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Sehgal R.,Penn State Milton rshey Medical Center | Sehgal R.,Penn State College of Medicine | Berg A.,Penn State Milton rshey Medical Center | Berg A.,Center for Statistical Genetics | And 8 more authors.
Diseases of the Colon and Rectum | Year: 2012

BACKGROUND: Severe pouchitis and Crohn's disease-like complications are 2 adverse postoperative complications that confound the success of the IPAA in patients with ulcerative colitis. To date, approximately 83 single nucleotide polymorphisms within 55 genes have been associated with IBD. OBJECTIVE: The aim of this study was to identify singlenucleotide polymorphisms that correlate with complications after IPAA that could be utilized in a gene signature fashion to predict postoperative complications and aid in preoperative surgical decision making. DESIGN: One hundred forty-two IPAA patients were retrospectively classified as "asymptomatic" (n = 104, defined as no Crohn's disease-like complications or severe pouchitis for at least 2 years after IPAA) and compared with a "severe pouchitis" group (n = 12, ≤4 episodes pouchitis per year for 2 years including the need for long-term therapy to maintain remission) and a "Crohn's disease-like" group (n = 26, presence of fistulae, pouch inlet stricture, proximal small-bowel disease, or pouch granulomata, occurring at least 6 months after surgery). Genotyping for 83 singlenucleotide polymorphisms previously associated with Crohn's disease and/or ulcerative colitis was performed on a customized Illumina genotyping platform. The top 2 single-nucleotide polymorphisms statistically identified as being independently associated with each of Crohn's disease-like and severe pouchitis were used in a multivariate logistic regression model. These singlenucleotide polymorphisms were then used to create probability equations to predict overall chance of a positive or negative outcome for that complication. RESULTS: The top 2 single-nucleotide polymorphisms for Crohn's disease-like complications were in the 10q21 locus and the gene for PTGER4 (p = 0.006 and 0.007), whereas for severe pouchitis it was NOD2 and TNFSF15 (p = 0.003 and 0.011). Probability equations suggested that the risk of these 2 complications greatly increased with increasing number of risk alleles, going as high as 92% for severe pouchitis and 65% for Crohn's diseaselike complications. CONCLUSION: In this IPAA patient cohort, mutations in the 10q21 locus and the PTGER4 gene were associated with Crohn's disease-like complications, whereas mutations in NOD2 and TNFSF15 correlated with severe pouchitis. Preoperative genetic analysis and use of such gene signatures hold promise for improved preoperative surgical patient selection to minimize these IPAA complications. © The ASCRS 2012. Source

Sehgal R.,Penn State College of Medicine | Berg A.,Penn State College of Medicine | Berg A.,Center for Statistical Genetics | Polinski J.I.,Penn State College of Medicine | And 7 more authors.
Diseases of the Colon and Rectum | Year: 2012

BACKGROUND: There are no clear criteria for judging the severity of disease in patients with Crohn's disease. Yet classification of patients into low- and high-risk severity groups would benefit both medical and surgical management. At the time of this study, approximately 80 single-nucleotide polymorphisms within 55 genes had been associated with IBD. OBJECTIVE: The aim of this study was to identify genetic determinants (single-nucleotide polymorphisms) that could be markers of Crohn's disease severity by the use of frequency of ileocolic surgery as a surrogate for disease severity. DESIGN: Sixty-six patients (30 male) with ileocolonic Crohn's disease who previously underwent ileocolectomy were retrospectively studied. The severity of Crohn's disease was quantified by dividing the total number of ileocolectomy procedures by the time between IBD diagnosis and the patient's last clinic visit, the rationale being that more severe disease would be associated with a more frequent need for surgery. Genotyping for the 83 single-nucleotide polymorphisms associated with IBD was done on a customized Illumina Veracode genotyping platform. Three genetic models (general, additive, and dominant) were used to statistically quantify the genetic association of the studied single-nucleotide polymorphisms to the frequency of surgery after adjusting for covariates (age, smoking, family history, disease location, and disease behavior). RESULTS: For the entire group the average number of ileocolectomies per patient was 1.7 (range, 1-5) with an average duration of disease of 14.7 years. Single-nucleotide polymorphism rs4958847 in the IRGM gene (immunityrelated GTPase family, M) was the most significant singlenucleotide polymorphism in all 3 models tested (p±0.007) as being associated with ileocolectomy, and it remained significant even after a Benjamini-Hochberg false-discovery correction for multiple observations. Patients carrying the "at-risk" allele for this single-nucleotide polymorphism (n±20) had an average of 1 surgery every 6.87±1.33 years in comparison with patients carrying the wild-type genotype (n±46) who averaged 1 surgery in 11.43±1.21 years (p± 0.007, Mann-Whitney U test). CONCLUSIONS: Single-nucleotide polymorphism rs4958847 in the IRGM gene correlated very significantly with frequency of surgery in patients with ileocolonic Crohn's disease. IRGM is a mediator of innate immune responses and is involved in autophagy. The presence of this IRGM SNP may be a marker for disease severity and/ or early recurrence after ileocolectomy and may assist in surgical and medical decision making. © ASCRS 2012. Source

Schick U.M.,Fred Hutchinson Cancer Research Center | Auer P.L.,Fred Hutchinson Cancer Research Center | Auer P.L.,University of Wisconsin - Milwaukee | Bis J.C.,University of Washington | And 47 more authors.
Human Molecular Genetics | Year: 2015

C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that isassociated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ~25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency 5 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10-6). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10-15). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-∈2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10-8), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In genebased tests, a burden of rare/lower frequency variation inCRPin EAs (P ≤ 6.8 × 10-4) and in retinoic acid receptor-related orphan receptor a (RORA) in AAs (P = 1.7 × 10-3) were associated with CRP levels at the candidate gene level (P < 2.0 × 10-3). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels. © The Author 2014. Source

Santos-Cortez R.L.P.,Center for Statistical Genetics | Lee K.,Center for Statistical Genetics | Giese A.P.,University of Cincinnati | Ansar M.,Center for Statistical Genetics | And 15 more authors.
Human Molecular Genetics | Year: 2014

CyclicAMP(cAMP) production, whichis important for mechanotransduction within the inner ear, is catalyzed by adenylate cyclases (AC). However, knowledge of the role of ACs in hearing is limited. Previously, a novel autosomal recessive non-syndromic hearing impairment locus DFNB44 wasmapped to chromosome 7p14.1-q11.22 in a consanguineous family from Pakistan. Through whole-exome sequencing of DNA samples from hearingimpaired family members, a nonsense mutation c.3112C >T (p.Arg1038*) within adenylate cyclase 1 (ADCY1) was identified. This stop-gained mutation segregated with hearing impairment within the family and was not identified in ethnically matched controls or within variant databases. This mutation is predicted to cause the loss of 82 amino acids from the carboxyl tail, including highly conserved residues within the catalytic domain, plus a calmodulin-stimulation defect, both of which are expected to decrease enzymatic efficiency. Individualswhoare homozygous for this mutation had symmetric, mild-to-moderate mixed hearing impairment. Zebrafishadcy1bmorphantshadnoFM1-43dyeuptakeandlacked startle response, indicating hair cell dysfunction and gross hearing impairment. In the mouse, Adcy1 expression was observed throughout inner ear development and maturation. ADCY1 was localized to the cytoplasm of supporting cells and hair cells of the cochlea and vestibule and also to cochlear hair cell nuclei and stereocilia. Ex vivo studies in COS-7 cells suggest that the carboxyl tail of ADCY1 is essential for localization to actin-based microvilli. These results demonstrate that ADCY1has an evolutionarily conserved role in hearing and thatcAMP signaling is important to hair cell function within the inner ear © The Author 2014.Published by Oxford University Press. All rights reserved. Source

Udler M.S.,Massachusetts General Hospital | Nadkarni G.N.,Massachusetts General Hospital | Wyatt C.,Massachusetts General Hospital | Bottinger E.P.,Massachusetts General Hospital | And 3 more authors.
Journal of the American Society of Nephrology | Year: 2015

Self-reported ancestry, genetically determined ancestry, and APOL1 polymorphisms are associated with variation in kidney function and related disease risk, but the relative importance of these factors remains unclear. We estimated the global proportion of African ancestry for 9048 individuals at Mount Sinai Medical Center in Manhattan (3189 African Americans, 1721 European Americans, and 4138 Hispanic/Latino Americans by self-report) using genome-wide genotype data. CKD-EPI eGFR and genotypes of three APOL1 coding variants were available. In admixed African Americans and Hispanic/Latino Americans, serum creatinine values increased as African ancestry increased (per 10% increase in African ancestry, creatinine values increased 1% in African Americans and 0.9% in Hispanic/Latino Americans; P 1x1027). eGFR was likewise significantly associated with African genetic ancestry in both populations. In contrast, APOL1 risk haplotypes were significantly associated with CKD, eGFR,45 ml/min per 1.73 m2, and ESRD, with effects increasing with worsening disease states and the contribution of genetic African ancestry decreasing in parallel. Using genetic ancestry in the eGFR equation to reclassify patients as black on the basis of 50%African ancestry resulted in higher eGFR for 14.7% of Hispanic/Latino Americans and lower eGFR for 4.1% of African Americans, affecting CKD staging in 4.3% and 1% of participants, respectively. Reclassified individuals had electrolyte values consistentwith their newly assignedCKDstage. In summary, proportion of African ancestry was significantly associated with normal-range creatinine and eGFR, whereas APOL1 risk haplotypes drove the associations with CKD. Recalculation of eGFR on the basis of genetic ancestry affected CKD staging and warrants additional investigation. Copyright © 2015 by the American Society of Nephrology. Source

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