👤 Salah Daghlas

Clinical trials have shown that interleukin-6 (IL-6) signaling inhibitors reduce lipoprotein(a) [Lp(a)] levels, though the relevance of this reduction to atherosclerotic cardiovascular disease (ASCVD) risk is uncertain. We leveraged Mendelian randomization (MR) to investigate the extent to which Lp(a) reduction mediates the effects of IL-6 signaling inhibition on ASCVD. IL-6 signaling inhibition was proxied by the IL6R variant p.Asp358Ala and scaled to C-reactive protein (CRP) levels. Genetic associations with Lp(a) were obtained from UK Biobank (n = 343,681). Outcomes included large-artery atherosclerotic stroke (LAAS: 6399 cases), carotid plaque (29,760 cases), and coronary artery disease (CAD: 181,522 cases). MR analyses estimated the association of IL-6 signaling inhibition with Lp(a) and ASCVD, and we quantified the proportion of the IL-6-ASCVD association mediated by Lp(a). Individual-level analyses tested whether effects of IL-6 signaling inhibition on Lp(a) and CAD were amplified in carriers of Lp(a)-raising variants. Genetically proxied IL-6 signaling inhibition modestly reduced Lp(a) (-3.01 mg/dL per 1-ln(CRP) reduction, 95% CI -4.79, -1.23) and protected against all ASCVD outcomes (ORs: 0.34-0.69). Lp(a) mediated only a small proportion of the IL-6-ASCVD association (range: 1.3%-4.8%). In carriers of Lp(a)-raising variants, the IL-6-Lp(a) association was stronger (-9.8 mg/dL, 95% CI -14.6, -5.1; p These findings suggest that Lp(a) minimally mediates and does not modify the cardiovascular benefits of IL-6 signaling inhibition, supporting these targets as independent and complementary for ASCVD. The amplified IL-6-Lp(a) association in carriers of Lp(a)-raising variants warrants replication. Show less

Lipoprotein(a) (Lp(a)) is a highly atherogenic lipoprotein and the target of investigational therapies. Using a Mendelian randomization study design, we aimed to clarify associations between genetically predicted Lp(a) levels and cerebrovascular disease outcomes and related phenotypes. We obtained genetic associations with Lp(a) levels ( Genetically predicted Lp(a) levels associated with significantly increased risk of all-cause ischemic stroke (odds ratio [OR], 1.04 [95% CI, 1.02-1.07], Elevated Lp(a) is primarily associated with ischemic stroke due to large artery atherosclerosis, while showing no link to cerebral small vessel disease. These findings support prioritization of patients with atherosclerotic cerebrovascular disease in Lp(a)-lowering stroke prevention trials. Show less

Primary Raynaud's phenomenon (RP) is a common and self-limiting condition, which is not secondary to any other disease process. In contrast, secondary RP has an underlying etiology. Several conditions can lead to secondary RP, which creates a challenging landscape for clinicians. Differentiation between primary and secondary RP is vital as failure to do so can lead to delays in treatment and poor patient outcomes. We present a case of a 77-year-old male who experienced digit discoloration when exposed to cold temperatures. He had been initially diagnosed with primary RP, but his symptoms had increased in frequency and progressed to digit necrosis requiring amputation. He was admitted to our tertiary care center for further workup. Subsequently, a diagnosis of type I cryoglobulinemia secondary to lymphoplasmacytic lymphoma (LPL) was made instead of the initial diagnosis of primary RP as the cause of his digit necrosis. This report emphasizes the importance of differentiating between primary and secondary RP and highlights the need for comprehensive workup in patients with RP, especially those presenting with atypical features. Show less

The aim of this study was to leverage human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide (GIP) signalling. Data were obtained from summary statistics of large-scale genome-wide association studies. We examined whether genetic associations for type 2 diabetes liability in the GIP and GIPR genes co-localised with genetic associations for 11 cardiometabolic outcomes. For those outcomes that showed evidence of co-localisation (posterior probability >0.8), we performed Mendelian randomisation analyses to estimate the association of genetically proxied GIP signalling with risk of cardiometabolic outcomes, and to test whether this exceeded the estimate observed when considering type 2 diabetes liability variants from other regions of the genome. Evidence of co-localisation with genetic associations of type 2 diabetes liability at both the GIP and GIPR genes was observed for five outcomes. Mendelian randomisation analyses provided evidence for associations of lower genetically proxied type 2 diabetes liability at the GIP and GIPR genes with lower BMI (estimate in SD units -0.16, 95% CI -0.30, -0.02), C-reactive protein (-0.13, 95% CI -0.19, -0.08) and triacylglycerol levels (-0.17, 95% CI -0.22, -0.12), and higher HDL-cholesterol levels (0.19, 95% CI 0.14, 0.25). For all of these outcomes, the estimates were greater in magnitude than those observed when considering type 2 diabetes liability variants from other regions of the genome. This study provides genetic evidence to support a beneficial role of sustained GIP signalling on cardiometabolic health greater than that expected from improved glycaemic control alone. Further clinical investigation is warranted. All data used in this study are publicly available. The scripts for the analysis are available at: https://github.com/vkarhune/GeneticallyProxiedGIP . Show less

To evaluate phenotypic and genetic relationships between migraine and lipoprotein subfractions. We evaluated phenotypic associations between migraine and 19 lipoprotein subfraction measures in the Women's Genome Health Study (n = 22,788). We then investigated genetic relationships between these traits using summary statistics from the International Headache Genetics Consortium for migraine (n There was a significant phenotypic association (odds ratio 1.27 [95% confidence interval 1.12-1.44]) and a significant genetic correlation at 0.18 ( The study supports the association between certain lipoprotein subfractions, especially for TRLP, and migraine in populations of European ancestry. The corresponding shared genetic components may help identify potential targets for future migraine therapeutics. This study provides Class I evidence that migraine is significantly associated with some lipoprotein subfractions. Show less

Daytime napping is a common, heritable behavior, but its genetic basis and causal relationship with cardiometabolic health remain unclear. Here, we perform a genome-wide association study of self-reported daytime napping in the UK Biobank (n = 452,633) and identify 123 loci of which 61 replicate in the 23andMe research cohort (n = 541,333). Findings include missense variants in established drug targets for sleep disorders (HCRTR1, HCRTR2), genes with roles in arousal (TRPC6, PNOC), and genes suggesting an obesity-hypersomnolence pathway (PNOC, PATJ). Association signals are concordant with accelerometer-measured daytime inactivity duration and 33 loci colocalize with loci for other sleep phenotypes. Cluster analysis identifies three distinct clusters of nap-promoting mechanisms with heterogeneous associations with cardiometabolic outcomes. Mendelian randomization shows potential causal links between more frequent daytime napping and higher blood pressure and waist circumference. Show less

Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (N Show less