Browsing by Author "LaRusch, Jessica"

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    Constant-Severe Pain in Chronic Pancreatitis is Associated with Genetic Loci for Major Depression in the NAPS2 Cohort
    (Springer, 2020) Dunbar, Ellyn; Greer, Phil J.; Melhem, Nadine; Alkaade, Samer; Amann, Stephen T.; Brand, Randall; Coté, Gregory A.; Forsmark, Christopher E.; Gardner, Timothy B.; Gelrud, Andres; Guda, Nalini M.; LaRusch, Jessica; Lewis, Michele D.; Machicado, Jorge D.; Muniraj, Thiruvengadam; Papachristou, Georgios I.; Romagnuolo, Joseph; Sandhu, Bimaljit S.; Sherman, Stuart; Wilcox, Charles M.; Singh, Vikesh K.; Yadav, Dhiraj; Whitcomb, David C.; NAPS2 study group; Medicine, School of Medicine
    Background: Pain is the most debilitating symptom of recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) and often requires chronic opioids or total pancreatectomy with islet autotransplantation to manage. Pain is a complex experience that can be exacerbated by depression and vice versa. Our aim was to test the hypothesis that depression-associated genes are associated with a constant-severe pain experience in RAP/CP patients. Study: A retrospective study was done using North American Pancreatitis Study II (NAPS2) genotyped RAP and CP patients with completed case report forms (n = 1,357). Subjects were divided based on pattern of pain and pain severity as constant-severe pain (n = 787) versus not constant-severe pain (n = 570) to conduct a nested genome-wide association study. The association between reported antidepressant medication use and depression gene loci was tested. Results: Constant-severe pain was reported in 58% (n = 787) of pancreatitis patients. No differences in sex or alcohol consumption were found based on pain severity. Antidepressant use was reported in 28% (n = 223), and they had lower SF-12 mental quality of life (MCS, p < 2.2 × 10- 16). Fifteen loci associated with constant-severe pain (p < 0.00001) were found to be in or near depression-associated genes including ROBO2, CTNND2, SGCZ, CNTN5 and BAIAP2. Three of these genes respond to antidepressant use (SGCZ, ROBO2, and CTNND2). Conclusion: Depression is a major co-factor in the pain experience. This genetic predisposition to depression may have utility in counseling patients and in instituting early antidepressant therapy for pain management of pancreatitis patients. Prospective randomized trials are warranted.
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    Differences in Age at Onset of Symptoms, and Effects of Genetic Variants, in Patients With Early- vs Late-Onset Idiopathic Chronic Pancreatitis in a North American Cohort
    (Elsevier, 2020) Lewis, Michele D.; Talluri, Jyothsna; Wilcox, C. Mel; Abberbock, Judah N.; Tang, Gong; Conwell, Darwin L.; Banks, Peter A.; Cote, Gregory A.; Sherman, Stuart; Alkaade, Samer; Gardner, Timothy B.; Anderson, Michelle A.; Sandhu, Bimaljit S.; Muniraj, Thiruvengadam; Forsmark, Chris E.; Guda, Nalini; Gelrud, Andres; Romagnuolo, Joseph; Brand, Randall; LaRusch, Jessica; Amann, Stephen T.; Slivka, Adam; Whitcomb, David C.; Yadav, Dhiraj; Medicine, School of Medicine
    Background & Aims Idiopathic chronic pancreatitis (ICP) is the second most common subtype of CP. In 1994, researchers reported the bimodal age at onset of ICP symptoms: early-onset ICP (EO-ICP; median age, 19.2 years) and late-onset ICP (LO-ICP; median age, 56.2 years). Ages of onset and clinical features of ICP differed from those of alcohol-related CP (ACP). However, variants in PRSS1 had not yet been associated with ICP. We reexamined ages of onset of ICP in a large, North American cohort of patients, and investigated the effects of genetic factors and alcohol use in patients with EO-ICP, LO-ICP, or ACP. Methods We performed a cross-sectional analysis of patients with CP of European ancestry enrolled in the North American Pancreatitis Study 2 studies, a prospective study of 1195 patients with CP from 26 centers in the United States from August 2000 through December 2014. We compared age at onset of symptoms for 130 patients with CP who were lifetime abstainers from alcohol (61 patients with early onset and 69 patients with late onset), 308 light to moderate alcohol drinkers with CP, and 225 patients with ACP and heavy to very heavy alcohol use. DNA from available patients was analyzed for variants associated with CP in SPINK1, CFTR, and CTRC. The Kruskal-Wallis test was used to compare continuous variables across groups and based on genetic variants. Results Median ages at onset of symptoms were 20 years for patients with EO-ICP and no alcohol use, 58 years for patients with LO-ICP and no alcohol use, 47 years for light to moderate alcohol drinkers with CP, and 44 years for patients with ACP. A higher proportion of patients with EO-ICP had constant pain (65%) than patients with LO-ICP (31%) (P=.04). A higher proportion of patients with ACP had pseudocysts (43%) than patients with EO-ICP (11%) (P=.001). A higher proportion of patients with EO-ICP had pathogenic variants in SPINK1, CFTR, or CTRC (49%) than patients with LO-ICP (23%), light to moderate alcohol drinking with CP (26%), or ACP (23%) (P=.001). Among patients with variants in SPINK1, those with EO-ICP had onset of symptoms at a median age of 12 years, and light to moderate alcohol drinkers with CP had an age at onset of 24 years. Among patients with variants in CFTR, light to moderate alcohol drinkers had an age at onset of symptoms of 41 years, but this variant did not affect age at onset of EO-ICP or ACP. Conclusions We confirmed previously reported ages at onset of symptoms for EO-ICP and LO-ICP in a North American cohort. We found differences in clinical features among patients with EO-ICP, LO-ICP, and ACP. Almost half of patients with EO-ICP have genetic variants associated with CP, compared to about one-quarter of patients with LO-CP or ACP. Genetic variants affect ages at onset of symptoms in some groups.