk production and composition was developed. Thirty-nine SNPs belonging to 22 candidate genes were genotyped on 1643 animals (Holstein and Holstein x Jersey). The genotypes obtained were subjected to association studies considering the whole population and discriminating the population by Holstein breed percentage. Phenotypic data consisted of milk production values recorded during the first lactation of 1156 Holstein and 462 Holstein x Jersey cows from 18 dairy farms located in the central dairy area of Argentina. From these records, 305-day cumulative milk production values were predicted.ResultsEight SNPs (rs43375517, rs29004488, rs132812135, rs137651874, rs109191047, rs135164815, rs43706485, and rs41255693), located on six Bos taurus autosomes (BTA4, BTA6, BTA19, BTA20, BTA22, and BTA26), showed suggestive associations with 305-day cumulative milk production (under Benjamini-Hochberg procedure with a false discovery rate of 0.1). Two of those SNPs (rs43375517 and rs135164815) were significantly associated with milk production (Bonferroni adjusted p-values < 0.05) when considering the Holstein population.ConclusionsThe results obtained are consistent with previously reported associations in other Holstein populations. Furthermore, the SNPs found to influence bovine milk production in this study may be used as possible candidate SNPs for marker-assisted selection programs in Argentinean dairy cattle.

Association of polymorphism of some candidate genes with the development of non-infectious and infectious endocarditis

Aim . To study association between polymorphisms of candidate genes and the development of non-infectious and infectious endocarditis (IE). Material and methods . During the study 175 patients were examined. They were divided into two groups: the first group — 81 patients with non-infectious endocarditis and the second one — 94 patients with IE. We present a comparative analysis of the genotype frequencies of the five genes polymorphisms: rs11697325 (-8202 A/G) of the MMP9 gene, 4a/4b of the NOS3 gene, rs4340 of the ACE gene, rs2476601 (С1858Т) of the PTPN22 gene, rs231775 (49 A/G) of the CTLA4 gene in groups of patients with endocarditis and healthy individuals. Results . We found association between endocarditis and rs11697325 (-8202 A/G) of the MMP9 gene, 4a/4b of the NOS3 gene, as well as rs2476601 (C1858T) of the PTPN22 gene with IE. Conclusion . Thus, association between three of the five polymorphisms and vegetations on the valvular heart apparatus was revealed.

Associations of genetic markers of the sympathoadrenal system and endothelial dysfunction with coronary heart disease on the example of a small Shoriya population

Aim . To establish associations of polymorphisms of candidate genes coding for the components of the endothelial (NOS3, MTHFR) and sympathoadrenal systems (ADRB1, ADRA2B) with coronary heart disease (CHD) in the cohort of the small population of Mountain Shoriya. Material and methods . A clinical and epidemiological study was conducted in the areas of Mountain Shoriya (Orton, Ust-Kabyrza, Sheregesh, Tashtagol). Analysis of risk factors included recording the age, sex, body mass index, waist circumference, presence/absence of arterial hypertension (AH), smoking, and the presence of disorders of lipid and carbohydrate metabolism. CHD diagnosis was made by three epidemiological criteria: coding of the electrocardiogram according to the Minnesota code, Rose questionnaire, and a history of myocardial infarction. The patient underwent molecular genetic testing. DNA isolation from blood was carried out by the method of phenol-chloroform extraction. Statistical processing was carried out using the programs STATISTICA 6.1 (StatSoft Inc., USA) and SNPStats. Results . The prevalence of CHD in the Shoriya cohort was 9,7%. The results of our study established the relationship of genetic markers of the sympathoadrenal and endothelial systems with coronary atherosclerosis in the indigenous population of Shoriya. The high risk of atherosclerotic heart disease was associated with the 4b/4a genotype of the NOS3 gene (OR 2,57 95% CI (1,12-5,86), p=0,026) according to the dominant mode of inheritance. The relationship of the T/T genotype of the MTHFR gene with CHD by recessive inheritance was established (OR 13,28; 95% CI (1,79-98,40), p=0,024). Conclusion . Due to genetic research, there is a real opportunity not only to carry out accurate molecular diagnostics, but also to determine an underlying risk for a disease. Detection of genetic disposition to CHD can be carried out long before the onset of clinical symptoms, which can effectively prevent its development.

A preliminary integrated genetic map distinguishes every chromosome pair and locates essential genes related to abiotic adaptation of Crassostrea angulata/gigas

BackgroundThe re-sequencing of C. angulata has revealed many polymorphisms in candidate genes related to adaptation to abiotic stress that are not present in C. gigas; these genes, therefore, are probably related to the ability of this oyster to retain high concentrations of toxic heavy metals. There is, in addition, an unresolved controversy as to whether or not C. angulata and C. gigas are the same species or subspecies. Both oysters have 20 metacentric chromosomes of similar size that are morphologically indistinguishable. From a genomic perspective, as a result of the great variation and selection for heterozygotes in C. gigas, the assembly of its draft genome was difficult: it is fragmented in more than seven thousand scaffolds.ResultsIn this work sixty BAC sequences of C. gigas downloaded from NCBI were assembled in BAC-contigs and assigned to BACs that were used as probes for mFISH in C. angulata and C. gigas. In addition, probes of H3, H4 histone, 18S and 5S rDNA genes were also used. Hence we obtained markers identifying 8 out the 10 chromosomes constituting the karyotype. Chromosomes 1 and 9 can be distinguished morphologically. The bioinformatic analysis carried out with the BAC-contigs annotated 88 genes. As a result, genes associated with abiotic adaptation, such as metallothioneins, have been positioned in the genome. The gene ontology analysis has also shown many molecular functions related to metal ion binding, a phenomenon associated with detoxification processes that are characteristic in oysters. Hence the provisional integrated map obtained in this study is a useful complementary tool for the study of oyster genomes.ConclusionsIn this study 8 out of 10 chromosome pairs of Crassostrea angulata/gigas were identified using BAC clones as probes. As a result all chromosomes can now be distinguished. Moreover, FISH showed that H3 and H4 co-localized in two pairs of chromosomes different that those previously escribed. 88 genes were annotated in the BAC-contigs most of them related with Molecular Functions of protein binding, related to the resistance of the species to abiotic stress. An integrated genetic map anchored to the genome has been obtained in which the BAC-contigs structure were not concordant with the gene structure of the C. gigas scaffolds displayed in the Genomicus database.

Clinicalgenetic determinants of albuminury development among patients with arterial hypertension.

Purpose. To establish the associations of polymorphisms of АСЕ, AGT, AGTR1, ADR81, ADRA2B, MTHFR and NOS3 candidate genes with microalbuminuria in patients with arterial hypertension (AH) among indigenous (the shors) and non-indigenous population of Mountain Shoria. Material and methods. A clinical and epidemiological study of the compactly settled population in the remote areas ofMountain Shoria was conducted. This region of middle mountains is located in the south of Western Siberia. 1409persons [901 subjects - the representatives of indigenous nationality (the shors), 508 subjects - representatives of non-indigenous nationality (90% among them were the representatives of the European ethnicity)] were examined. AH was diagnosed according to the National Guidelines of the Russian Society of Cardiology/the Russian Medical Society on Arterial Hypertension (2010). Photometric method was used to study the urine albumin level. The albuminuria index of more than 30 mg/day was taken as elevated. Polymorphisms of genes ACE (I/D, rs 4340), АGT (c.803T&gt;C, rs699), AGTR1 (А1166С, rs5186), ADRB1 (с.145A&gt;G, Ser49Gly, rs1801252), ADRA2B (I/D, rs 28365031), MTHFR (c.6770T, Ala222Val, rs1801133) andNOS3 (VNTR, 4b/4a) were investigated using polymerase chain reaction test. Results. An increase of the chances of microalbuminuria frequency development in patients with 3rd grade AH and duration of anamnesis of this disease for more than 10 years in both ethnic groups was established. In cohort of shor people the elevated level of albuminuria was interrelated with hypertriglyceridemia (OR 2.86), hypoalphacholesterolemia (OR 5.57) and hyperbetacholesterolemia (OR 2.49). The ACE gene was associated with a high risk of microalbuminuria (OR 2.05) in the log-additive type of inheritance, the D/D genotype of the ADRA2B gene (OR 6.00) - according to the recessive type of inheritance. At division of the examined population of shors according to age sign the relationship of heterozygous C/T genotype of MTHFR gene with the appearance of microaluminuria in persons of the age group of 18-64 years was established (OR 3.25). In the cohort of the non-indigenous ethnos the increased albuminuria level was influenced by obesity (OR 2.72), including abdominal (OR 3.14). Minor genotype C/C of the AGTR1 gene was associated with this target organ damage (OR 8.66) according to the recessive type of inheritance, the prognostically adverse genotype D / D of the ADRA2B gene (OR 6.53) - by the dominant type. The genotype T/T of the MTHFR gene was also proved to be interrelated with the microalbuminuria (OR 7.16) by the recessive type of inheritance. Conclusion. The determination of polymorphisms of AH candidate genes and the detection of associations with microalbuminuria expands understanding the concept of the genetic component of the cardiorenal continuum and creates the prerequisites for the development of a more advanced and effective prevention program.

Functional variant of MTOR rs2536 and survival of Chinese gastric cancer patients

We previously reported that some single nucleotide polymorphisms (SNPs) of candidate genes involved in the MTOR complex1 (MTORC1) were associated with risk of gastric cancer (GCa). In the present study, we further evaluated associations of eight potentially functional SNPs of MTOR, MLST8 and RPTOR with survival of 1002 GCa patients and also investigated molecular mechanisms underlying such associations. Specifically, we found that the MTOR rs2536 C allele at the microRNA binding site was independently associated with a 26% reduction of death risk (HR = 0.74, 95% CI = 0.57-0.96, p = 0.022). The results remained noteworthy with a prior false positive probability of 0.1. Genotype-phenotype correlation analysis in 144 patients' adjacent normal gastric tissue samples revealed that the MTOR expression levels were lower in rs2536 TC/CC carriers than that in wild-type TT carriers (p = 0.043). Dual luciferase assays revealed that the rs2536 C allele had a higher binding affinity to microRNA-150, leading to a decreased transcriptional activity of MTOR, compared to the rs2536 T allele. Further functional analysis revealed that MTOR knockdown by small interference RNA impaired proliferation, migration, and invasion ability in GCa cell lines. In conclusion, The MTOR rs2536 T > C change may be a biomarker for survival of Chinese GCa patients, likely by modulating microRNA-induced gene expression silencing. Additional studies are needed to validate our findings.

Association of DAT1 genetic variants with habitual sleep duration in the UK Biobank.

Short sleep duration has been linked to negative health effects, but is a complex phenotype with many contributing factors, including genetic. We evaluated 27 common single nucleotide polymorphisms (SNPs) in candidate genes previously reported to be associated with other sleep variables for association with self-reported habitual sleep duration in the UK Biobank in 111 975 individuals of European ancestry. Genetic variation in DAT1 (rs464049) was significantly associated with sleep duration after correction for multiple testing (p = 4.00 × 10-5), whereas SNPs correlated to a previously studied variable number tandem repeat (VNTR) in DAT1 were not significant in this population. We also replicated a previously reported association in DRD2. Independent replication of these associations and a second signal in DRD2 (rs11214607) was observed in an additional 261 870 participants of European ancestry from the UK Biobank. Meta-analysis confirmed genome-wide significant association of DAT1 rs464049 (G, beta [standard error, SE] = -0.96 [0.18] minutes/allele, p = 5.71 × 10-10) and study-wide significant association of DRD2 (rs17601612, C, beta [SE] = -0.66 [0.18] minutes/allele, p = 1.77 × 10-5; rs11214607, C, beta [SE] = 1.08 (0.24) minutes/allele, p = 1.39 × 10-6). Overall, SNPs in two dopamine-related genes were significantly associated with sleep duration, highlighting the important link of the dopamine system with adult sleep duration in humans.

Relationship between STAT5B Candidate Gene Polymorphism with Growth Related Traits and Ascites Index in Commercial Chicken Line

Relationship between STAT5B Candidate Gene Polymorphism with Growth Related Traits and Ascites Index in Commercial Chicken Line

The COMT Val158Met Polymorphism and Reaction to a Transgression: Findings of Genetic Associations in Both Chinese and German Samples.

After a transgression, people often either tend to avoid the transgressor or seek revenge. These tendencies can be investigated via a trait approach and surprisingly little is known about their biological underpinnings. One promising candidate gene polymorphism, which may influence individual differences in avoidance of a transgressor and vengefulness, is the COMT Val158Met (rs4680) polymorphism known to affect dopaminergic signaling and among others brain activity in situations in which people punish others for their behavior. We therefore investigated the molecular genetics of individual differences in Avoidance Motivation and vengefulness with a focus on this polymorphism. Possible genetic associations were first investigated in a sample of N = 730 Chinese participants (n = 196 females) using buccal cells to extract the DNA for genotyping. To replicate the findings we carried out a parallelized investigation in a sample of N = 585 German participants (n = 399 females). Chinese and German versions of the TRIM-12 and the Vengeance Scale were implemented to assess individual differences in tendencies to react to a transgression. Results show that Met allele carriers of the COMT Val158Met polymorphism (Val/Met and Met/Met) score significantly higher on the tendency to avoid a transgressor in the Chinese male and female samples, with an especially pronounced effect in the female subgroup. The same effect could be found in the German sample, again especially in females. Additionally, carrying a Met allele was associated with higher vengefulness in the Chinese sample only, especially in males. The present findings indicate that the COMT Val158Met polymorphism might influence individual differences in the motivation to avoid transgressors across cultures, especially in females. However, its association with vengefulness seems to be more complex and may exhibit some cultural and gender specific effects.

Genetic polymorphisms in candidate genes are not associated with increased vincristine-related peripheral neuropathy in Arab children treated for acute childhood leukemia: a single institution study.

The aim of this study was to evaluate the potential association between candidate genetic polymorphisms and vincristine-related peripheral neuropathy in Arab children with acute lymphoblastic leukemia (ALL). This is a retrospective evaluation of 133 Arab children treated for ALL at the Children's Cancer Center of Lebanon. Incidence and severity of, as well as the timing (in weeks) at which grade 2 or higher peripheral neuropathy occurred were recorded. Genotyping for ABCB1 (rs1045642), ABCB1 (rs1128503), ABCC2 (rs717620), CEP72 (rs924607), ETAA1 (rs17032980), and MTNR1B (rs12786200) was performed. A total of 26 (19.5%) individuals developed peripheral neuropathy, three of which occurred during the induction phase. No statistically significant associations were revealed for any of the polymorphisms with either incidence of vincristine-related toxicity, toxicity severity, or time to the first episode of grade 2 or higher vincristine-related peripheral neuropathy. This study presents the first pharmacogenetic analysis of vincristine-related peripheral neuropathy in children with ALL in an Arab country. We have shown that genetic polymorphisms in candidate genes are not associated with peripheral neuropathy secondary to chronic therapy with high-dose vincristine (2 mg/m) during the continuation phase. Concerning CEP72, our results are in line with the findings from the St Jude cohort of children treated for ALL with higher vincristine doses during chronic treatment. Larger high-throughput genetic analyses may be warranted to evaluate variants in other candidate genes such as CYP3A5 and reveal new nonpreviously reported alleles that may be peculiar to this region of the world.

Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study

SummaryBackgroundHuman genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms—many related to the structure or function of red blood cells—and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress.MethodsWe did a case-control study in Kilifi County, Kenya. We recruited as cases children presenting with severe malaria to the high-dependency ward of Kilifi County Hospital. We included as controls infants born in the local community between Aug 1, 2006, and Sept 30, 2010, who were part of a genetics study. We tested for associations between a range of candidate malaria-protective genes and risk for severe malaria and its specific phenotypes. We used a permutation approach to account for multiple comparisons between polymorphisms and severe malaria. We judged p values less than 0·005 significant for the primary analysis of the association between candidate genes and severe malaria.FindingsBetween June 11, 1995, and June 12, 2008, 2244 children with severe malaria were recruited to the study, and 3949 infants were included as controls. Overall, 263 (12%) of 2244 children with severe malaria died in hospital, including 196 (16%) of 1233 with cerebral malaria. We investigated 121 polymorphisms in 70 candidate severe malaria-associated genes. We found significant associations between risk for severe malaria overall and polymorphisms in 15 genes or locations, of which most were related to red blood cells: ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA (both HBA1 and HBA2), HBB, IL10, LPHN2 (also known as ADGRL2), LOC727982, RPS6KL1, CAND1, and GNAS. Combined, these genetic associations accounted for 5·2% of the variance in risk for developing severe malaria among individuals in the general population. We confirmed established associations between severe malaria and sickle-cell trait (odds ratio [OR] 0·15, 95% CI 0·11–0·20; p=2·61 × 10−58), blood group O (0·74, 0·66–0·82; p=6·26 × 10−8), and –α3·7-thalassaemia (0·83, 0·76–0·90; p=2·06 × 10−6). We also found strong associations between overall risk of severe malaria and polymorphisms in both ATP2B4 (OR 0·76, 95% CI 0·63–0·92; p=0·001) and FREM3 (0·64, 0·53–0·79; p=3·18 × 10−14). The association with FREM3 could be accounted for by linkage disequilibrium with a complex structural mutation within the glycophorin gene region (comprising GYPA, GYPB, and GYPE) that encodes for the rare Dantu blood group antigen. Heterozygosity for Dantu was associated with risk for severe malaria (OR 0·57, 95% CI 0·49–0·68; p=3·22 × 10−11), as was homozygosity (0·26, 0·11–0·62; p=0·002).InterpretationBoth ATP2B4 and the Dantu blood group antigen are associated with the structure and function of red blood cells. ATP2B4 codes for plasma membrane calcium-transporting ATPase 4 (the major calcium pump on red blood cells) and the glycophorins are ligands for parasites to invade red blood cells. Future work should aim at uncovering the mechanisms by which these polymorphisms can result in severe malaria protection and investigate the implications of these associations for wider health.FundingWellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative.

A Genetic Score Associates With Pioglitazone Response in Patients With Non-alcoholic Steatohepatitis.

Pioglitazone is used effectively to treat non-alcoholic steatohepatitis (NASH), but there is marked variability in response. This study examined whether genetic variation contributes to pioglitazone response variability in patients with NASH. This genetic substudy includes 55 participants of a randomized controlled trial designed to determine the efficacy of long-term pioglitazone treatment in patients with NASH. The primary outcome of the clinical trial was defined as ≥2-point reduction in the non-alcoholic fatty liver disease activity score (NAS). In this substudy, single nucleotide polymorphisms (SNPs) in putative candidate genes were tested for association with primary and secondary outcomes. A genetic response score was constructed based on the sum of response alleles for selected genes. The genetic response score was significantly associated with achievement of the primary outcome (odds ratio 1.74; 95% CI 1.27–2.54; p = 0.0015). ADORA1 rs903361 associated with resolution of NASH (p = 0.0005) and change in the ballooning score among Caucasian and Hispanic patients (p = 0.0005). LPL rs10099160 was significantly associated with change in ALT (p = 0.0005). The CYP2C8∗3 allele, which confers faster pioglitazone clearance in allele carriers, was associated with change in fibrosis score (p = 0.026). This study identified key genetic factors that explain some of the inter-individual variability in response to pioglitazone among patients with NASH.

Abstract 237: The genetic architecture of African esophageal cancer

Abstract Esophageal squamous cell carcinoma (ESCC) is common in many Black populations of sub-Saharan Africa, with high incidence regions in Eastern and Southern Africa. Clinical presentation in Africa is late, and treatment is mainly palliative with a very poor prognosis. Various environmental risk factors have been identified, but the possible contribution of inherited genetic variants to disease risk is unresolved. Genetic association studies of African ESCC have been limited to the analysis of small numbers of single nucleotide polymorphisms (SNPs) in candidate genes, and carried out only in the Black and Mixed Ancestry populations of the Western Cape of South Africa. Thus far no genetic associations with ESCC have been replicated in African populations. We tested SNPs which have been associated with ESCC in genome-wide association studies (GWAS) from Asian and European populations for association with ESCC in the South African Black population. Black cases with a histologically confirmed diagnosis of ESCC and matching population controls were recruited, after informed consent and institutional ethical approval, from the Western Cape and Gauteng provinces of South Africa. SNPs were genotyped either by individual TaqMan assays (Applied Biosystems) or in a multiplex MassARRAY (Agena Bioscience) and genotypes were tested for association. We genotyped 26 SNPs from OSCC risk loci and 10 ancestry informative markers in 880 Black South African (SAB) OSCC cases and 939 controls recruited by the Johannesburg Cancer Study. No significant associations were detected at the CASP8, ALS2CR12, ADH1C TMEM173, PLCE1, ALDH2, ATP1B2/TP53 or CHEK2 loci, although some SNPs showed the same direction of effect observed in other populations. 8 SNPs from these loci were genotyped in a further 493 cases and 820 controls from the Western Cape, and a combined test for association done in a total of 1373 cases and 1759 controls. The only SNP that was significantly associated with ESCC in the combined analysis after correction for multiple testing was rs1033667 in CHEK2 (OR = 1.18, P = 0.002). The lack of transference of most loci from Asian and European populations in an African population could result from smaller or absent effects of these loci in Africa. Alternatively, since we are likely to be genotyping tagging SNPs rather than the actual causal variants in these studies and linkage disequilibrium (LD) is lower in African genomes, our power to detect association with tagging SNPs will be reduced. This question could be resolved by carrying out a well-powered GWAS in African ESCC using a SNP array with sufficient African content to identify known or novel associations. We are currently conducting a GWAS for ESCC by genotyping 1700 ESCC cases and 6000 controls using a 2.4M SNP array designed by the H3 Africa Consortium. Citation Format: Christopher G. Mathew, Wenlong C. Chen, Hannah Bye, Natalie J. Prescott, Marco Matejcic, Robyn Kerr, Elvira Singh, Cathryn M. Lewis, Chantal Babb de Villiers, Mohamed I. Parker. The genetic architecture of African esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 237.

Potential role of PIN1 genotypes in predicting benefit from oxaliplatin-based and irinotecan-based treatment in patients with metastatic colorectal cancer.

PIN1-mediated substrate isomerization plays a role in the repair of DNA double-strand breaks. We hypothesized that genetic polymorphisms in PIN1-related pathways may affect tumor sensitivity to oxaliplatin or irinotecan in metastatic colorectal cancer (mCRC) patients. We analyzed genomic DNA from five cohorts of mCRC patients (total 950) treated with different first-line treatments: oxaliplatin cohorts 1 (n=146) and 2 (n=70); irinotecan cohorts 1 (n=228) and 2 (n=276); and combination cohort (n=230). Single nucleotide polymorphisms of candidate genes were analyzed by PCR-based direct sequencing. In the oxaliplatin cohort 1, patients carrying any PIN1 rs2233678 C allele had shorter progression-free survival (PFS) and overall survival (OS) than the G/G variant (PFS, 7.4 vs. 15.0 months, hazard ratio [HR] 3.24, P<0.001; OS, 16.9 vs. 31.5 months, HR: 2.38, P=0.003). In contrast, patients with C allele had longer median PFS than patients with G/G (11.9 vs. 9.4 months, HR: 0.64, 95%CI: 0.45–0.91, P=0.009) in the irinotecan cohort 1. No significant differences were observed in the combination cohort. In comparison between the irinotecan cohort 1 and combination cohort, the patients carrying the G/G variant benefit greatly from the combination compared with irinotecan-based regimen (PFS, 11.6 vs. 9.4 months, HR 0.61, 95%CI: 0.47–0.78, P<0.001; OS, 30.6 vs. 24.0 months, HR 0.79, 95%CI: 0.62–1.02, P=0.060), while no significant difference was shown in any C allele. Germline PIN1 polymorphisms may predict clinical outcomes in mCRC patients receiving oxaliplatin- or irinotecan-based therapy, and identify specific populations favorable to oxaliplatin plus irinotecan combination therapy.

Associations between obesity candidate gene polymorphisms (fat mass and obesity-associated (FTO), melanocortin-4 receptor (MC4R), leptin (LEP) and leptin receptor (LEPR)) and dietary intake in pregnant women.

Genetic variants associated with dietary intake may be important as factors underlying the development of obesity. We investigated the associations between the obesity candidate genes (fat mass and obesity-associated (FTO), melanocortin-4 receptor (MC4R), leptin (LEP) and leptin receptor) and total energy intake and percentage of energy from macronutrients and ultra-processed foods before and during pregnancy. A sample of 149 pregnant women was followed up in a prospective cohort in Rio de Janeiro, Brazil. A FFQ was administered at 5-13 and 30-36 weeks of gestation. Genotyping was performed using real-time PCR. Associations between polymorphisms and the outcomes were investigated through multiple linear regression and ANCOVA having pre-pregnancy dietary intake as a covariate. The A-allele of FTO-rs9939609 was associated with a -6·5 % (95 % CI -12·3, -0·4) decrease in the percentage of energy from protein and positively associated with the percentage of energy from carbohydrates before pregnancy (β=2·6; 95 % CI 0·5, 4·8) and with a 13·3 % (95 % CI 0·7, 27·5) increase in the total energy intake during pregnancy. The C-allele of MC4R-rs17782313 was associated with a -7·6 % (95 % CI -13·8, -1·0) decrease in the percentage of energy from protein, and positively associated with the percentage of energy from ultra-processed foods (β=5·4; 95 % CI 1·1, 9·8) during pregnancy. ANCOVA results revealed changes in dietary intake from pre-pregnancy to pregnancy for FTO-rs9939609 (percentage of energy from ultra-processed foods, P=0·03), MC4R-rs17782313 (total energy intake, P=0·02) and LEP-rs7799039 (total energy intake, P=0·04; percentage of energy from protein, P=0·04). These findings suggest significant associations between FTO-rs9939609, MC4R-rs17782313 and LEP-rs7799039 genes and the components of dietary intake in pregnant women.