Assessing the Relationship Between Serum Urate and Urolithiasis Using Mendelian Randomization: An Analysis of the UK Biobank.

RATIONALE & OBJECTIVE: The association between hyperuricemia and urolithiasis has been previously reported. However, this association is based on observational data, which are prone to residual confounding. The aim of this work was to use Mendelian randomization (MR) to evaluate if this relationship represents a causal effect of hyperuricemia. STUDY DESIGN: MR analysis using 2 approaches: 2-stage MR and 2-sample MR. SETTING & PARTICIPANTS: Participants aged 40-69 years from the UK Biobank Resource. EXPOSURE: Serum urate. OUTCOME: Urolithiasis. ANALYTICAL APPROACH: An observational analysis testing for an association between serum urate level and urolithiasis was performed using logistic regression. For MR analyses, serum urate-associated single-nucleotide polymorphisms, identified from genome-wide association data, were used as instrumental variables for serum urate. In the 2-stage MR analysis, a weighted genetic urate score was calculated from the instrumental variables, and a control function estimation model was fit. In the 2-sample MR analysis, multiple-instrument MR via the inverse-variance weighted method was performed. RESULTS: Individual-level data were available for 359,827 participants, of whom 6,398 (1.8%) reported urolithiasis. In the observational analysis, serum urate was positively associated with urolithiasis in an unadjusted analysis (odds ratio [OR], 1.47 [95% CI, 1.42-1.51]); however, after adjustment for relevant confounders, no association was observed (OR, 1.03 [95% CI, 0.99-1.08]). In the 2-stage MR analysis, no significant causal effect of serum urate level on urolithiasis was observed in the unadjusted (OR, 0.93 [95% CI, 0.81-1.08]) or adjusted (OR, 0.94 [95% CI, 0.80-1.09]) models. In the 2-sample MR analysis, multiple-instrument MR did not indicate a causal effect of serum urate on urolithiasis. LIMITATIONS: Stone composition and urinalysis data, including urine pH, were not available for this study. CONCLUSIONS: Our analyses do not support a causal effect of serum urate level on urolithiasis. The association between serum urate level and urolithiasis reported in observational studies is likely due to residual confounding.

Systematic genetic analysis of early-onset gout: ABCG2 is the only associated locus.

OBJECTIVE: The aim of this study was to examine whether serum urate-associated genetic variants are associated with early-onset gout. METHODS: Participants with gout in the Genetics of Gout in Aotearoa study with available genotyping were included (n = 1648). Early-onset gout was defined as the first presentation of gout <40 years of age. Single nucleotide polymorphisms (SNPs) for the 10 loci most strongly associated with serum urate were genotyped. Allelic association of the SNPs with early-onset gout was tested using logistic regression in an unadjusted model and in a model adjusted for sex, body mass index, tophus presence, flare frequency, serum creatinine and highest serum urate. The analysis was also done in two replication cohorts: Eurogout (n = 704) and Ardea (n = 755), and data were meta-analysed. RESULTS: In the Genetics of Gout in Aotearoa study, there were 638 (42.4%) participants with early-onset gout. The ABCG2 rs2231142 gout risk T-allele was present more frequently in participants with early-onset gout compared with the later-onset group. For the other SNPs tested, no differences in risk allele number were observed. In the allelic association analysis, the ABCG2 rs2231142 T-allele was associated with early-onset gout in unadjusted and adjusted models. Analysis of the replication cohorts confirmed the association of early-onset gout with the ABCG2 rs2231142 T-allele, but not with other serum urate-associated SNPs. In the meta-analysis, the odds ratio (95% CI) for early-onset gout for the ABCG2 rs2231142 T-allele was 1.60 (1.41, 1.83). CONCLUSION: In contrast to other serum urate-raising variants, the ABCG2 rs2231142 T-allele is strongly associated with early-onset gout.

A prediction tool for vitamin D deficiency in New Zealand adults.

PURPOSE: This study aims to develop a model for predicting vitamin D deficiency in New Zealand adults using easily accessible clinical characteristics. METHODS: Data were derived from the Vitamin D Assessment (ViDA) study dataset. Included participants in the main analysis were aged 50-84 years and resided in Auckland, New Zealand. The dataset was split into a discovery dataset in which the prediction model was developed (n = 2036) and a validation dataset in which it was tested (n = 2037). The prediction model was developed using clinical characteristics in a logistic regression analysis with deseasonalised serum 25OHD (DS-25OHD) as the dependent variable. RESULTS: DS-25OHD < 40 nmol/L was found in 8.2% of European participants, 18.8% of Maori participants, 23.1% of Pacific participants and 52.2% of South Asian participants. Predictors for DS-25OHD < 40 nmol/L in the European sub-cohort included increasing age, female sex, higher body mass index, current smoking, no alcohol intake, lower self-reported general health status, lower physical activity hours, lower outdoor hours and no use of vitamin D-containing supplementation. The area under the curve in the discovery dataset was 0.73, and in the validation dataset was 0.71. Of those with a prediction score ≥ 10 (total risk score range 0-21.5), the sensitivity and specificity for predicting vitamin D deficiency was 0.90 and 0.41, respectively. CONCLUSION: Non-European ethnicity is an important risk factor for vitamin D deficiency. Our vitamin D deficiency prediction model performed well and demonstrates its potential as a tool that can be integrated into clinical practice for the prediction of vitamin D deficiency.

Correlation of retinal nerve fiber layer measured by scanning laser polarimeter to visual field in ischemic optic neuropathy.

OBJECTIVE: To evaluate the relationship between retinal nerve fiber layer (RNFL) measurement with scanning laser polarimetry (SLP) and standard automated perimetry (SAP) in nonarteritic anterior ischemic optic neuropathy (NAION). METHODS: In this prospective observational case series, all subjects (28 eyes with NAION) underwent SAP and SLP. The RNFL retardation measurements and visual field test points were grouped into 6 corresponding sectors. The contralateral uninvolved eye was used as control. The relationship between RNFL retardation and SAP was evaluated with the Spearman nonparametric technique and linear regression analysis. The main outcome measure was correlation of SLP RNFL parameters and SAP. RESULTS: Global and sectoral SLP parameters showed a significant difference in affected eyes compared with controls. The strongest correlations were seen between mean deviation and number (r = -0.524; P = .004), ellipse modulation (r = 0.5026; P = .006), and maximum modulation (r = 0.526; P = .004). Superior sectoral visual field indexes showed a strong correlation with inferior RNFL changes (r = 0.522; P<.008). Linear regression confirmed a strong relationship between the superior sectoral visual field indexes and the inferior RNFL. CONCLUSION: Scanning laser polarimetry was able to identify structural changes of the RNFL globally and in the inferior SLP sector with functional loss in NAION.

Poor prognosis of visual outcome after visual loss from giant cell arteritis.

OBJECTIVE: To evaluate the incidence and extent of visual recovery in patients with giant cell arteritis (GCA) treated with high doses of systemic corticosteroids. DESIGN: Multicenter prospective case series. PARTICIPANTS: Thirty-four consecutive patients with biopsy-proven GCA and visual loss seen at either Wills Eye Hospital in Philadelphia or Auckland Hospital in New Zealand from 2001 to 2004 were evaluated prospectively. METHODS: All patients underwent a complete neuro-ophthalmic evaluation that included Snellen visual acuity, pseudoisochromatic Ishihara color plates, visual fields, intraocular pressure, slit-lamp examination, and binocular ophthalmoscopy. Formal visual field testing was performed on all patients who were capable of completing the test. All patients were treated with a standard protocol of 1 g of IV methylprednisolone daily for 3 days followed by oral prednisone 60 or 80 mg (depending on patient weight). Patients were evaluated initially at 2-week intervals (14-19 days) and then monthly (4-5 weeks), with subsequent dosages of prednisone modified based on erythrocyte sedimentation rate, C-reactive protein, and patient symptoms. At each visit, patients underwent a repeat complete neuro-ophthalmic evaluation. MAIN OUTCOME MEASURES: Alterations in visual acuity, visual field, and color vision. RESULTS: Patients with visual loss from GCA had a mean visual acuity of 20/400. Visual deterioration occurred in 27% of eyes within the first week despite high-dose IV corticosteroids. Fifteen percent of eyes showed an improvement of visual acuity within the first month, but only 5% have corresponding improvement in visual field. CONCLUSIONS: Visual recovery is uncommon in patients who lose vision from GCA. Recovery in visual acuity is not associated with visual field or color vision improvement in this series. Visual deterioration occurs in approximately 27% of eyes despite high-dose IV methylprednisolone. The greatest risk of visual deterioration is in the first 6 days.