scholarly journals Common Genetic Variants in Trypsin Regulating Genes Are Associated with AsparAginase-Associated Pancreatitis in Children with Acute Lymphoblastic Leukemia: A Ponte Di Legno Toxicity Working Group Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 885-885
Author(s):  
Benjamin Ole Wolthers ◽  
Thomas Leth Frandsen ◽  
Andishe Attarbaschi ◽  
Shlomit Barzilai ◽  
Antonella Colombini ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Genetic Variants ◽  
Working Group ◽  
Risk Allele ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Minor Allele ◽  
European Ancestry ◽  
Common Genetic Variants ◽  
Increased Risk

Abstract Background: Asparaginase-associated pancreatitis (AAP) is a well-known toxicity of childhood acute lymphoblastic leukemia (ALL) therapy. Recent multi-trial group phenotyping of 465AAP caseshas documented severe complications to AAP, including 8% risk of needing assisted mechanical ventilation, 26% risk of developing pancreatic pseudocysts and 9% risk of developing persisting diabetes (Wolthers et al. Lancet Oncology, 2017) . Investigation of host genome variation associated with AAP has been limited by varying phenotype definition, inclusion criteria and small study sizes. Objectives and Methods: To investigate genetic variants associated with risk of developing AAP, this genome-wide association study reports data on 1544 children (1.0−17.9 years) from 10 ALL trial groups treated with ALL from January 2000−January 2016. The Ponte di Legno toxicity working group consensus definition (Schmiegelow et al. Lancet Oncology, 2016) was used to diagnose AAP: At least two of i) amylase, pancreatic amylase, or pancreatic lipase >3x upper normal limit (UNL), ii) abdominal pain, iii) imaging compatible with AAP. Controls included children treated for ALL with verified completion of intended asparaginase therapy, 78% of whom (1024/1320) received at least 8 injections of PEG-asparaginase without developing AAP. Germline DNA obtained after clinical remission was genotyped on Illumina Infinium Omni2.5exome-8 BeadChip arrays. Association analyses were done in PLINK and annotation in Ensembl. Results: Of 1564 patients passing genotype quality control, 244 had AAP. 205 of 244 (84%) of cases and 1185/1320 (90%) of controls were of European ancestry. Median age was 8.1 years (IQR 4.3−13.1) and 5 (IQR: 3−9) for cases and controls, respectively. After filtering, 1401908 single nucleotide polymorphisms (SNPs) with a minor allele frequency above 1% were analyzed. In logistic regression analysis, adjusting for age and ancestry, the variant rs62228256 (reference allele=C, minor allele=T (C>T)) on 20q13.2 had the strongest association to AAP (OR=3.75; 95% CI 2.33−6.04; p=5.2∙10-8). rs62228256 is located in a non-coding region without known regulatory effects. rs13228878 (A>G; OR=0.61; 95% CI 0.5−0.76; p=7.1∙10-6) and rs10273639 (C>T; OR=0.62; 95% CI 0.5−0.77; p =1.1∙10-5) were among the top 30 SNPs most significantly associated to AAP. They are in high linkage disequilibrium (R2=0.94) and located in the PRSS1-PRSS2 locus on chromosome 7. The rs13228878 A risk allele was not associated with level of amylase (p=0.1) or lipase (p=0,68) at diagnosis of AAP, age at diagnosis of AAP (p=0.63), or risk of pseudocysts (p=0.78). Using identical diagnostic criteria for pancreatitis, the major C allele in rs10273639 has been associated with pancreatitis risk in adults (Whitcomb et al. Nature Genetics, 2012; Masson et al. Gut, 2017) with identical risk allele and similar odds ratios. PRSS1 and PRSS2 encode cationic and anionic trypsinogen, respectively. rs10273639 is an expressive quantitative locus for PRSS1 and the C risk-variant is associated with elevated expression of trypsinogen in pancreatic tissue. Gain of function mutations in PRSS1, known from hereditary pancreatitis, lead to increased autoactivation, increased intra-acinar trypsin levels, and increased risk of auto-digestion leading to pancreatitis. Further investigation of previously validated SNPs known to regulate trypsin activation gave the following results for associations with AAP; rs17107315 in pancreatic secretory trypsin inhibitor (SPINK1; OR=2.87; 95% CI 1.36−5.8; p=4∙10-3), rs10436957 in chymotrypsin C (CTRC ; OR=0.69; 95% CI 0.53−0.89; p=5∙10-3) and rs4409525 in Claudin-2 (CLDN2 ; OR=1.41; 95% CI 1.08−1.83; p=1∙10-2). In total, 207 out of 244 cases were homozygous for the risk allele in rs13228878 (n=104), rs17107315 (n=1), rs10436957 (n=165) and/or rs4409525 (n=16). However, no significant additive effect of having more than one risk allele was found. Conclusion: Children who develop AAP possess the same pancreatitis risk variants as adults with non-asparaginase associated pancreatitis. This shared genetic disposition may facilitate research into pathogenesis and identification of effective interventions towards AAP. Disclosures No relevant conflicts of interest to declare.

scholarly journals Variants in ARID5B Gene Are Associated with the Development of Acute Lymphoblastic Leukemia in Mexican Children

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1556-1556
Author(s):  
Adriana Reyes-León ◽  
Diana Fernández-García ◽  
Maribel Ramírez-Martínez ◽  
David Amaro-Muñoz ◽  
José Antonio Velázquez-Aragón ◽  
...  
Keyword(s):  
Native American ◽  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
European Ancestry ◽  
Taqman Assay ◽  
Childhood All ◽  
Risk Alleles ◽  
Mexican Children ◽  
Increased Risk

Abstract Introduction: Acute lymphoblastic leukemia (ALL) is the most common subtype of leukemia diagnosed in children under 18 years. According to the statistics of the Popular Medical Insurance Program in Mexico, the ALL incidence is 79.8 cases per million per year, and it is significantly increasing. Recently, several SNPs of ARID5B gene have been associated with ALL susceptibility and are more strongly related with ALL risk in Hispanics. However, these observations are not necessarily representative of the situation in Mexico, since the proportion of Mexican patients included in these studies is unknown. It is essential for us to know if the genetic variants of ARID5B confer susceptibility to the development of the disease in our population and if these variants contribute to the higher incidence of childhood ALL in Mexico. Aim: The purpose of this study was to determine the association between the SNPs rs10821936, rs10994982, rs7089424, rs2393732, rs2393782, rs2893881, and rs4948488 of ARID5B gene with the susceptibility to develop ALL in Mexican children. Methods: The study included 384 controls and 298 children with ALL recruited at Instituto Nacional de Pediatria in Mexico city and Hospital de Especialidades Pediatricas de Tuxtla Gutierrez, Chiapas, Mexico. This study was reviewed and approved by the Institutional Research and Ethics Committees from both participant Institutions in accordance to the ethical principles of the Declaration of Helsinki. Volunteers, parents, or legal tutors of patients were previously informed about the study, and before the biological samples were collected, they provided a signed, written informed consent letter to participate. Genomic DNA was extracted from peripheral blood and saliva samples. Genotyping analysis was performed by real-time polymerase chain reaction (RT-PCR) using a pre-designed TaqMan assay for 7 SNPs (rs10821936, rs10994982, rs7089424, rs2393732, rs2393782, rs2893881, and rs4948488) of ARID5B. Genotypic and allelic frequencies were calculated to compare the differences between controls and patients (Fisher's exact test). The odds ratio (OR) was calculated to determine the association between SNPs and ALL susceptibility. Ancestry analysis was conducted for controls and patients (STRUCTURE program), and Haplotype analysis (Haploview program). Results: The estimated proportion of Native American and European ancestry was not statistically different between controls and patients; all SNPs in ARID5B were in Hardy-Weinberg equilibrium. The frequency of the risk alleles was higher in patients than in controls, but only 3 SNPs showed statistically significant differences (p<0.05). The SNPs rs10821936, rs10994982, and rs7089424 were associated with ALL and pre-B ALL susceptibility, and rs2393732 was specifically associated with pre-B ALL. No association betwwen SNPs of ARID5B gene and T-ALL was found. The CAG haplotype (rs10821936, rs10994982, and rs7089424) was strongly associated with ALL risk in our population. The SNPs rs10821936, rs10994982, rs7089424, and rs2393732 were significantly associated with an increased risk for developing childhood ALL, specifically pre-B ALL. Conslusions: The frequency of the risk alleles was higher than in Hispanic children with ALL. Each SNP of ARID5B confers an individual effect on the risk for developing the disease, and the CAG haplotype was strongly associated with ALL susceptibility. The genetic background of our population could be positively influencing the susceptibility to ALL development, specifically pre-B ALL. The SNPs rs10821936, rs10994982, rs7089424 and rs2393732 of ARID5B gene are significantly associated with an increased risk to develop childhood ALL and this could also explain in part the high incidence of childhood ALL in Mexico. Acknowledgments: This work was supported by the grants from Fondos del Presupuesto Federal para la Investigación (project 085/2012), Consejo Nacional de Ciencia y Tecnologia (CONACyT) - Desarrollo Cientifico para Atender Problemas Nacionales (project 216163), and in part by the Intramural Program of the National Cancer Institute. Conflict-of-interest disclosure: The authors state that there are no conflicts of interest. Disclosures No relevant conflicts of interest to declare.

Itraconazol Inhibits the P-Glycoprotein Pump and Increases Vincristine Induced Toxicity in Patients with Acute Lymphoblastic Leukemia Carrying a Genetic Variant of the MDR1 Gene

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 231-231
Author(s):  
D. Maroeska W.M. te Loo ◽  
Melanie Hagleitner ◽  
Peter M. Hoogerbrugge ◽  
Rosalinde Masareeuw ◽  
Marieke Coenen
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Genetic Variant ◽  
Efflux Pump ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Mdr1 Gene ◽  
Peripheral Neurotoxicity ◽  
P Glycoprotein ◽  
Increased Risk

Abstract Abstract 231 One of the most well known drug interactions in pediatric oncology concerns the interaction of vincristine, one of the cornerstones in treatment of acute lymphoblastic leukemia( ALL), and the antifungal agent itraconazole. Several studies have shown that the co-administration of itraconazole with vincristine can induce increased neurotoxicity. It is believed that this increased neurotoxicity is mainly caused by the inhibitory effect of itraconazole on the CYP3A subfamily enzymes system (e.g. CYP3A4/5) and that, depending on the genetic variation, some patients are more prone to exhibit this neurotoxicity. However, itraconazole can also inhibit the efflux pump P-glycoprotein (Pg) but so far, data on the role of the Pg pump on vincristine toxicity are lacking. We therefore performed a pharmacogenetic analysis in 103 Caucasian pediatric patients with ALL analyzing both the MDR1 gene and the CYP3A5 gene in the germ-line. CYP3A5 was not associated with vincristine-related toxicity in our cohort. However, one SNP in MDR1 (3435C>T) was significantly associated with developing peripheral neuropathy (Odds Ratio [OR] = 3.8, 95% confidence interval [CI] 1.2 – 11.9, p=0.026). It is known that this genetic variant of the MDR gene (3435T/2677T), leads to a reduced expression of the Pg-pump. Peripheral neurotoxicity in patients carrying this SNP was present even without the co-administration of itraconazole. A subgroup of these patients did receive itraconazole, and the patients with the genetic variant 3435T/2677T of MDR1 showed not only increased peripheral neurotoxicity, but also developed central nervous toxicity (OR=6.4, 95% CI 1.1 – 37.4 p=0.038) upon combined VCR-itraconazole therapy. To gain more insight in the mechanisms of increased vincristine induced toxicity during azole treatment, in vitro experiments using the LLC-PK1-MDR cell line that over-expresses the MDR1 gene and has no expression of the CYP3A4, were performed. The LLC-PK1-MDR cells were resistant to vincristine exposure in vitro, but became sensitive for VCR after inhibition of the Pg-pump bij PSC833. In contrast, LLC-PK1-MDR1 cells exposed to vincristine in the presence of itraconazole (0.5 and 5 microgram/ml) showed significantly decreased survival in a dose dependent way (LD50 at a dose of 10 −4M and 10−7 M vincristine at dose respectively of 0.5 and 5.0 microgram/ml itraconazole), in contrast to a cell survival of 100% with the same dose of vincristine itraconazole (p< 0.001). These results indicate that itraconazol indeed inhibits the efflux Pg-pump which may explain the CNS toxicity that occurred in our patient group during the period in which itraconazole was co-administerd during vincristine treatment. Based on these data, we conclude that the Pg- pump plays a dominant role in increased vincristine toxicity during azole treatment. Furthermore, those patients carrying the genetic variant 3435T/2677T of the MDR gene are at increased risk for this toxicity due to reduced expression of the efflux pump Pg. Disclosures: No relevant conflicts of interest to declare.

Genetic Variants of Ataxia Telangiectasia Mutated (ATM) and Susceptibility for Childhood T-Lineage Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1892-1892
Author(s):  
Marrit Meier ◽  
Monique L. Den Boer ◽  
Andrew G. Hall ◽  
Julie Irving ◽  
Monique Passier ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Clinical Outcome ◽  
Genetic Variants ◽  
Ataxia Telangiectasia ◽  
Lymphoblastic Leukemia ◽  
Young Age ◽  
Cellular Resistance ◽  
Lymphoid Malignancies ◽  
Increased Risk ◽  
Atm Gene

Abstract ATM was identified as the gene mutated in Ataxia Telangiectasia (AT), a degenerative neurological disorder that is characterized by, amongst others, an increased risk to develop a hematomalignancy at young age. Striking is the high incidence of T cell derived lymphoid malignancies amongst AT patients. As sporadic T-lineage Acute Lymphoblastic Leukemia (T-ALL) is particularly found in childhood, we have investigated the occurrence and frequency of mutations in 62 coding exons of the ATM gene in 41 children with T-ALL at initial diagnosis and their relation to susceptibility for T-ALL. Moreover, as ATM is implicated in cellular signaling events in response to DNA damaging agents, we have also investigated whether genetic variants of ATM are possibly related to cellular resistance to drugs and clinical outcome in childhood T-ALL. We have identified 18 different ATM alterations, of which 9 were not previously reported, in 68% of T-ALL patients. None of the alterations co-segregated with loss of heterozygosity of the ATM gene. The simultaneous presence of more than one genetic variant was observed in 32% of T-ALL patients compared to only 12% of healthy controls (P = 0.006). An increased frequency of ATM alterations was of no influence on the level of ATM mRNA and did not associate with cellular resistance to daunorubicin, prednisolone, vincristine and L-asparaginase nor with age at diagnosis, white blood cell count or long-term clinical outcome. However, the presence of specific genetic variants, i.e. S707P, F858L, T896A, P1054R and L1472W was related to an age younger than 10 years (P = 0.034) and an increased relapse-risk (P = 0.025). In addition, an increased frequency of carriers of these genetic variants was observed amongst T-ALL children (29%) compared to controls (11%) (P = 0.028). We conclude that ATM gene alterations might pre-dispose carriers to develop T-ALL in childhood, in particular involving specific genetic variants of ATM as their occurrence is significantly associated with a young age.

scholarly journals The Association Between L-Asparaginase Hypersensitivity and Genetic Variants in Japanese Childhood ALL Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5141-5141 ◽  
Author(s):  
Yoichi Tanaka ◽  
Kevin Y Urayama ◽  
Takahisa Kawaguchi ◽  
Makiko Mori ◽  
Daisuke Hasegawa ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Multiple Testing ◽  
Genome Wide Association Study ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
European Ancestry ◽  
Study Patient ◽  
Illumina Platform ◽  
Childhood All ◽  
Genome Wide

Abstract Background L-asparaginase is important in successfully treating childhood acute lymphoblastic leukemia (ALL). However, some patients experience hypersensitivity, mechanisms for which have not been fully elucidated. Previous studies, predominately based on populations of European ancestry, have described L-asparaginase hypersensitivity associations with genetic variant tagging the NFATC2, GRIA1, ASNS, and HLA-DRB1genes. The aim of this study was to evaluate the association between L-asparaginase hypersensitivity and genetic variants in Japanese childhood ALL patients. Methods This study included 472 Japanese children with ALL who received E. coli derived L-asparaginase comprising 6000 U/m2 intravenously or 10000 U/m2 subcutaneously according to the Tokyo Children's Cancer Study Group (TCCSG) L84-11, L89-12, L92-13, L95-14, L99-15, L04-16, and more recent protocols. L-asparaginase hypersensitivity was defined as experience of fever, rash, and other allergic reaction after L-asparaginase infusion. Through an ongoing genome-wide association study, patient DNA from saliva were genotyped using the Illumina platform and genome-wide single nucleotide polymorphism (SNP) imputation was performed using the 1000 Genomes Project Phase I Version 3 as the reference population. Tests of association between childhood ALL and SNP genotypes across the candidate loci, NFATC2, GRIA1, and ASNS, were performed using logistic regression and assuming a log-additive model of inheritance. Results We observed 47 (10%) hypersensitivity patients, of which 32 patients could not be infused again. These L-asparaginase hypersensitivities were not associated with patients' gender and age in this population. SNPs previously reported in NFATC2 rs6021191, GRIA1 rs4958351, and ANSN rs3832526 were not significantly associated with L-asparaginase hypersensitivity (P = 0.76, 0.99, and 0.53, respectively). For confirmation, the NFATC2 rs6021191 SNP was directly genotyped in a large subset of the ALL patients, but no association was observed (P = 0.44; 377 patients). Evaluation of other variants within those genes and flanking regions showed evidence of association with rs11482430 (NFATC2, P = 0.01), rs558550699 (GRIA1, P = 0.02), and rs7803055 (ANSN, P= 0.04), although not significant after correction for multiple testing. Conclusion This lack of association with variants reported in populations of European ancestry may be influenced by ethnic specific differences in genetic structure surrounding these variants as exemplified by differences in observed minor allele frequency of the reported NFATC2 rs6021191 and GRIA1 rs4958351 SNPs in Japanese (0.11 and 0.01) and Europeans (< 0.01 and 0.36). Moreover, the type of L-asparaginase, and/or differences in therapeutic protocol may also contribute to inconsistencies with the previous reports. There is indication of an involvement of genetic variation of NFATC2 in L-asparaginase hypersensitivity, but whether the signal is representing the same regions as the previous reports needs to be further examined. Disclosures No relevant conflicts of interest to declare.

scholarly journals Increased Levels of Adipocyte and Epidermal Fatty Acid-Binding Proteins in Acute Lymphoblastic Leukemia Survivors

2021 ◽  
Vol 10 (8) ◽  
pp. 1567
Author(s):  
Katarzyna Konończuk ◽  
Eryk Latoch ◽  
Beata Żelazowska-Rutkowska ◽  
Maryna Krawczuk-Rybak ◽  
Katarzyna Muszyńska-Rosłan
Keyword(s):  
Metabolic Syndrome ◽  
Fatty Acid ◽  
Acute Lymphoblastic Leukemia ◽  
Binding Proteins ◽  
Lymphoblastic Leukemia ◽  
Fatty Acid Binding Proteins ◽  
Fatty Acid Binding ◽  
The Metabolic Syndrome ◽  
Increased Risk ◽  
Significant Difference

Childhood cancer survivors are highly exposed to the development of side effects after many years of cessation of anticancer treatment, including altered lipid metabolism that may result in an increased risk of overweight and metabolic syndrome. Adipocyte (A-FABP) and epidermal (E-FABP) fatty acid-binding proteins are expressed in adipocytes and are assumed to play an important role in the development of lipid disturbances leading to the onset of metabolic syndrome. The aim of this study was to investigate the association between serum A-FABP and E-FABP levels, overweight, and components of the metabolic syndrome in acute lymphoblastic leukemia survivors. Sixty-two acute lymphoblastic leukemia (ALL) survivors (34 females) were included in the study. The mean age at the time of the study was 12.41 ± 4.98 years (range 4.71–23.43). Serum levels of A-FABP and E-FABP were analyzed using a commercially available ELISA kit. The ALL survivors presented statistically higher A-FABP levels in comparison with the healthy controls (25.57 ± 14.46 vs. 15.13 ± 7.61 ng/mL, p < 0.001). The subjects with body mass index (BMI) above the normal range (18 overweight, 10 obese) had a greater level of A-FABP compared to the ALL group with normal BMI (32.02 ± 17.10 vs. 20.33 ± 9.24 ng/mL, p = 0.006). Of all participants, 53.23% had at least one risk factor of metabolic syndrome; in this group, only the A-FABP level showed a statistically significant difference compared to the healthy control group (30.63 ± 15.91 vs. 15.13 ± 7.61 ng/mL, p < 0.001). The subjects with two or more metabolic risk factors (16.13%) presented higher levels of both A-FABP (33.62 ± 17.16 vs. 15.13 ± 7.61 ng/mL, p = 0.001) and E-FABP (13.37 ± 3.62 vs. 10.12 ± 3.21 ng/mL, p = 0.021) compared to the controls. Univariable regression models showed significant associations between BMI and systolic blood pressure with the A-FABP level (coeff. 1.02 and 13.74, respectively; p < 0.05). In contrast, the E-FABP level was only affected by BMI (coeff. 0.48; p < 0.01). The findings reported herein suggest that the increased levels of A-FABP and E-FABP may be involved in the pathogenesis of overweight and the onset of metabolic syndrome in acute lymphoblastic leukemia. However, further longitudinal, prospective studies of fatty acid-binding proteins and their potential role in the pathogenesis of obesity and metabolic syndrome in ALL survivors remain to be performed.

ALL-414: Obesity is Not Associated with an Increased Risk of Venous Thromboembolism in AYA Patients with Acute Lymphoblastic Leukemia

2021 ◽  
Vol 21 ◽  
pp. S276
Author(s):  
Sandra Renee Jones ◽  
Roshni Bharati Patel ◽  
Mahvish Qureshi Rahim ◽  
Sandra K. Althouse ◽  
Sandeep Batra
Keyword(s):  
Venous Thromboembolism ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Increased Risk

Abstract 2924: Association of NOS1AP Genetic Variants with QT Interval Duration in Families from the Diabetes Heart Study

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Allison B Lehtinen ◽  
Christopher Newton-Cheh ◽  
Julie T Ziegler ◽  
Carl D Langefeld ◽  
Barry I Freedman ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Qt Interval ◽  
Genetic Model ◽  
Additive Model ◽  
Adaptor Protein ◽  
European Ancestry ◽  
Nucleotide Polymorphisms ◽  
Interval Duration ◽  
Common Genetic Variants ◽  
Qt Interval Duration

Background: Prolongation of the electrocardiographic QT interval is a risk factor for sudden cardiac death (SCD) in unselected samples as well as in post-myocardial infarction patients or those with diabetes. Common genetic variants in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene have been reported to be associated with QT interval duration in individuals of European ancestry. We sought to replicate the association of NOS1AP variants with QT interval duration in pedigrees enriched for type 2 diabetes mellitus (T2DM). Methods and Results: Two single nucleotide polymorphisms (SNPs) in the NOS1AP gene, rs10494366 and rs10918594, were genotyped in a collection of 937 European Americans (EAs) and 177 African Americans (AAs) in 450 pedigrees containing at least two siblings with T2DM. An additive genetic model was tested for each SNP in ancestry-specific analyses using SOLAR in the total sample and in the diabetic subset (EA n=778, AA n=159), with and without exclusion of QT-altering medications. In the EA individuals, rs10494366 minor allele homozygotes had an 8.9 msec longer mean QT interval compared to major homozygotes (additive model p=4.4x10 -3 ); rs10918594 minor homozygotes had a 12.9 msec longer mean QT interval compared to major homozygotes (p=9.9x10 -5 ). Excluding users of QT-altering medications in the diabetic-only EA sample (n=514) strengthened the association despite the reduction in sample size (20.6 msec difference, p=2.0x10 -5 ; 23.4 msec difference, p=8.9x10 -7 , respectively). No association between the NOS1AP SNPs and QT interval duration was observed in the limited number of AA individuals examined. Conclusions: Two NOS1AP SNPs are strongly associated with QT interval duration in a predominately diabetic EA sample. Stronger effects of NOS1AP variants in diabetic individuals compared to previously reported unselected samples suggest that this patient subset may be particularly susceptible to genetic variants that influence myocardial depolarization and repolarization as manifest in the QT interval.

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