Habitual Coffee Consumption Increases Risk of Primary Open-Angle Glaucoma: A Mendelian Randomization Study.

PURPOSE: To explore whether there is a causal relationship between coffee consumption and primary open-angle glaucoma (POAG). DESIGN: Two-sample Mendelian randomization (MR). PARTICIPANTS: The single-nucleotide polymorphisms (SNPs) associated with coffee consumption (including phenotypes 1 and 2) were selected from a genome-wide association study (GWAS) involving 121 824 individuals of European descent. Coffee intake from the MRC-IEU UK Biobank was also used to identify instruments for coffee intake. Summary-level data for POAG were obtained from the largest publicly available meta-analyses involving 16 677 POAG cases and 199 580 controls of European descent. METHODS: The inverse variance-weighted (IVW) method was the main MR analysis, whereas weighted-median, weighted mode-based estimate (MBE), MR Pleiotropy RESidual Sum and Outlier (PRESSO) test, and MR-Egger regression were used for sensitivity analysis. MAIN OUTCOME MEASURES: Diagnosis of POAG. RESULTS: Three sets of instrumental variables were used to evaluate the causal association between coffee consumption and POAG risk. Results showed that genetically predicted higher coffee consumption phenotype 1 (cups/day) was significantly associated with higher risk of POAG (odds ratio [OR], 1.241; 95% confidence interval [CI], 1.041-1.480; P = 0.016). Genetically predicted higher coffee consumption phenotype 2 (high vs. no/low) was also significantly associated with higher risk of POAG (OR, 1.155; 95% CI, 1.038-1.284; P = 0.008, using the IVW method). Moreover, genetically predicted higher coffee intake from the MRC-IEU UK Biobank OpenGWAS was significantly associated with a higher risk of POAG (OR, 1.727; 95% CI, 1.230-2.425; P = 0.002, using the IVW method). Sensitivity analyses confirmed that the findings were robust to possible pleiotropy. CONCLUSIONS: These findings provide the genetic evidence that higher coffee consumption is associated with a higher risk of POAG. Given that coffee is widely consumed, our findings provide new insights into potential strategies to prevent and manage POAG.

Causal Associations of Thyroid Function and Age-Related Macular Degeneration: A Two-Sample Mendelian Randomization Study.

PURPOSE: To determine whether causal association lies between thyroid function and age-related macular degeneration (AMD) risk in human beings. DESIGN: Two-sample Mendelian randomization (MR) study. METHODS: The single-nucleotide polymorphisms associated with free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were selected from a genome-wide association study (GWAS) of 72,167 individuals of European descent. Summary-level data for AMD were obtained from a GWAS published by the International Age-related Macular Degeneration Genomics Consortium of 33,526 individuals (16,144 cases and 17,832 controls). An inverse-variance-weighted (IVW) method was the main MR analysis. Maximum likelihood, weighted median, MR-Egger, MR-pleiotropy residual sum outlier methods were used for the sensitivity analysis. RESULTS: An increase of 1 SD in genetically predicted FT4 levels was found to be significantly associated with an 18.9 % increase in the overall AMD risk (P = .005). In the multivariable MR analysis controlling for TSH level, the causal effect of FT4 level on the risk of AMD remained (odds ratio [OR] = 1.207, P = .004). A 1-SD increase in TSH levels was nominally associated with a 10.0% decrease in the overall AMD risk (P = .032). After adjusting for FT4 level by multivariable MR analysis, no direct causal relationship was found between TSH level and AMD risk (95% CI = 0.810, 1.125, P = .582). CONCLUSIONS: Genetic variants predisposing to higher FT4 levels within the normal range were associated with higher AMD risk. Further studies are required to understand the mechanism underlying this putative causal relationship.

Development of atherosclerotic-moyamoya syndrome with genetic variant of RNF213 p.R4810K and p.T1727M: A case report.

OBJECTIVE: We report a rare case of atherosclerotic-moyamoya syndrome (A-MMS) in an adult female with genetic variant of both ring finger 213 (RNF213) p.R4810K and p.T1727M. CASE REPORT: A 46-year-old previously healthy, right-handed woman displayed transient slurred speech, which started to worsen four years ago. Initial magnetic resonance angiography (MRA) revealed stenosis in left middle cerebral artery (MCA), bilateral anterior cerebral artery (ACA), and left posterior cerebral artery (PCA). The patient subsequently underwent catheter angiography, which confirmed the formation of moyamoya vessels, with Suzuki's angiographic staging of grade-3 on the left side. Although the patient had been on both anti-platelet and statin therapy at the time, a follow-up examination showed further exacerbation of left MCA stenosis, along with enhanced moyamoya vessel formation. On black-blood imaging using DANTE-SPACE, there were eccentric, evolving lesions in the left MCA. We next screened for potential genetic variants, using genomic DNA samples isolated from both the patient and her immediate family members. The results showed that the patient, along with her mother, sister, and brother, possessed the heterozygous variant of the RNF213 gene, including c.14429G > A (p.R4810K) and c.5180C > T (p.T1727M). The patient's daughter did not have the variant. CONCLUSION: Collectively, we present a unique case of A-MMS with genetic variant of RNF213 p.R4810K and p.T1727M, manifesting as progression. Based on the family tree, these two mutations are on the same RNF213 haplotype. Whether atherosclerosis is the cause of A-MMS or it further exacerbates the injury of MMD to the A-MMS patients with RNF213 gene variant is a question to be investigated.