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Genetic variants of GCH1 associate with chronic and acute crisis pain in African Americans with sickle cell disease.

ABSTRACT: The multidimensional nature of pain in sickle cell disease (SCD) has rendered its therapeutic management extremely challenging. In this study, we explored the role of five single nucleotide polymorphisms (SNPs) of candidate gene GCH1 in SCD pain. Composite pain index (CPI) scores and acute care utilization rates were used as phenotype markers. Rs8007267 was associated with chronic pain (additive model: B?=?-3.76, p?=?0.037; dominant model: B?=?-5.61, p?=?0.021) and rs3783641 (additive model: incident rate ratio [IRR]?=?1.37, p?=?0.024; recessive model: IRR?=?1.81, p?=?0.018) with utilization rate. These associations persisted when subjects with HbSS and HbS?° genotype only were analyzed. We also identified two haploblocks (rs10483639[G>C]-rs752688[C>T]-rs4411417[T>C] and rs3783641[T>A]-rs8007267[T>C]) with SNPs in high linkage disequilibrium. Of these, haplotype T-C of haploblock rs3783641-rs8007267 showed significant association with rate of utilization (odds ratio [OR]?=?0.31, p?=?0.001). Our study indicates potential contribution of GCH1 polymorphisms to the variability of pain in African Americans with SCD.

SUBMITTER: Sadhu N

PROVIDER: S-EPMC6175655 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Genetic variants of GCH1 associate with chronic and acute crisis pain in African Americans with sickle cell disease.

Sadhu Nilanjana N Jhun Ellie H EH Yao Yingwei Y He Ying Y Molokie Robert E RE Wilkie Diana J DJ Wang Zaijie Jim ZJ

Experimental hematology 20180719

The multidimensional nature of pain in sickle cell disease (SCD) has rendered its therapeutic management extremely challenging. In this study, we explored the role of five single nucleotide polymorphisms (SNPs) of candidate gene GCH1 in SCD pain. Composite pain index (CPI) scores and acute care utilization rates were used as phenotype markers. Rs8007267 was associated with chronic pain (additive model: B = -3.76, p = 0.037; dominant model: B = -5.61, p = 0.021) and rs3783641 (additive model: inc ...[more]

PMID: 30031848

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Project description:The association between sickle cell trait (SCT) and chronic kidney disease (CKD) is uncertain.To describe the relationship between SCT and CKD and albuminuria in self-identified African Americans.Using 5 large, prospective, US population-based studies (the Atherosclerosis Risk in Communities Study [ARIC, 1987-2013; n?=?3402], Jackson Heart Study [JHS, 2000-2012; n?=?2105], Coronary Artery Risk Development in Young Adults [CARDIA, 1985-2006; n?=?848], Multi-Ethnic Study of Atherosclerosis [MESA, 2000-2012; n?=?1620], and Women's Health Initiative [WHI, 1993-2012; n?=?8000]), we evaluated 15,975 self-identified African Americans (1248 participants with SCT [SCT carriers] and 14,727 participants without SCT [noncarriers]).Primary outcomes were CKD (defined as an estimated glomerular filtration rate [eGFR] of <60 mL/min/1.73 m2 at baseline or follow-up), incident CKD, albuminuria (defined as a spot urine albumin:creatinine ratio of >30 mg/g or albumin excretion rate >30 mg/24 hours), and decline in eGFR (defined as a decrease of >3 mL/min/1.73 m2 per year). Effect sizes were calculated separately for each cohort and were subsequently meta-analyzed using a random-effects model.A total of 2233 individuals (239 of 1247 SCT carriers [19.2%] vs 1994 of 14,722 noncarriers [13.5%]) had CKD, 1298 (140 of 675 SCT carriers [20.7%] vs 1158 of 8481 noncarriers [13.7%]) experienced incident CKD, 1719 (150 of 665 SCT carriers [22.6%] vs 1569 of 8249 noncarriers [19.0%]) experienced decline in eGFR, and 1322 (154 of 485 SCT carriers [31.8%] vs 1168 of 5947 noncarriers [19.6%]) had albuminuria during the study period. Individuals with SCT had an increased risk of CKD (odds ratio [OR], 1.57 [95% CI, 1.34-1.84]; absolute risk difference [ARD], 7.6% [95% CI, 4.7%-10.8%]), incident CKD (OR, 1.79 [95% CI, 1.45-2.20]; ARD, 8.5% [95% CI, 5.1%-12.3%]), and decline in eGFR (OR, 1.32 [95% CI, 1.07-1.61]; ARD, 6.1% [95% CI, 1.4%-13.0%]) compared with noncarriers. Sickle cell trait was also associated with albuminuria (OR, 1.86 [95% CI, 1.49-2.31]; ARD, 12.6% [95% CI, 7.7%-17.7%]).Among African Americans in these cohorts, the presence of SCT was associated with an increased risk of CKD, decline in eGFR, and albuminuria, compared with noncarriers. These findings suggest that SCT may be associated with the higher risk of kidney disease in African Americans.

Project description:CONTEXT:Inhaled nitric oxide has shown evidence of efficacy in mouse models of sickle cell disease (SCD), case series of patients with acute chest syndrome, and 2 small placebo-controlled trials for treatment of vaso-occlusive pain crisis (VOC). OBJECTIVE:To determine whether inhaled nitric oxide gas reduces the duration of painful crisis in patients with SCD who present to the emergency department or hospital for care. DESIGN, SETTING, AND PARTICIPANTS:Prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial for up to 72 hours of inhaled nitric oxide gas vs inhaled nitrogen placebo in 150 participants presenting with VOC of SCD at 11 centers between October 5, 2004, and December 22, 2008. Intervention Inhaled nitric oxide gas vs inhaled nitrogen placebo. MAIN OUTCOME MEASURES:The primary end point was the time to resolution of painful crisis, defined by (1) freedom from parenteral opioid use for 5 hours; (2) pain relief as assessed by visual analog pain scale scores of 6 cm or lower (on 0-10 scale); (3) ability to walk; and (4) patient's and family's decision, with physician consensus, that the remaining pain could be managed at home. RESULTS:There was no significant change in the primary end point between the nitric oxide and placebo groups, with a median time to resolution of crisis of 73.0 hours (95% confidence interval [CI], 46.0-91.0) and 65.5 hours (95% CI, 48.1-84.0), respectively (P = .87). There were no significant differences in secondary outcome measures, including length of hospitalization, visual analog pain scale scores, cumulative opioid usage, and rate of acute chest syndrome. Inhaled nitric oxide was well tolerated, with no increase in serious adverse events. Increases in venous methemoglobin concentration confirmed adherence and randomization but did not exceed 5% in any study participant. Significant increases in plasma nitrate occurred in the treatment group, but there were no observed increases in plasma or whole blood nitrite. CONCLUSION:Among patients with SCD hospitalized with VOC, the use of inhaled nitric oxide compared with placebo did not improve time to crisis resolution. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT00094887.

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Genetic variants of GCH1 associate with chronic and acute crisis pain in African Americans with sickle cell disease.

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Genetic variants of GCH1 associate with chronic and acute crisis pain in African Americans with sickle cell disease.

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