L. Philip Schumm

A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.

The inflammatory bowel diseases Crohns disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohns disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohns disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohns disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.

Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease

Several risk factors for Crohns disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohns disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.

Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis

We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations (combined P < 10−10) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.

Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study

Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 × 10−13, combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 × 10−12, combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 × 10−16, combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 × 10−8, combined OR = 0.56; rs10889677, combined P = 1.3 × 10−8, combined OR = 1.29).

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

Summary Background Crohns disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohns disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohns disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohns disease, ileal Crohns disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. Findings After quality control, the primary analysis included 29 838 patients (16 902 with Crohns disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10−78), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10−18). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohns disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10−4). Interpretation Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohns disease, colonic Crohns disease, and ulcerative colitis) than by Crohns disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patients disease, in part genetically determined, and the major driver to changes in disease behaviour over time. Funding International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).

Sexuality: Measures of Partnerships, Practices, Attitudes, and Problems in the National Social Life, Health, and Aging Study

OBJECTIVES The National Social Life, Health, and Aging Project (NSHAP) was designed to examine the relationship between sexual behavior, sexual problems, and health among older women and men. We describe measures of sexual partnerships, sexual practices, sexual problems, attitudes toward sex, and nonsexual intimacy in the first wave of NSHAP. METHODS We compare measures of sexuality for those 57-85 years old, by age, separately for men and women. We construct scales of sexual mores, sexual interest, and relationship satisfaction and discuss properties of each scale. RESULTS Sexuality among older adults tends to vary with age and gender. At all ages in this study, men are more likely than women to have a partner, more likely to be sexually active with that partner, and tend to have more positive and permissive attitudes toward sex. The proportions in a sexual partnership, behavior, problems, and attitudes all differ substantially by age. And these age patterns often differ for men and women. DISCUSSION Data obtained in the NSHAP can be used to construct key measures of sexuality among older adults; to examine sexuality itself; and to explore the link between sexuality, health, well-being, and other dimensions of the lives of older adults.

Changes in Prescription and Over-the-Counter Medication and Dietary Supplement Use Among Older Adults in the United States, 2005 vs 2011

IMPORTANCE Prescription and over-the-counter medicines and dietary supplements are commonly used, alone and together, among older adults. However, the effect of recent regulatory and market forces on these patterns is not known. OBJECTIVES To characterize changes in the prevalence of medication use, including concurrent use of prescription and over-the-counter medications and dietary supplements, and to quantify the frequency and types of potential major drug-drug interactions. DESIGN, SETTING, AND PARTICIPANTS Descriptive analyses of a longitudinal, nationally representative sample of community-dwelling older adults 62 to 85 years old. In-home interviews with direct medication inspection were conducted in 2005-2006 and again in 2010-2011. The dates of the analysis were March to November 2015. We defined medication use as the use of at least 1 prescription or over-the-counter medication or dietary supplement at least daily or weekly and defined concurrent use as the regular use of at least 2 medications. We used Micromedex to identify potential major drug-drug interactions. MAIN OUTCOMES AND MEASURES Population estimates of the prevalence of medication use (in aggregate and by therapeutic class), concurrent use, and major drug-drug interactions. RESULTS The study cohort comprised 2351 participants in 2005-2006 and 2206 in 2010-2011. Their mean age was 70.9 years in 2005-2006 and 71.4 years in 2010-2011. Fifty-three percent of participants were female in 2005-2006, and 51.6% were female in 2010-2011. The use of at least 1 prescription medication slightly increased from 84.1% in 2005-2006 to 87.7% in 2010-2011 (P = .003). Concurrent use of at least 5 prescription medications increased from 30.6% to 35.8% (P = .02). While the use of over-the-counter medications declined from 44.4% to 37.9%, the use of dietary supplements increased from 51.8% to 63.7% (P < .001 for both). There were clinically significant increases in the use of statins (33.8% to 46.2%), antiplatelets (32.8% to 43.0%), and omega-3 fish oils (4.7% to 18.6%) (P < .05 for all). In 2010-2011, approximately 15.1% of older adults were at risk for a potential major drug-drug interaction compared with an estimated 8.4% in 2005-2006 (P < .001). Most of these interacting regimens involved medications and dietary supplements increasingly used in 2010-2011. CONCLUSIONS AND RELEVANCE In this study, the use of prescription medications and dietary supplements, and concurrent use of interacting medications, has increased since 2005, with 15% of older adults potentially at risk for a major drug-drug interaction. Improving safety with the use of multiple medications has the potential to reduce preventable adverse drug events associated with medications commonly used among older adults.

High density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis

Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohns disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohns disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

Refined genomic localization and ethnic differences observed for the IBD5 association with Crohn's disease.

Although the general association of the inflammatory bowel disease (IBD) 5 region on chromosome 5q31 to Crohns disease (CD) has been replicated repeatedly, the identity of the precise causal variant within the region remains unknown. A recent report proposed polymorphisms in solute carrier family 22, member 4 (SLC22A4) organic cation transporter 1(OCTN1) and solute carrier family 22, member 5 (SLC22A5) (OCTN2) as responsible for the IBD5 association, but definitive, large-sample comparison of those polymorphisms with others known to be in strong linkage disequilibrium was not performed. We evaluated 1879 affected offspring and parents ascertained by a North American IBD Genetics Consortium for six IBD5 tag single nucleotide polymorphisms (SNPs) to evaluate association localization and ethnic and subphenotypic specificity. We confirm association to the IBD5 region (best SNP IGR2096a_1/rs12521868, P<0.0005) and show this association to be exclusive to the non-Jewish (NJ) population (P=0.00005) (risk allele undertransmitted in Ashkenazi Jews). Using Phase II HapMap data, we demonstrate that there are a set of polymorphisms, spanning genes from prolyl 4-hydroxylase (P4HA2) through interferon regulatory factor 1 (IRF1) with equivalent statistical evidence of association to the reported SLC22A4 variant and that each, by itself, could entirely explain the IBD5 association to CD. Additionally, the previously reported SLC22A5 SNP is rejected as the potential causal variant. No specificity of association was seen with respect to disease type and location, and a modest association to ulcerative colitis is also observed. We confirm the importance of IBD5 to CD susceptibility, demonstrate that the locus may play a role in NJ individuals only, and establish that IRF1, PDLIM, and P4HA2 may be equally as likely to contain the IBD5 causal variant as the OCTN genes.

Olfactory Dysfunction Predicts 5-Year Mortality in Older Adults

Prediction of mortality has focused on disease and frailty, although antecedent biomarkers may herald broad physiological decline. Olfaction, an ancestral chemical system, is a strong candidate biomarker because it is linked to diverse physiological processes. We sought to determine if olfactory dysfunction is a harbinger of 5-year mortality in the National Social Life, Health and Aging Project [NSHAP], a nationally representative sample of older U.S. adults. 3,005 community-dwelling adults aged 57–85 were studied in 2005–6 (Wave 1) and their mortality determined in 2010–11 (Wave 2). Olfactory dysfunction, determined objectively at Wave 1, was used to estimate the odds of 5-year, all cause mortality via logistic regression, controlling for demographics and health factors. Mortality for anosmic older adults was four times that of normosmic individuals while hyposmic individuals had intermediate mortality (p<0.001), a “dose-dependent” effect present across the age range. In a comprehensive model that included potential confounding factors, anosmic older adults had over three times the odds of death compared to normosmic individuals (OR, 3.37 [95%CI 2.04, 5.57]), higher than and independent of known leading causes of death, and did not result from the following mechanisms: nutrition, cognitive function, mental health, smoking and alcohol abuse or frailty. Olfactory function is thus one of the strongest predictors of 5-year mortality and may serve as a bellwether for slowed cellular regeneration or as a marker of cumulative toxic environmental exposures. This finding provides clues for pinpointing an underlying mechanism related to a fundamental component of the aging process.