Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic Cohorts.

BACKGROUND & AIMS: The sucrase-isomaltase (SI) c.273_274delAG loss-of-function variant is common in Arctic populations and causes congenital sucrase-isomaltase deficiency, which is an inability to break down and absorb sucrose and isomaltose. Children with this condition experience gastrointestinal symptoms when dietary sucrose is introduced. We aimed to describe the health of adults with sucrase-isomaltase deficiency. METHODS: The association between c.273_274delAG and phenotypes related to metabolic health was assessed in 2 cohorts of Greenlandic adults (n = 4922 and n = 1629). A sucrase-isomaltase knockout (Sis-KO) mouse model was used to further elucidate the findings. RESULTS: Homozygous carriers of the variant had a markedly healthier metabolic profile than the remaining population, including lower body mass index (ß [standard error], -2.0 [0.5] kg/m2; P = 3.1 × 10-5), body weight (-4.8 [1.4] kg; P = 5.1 × 10-4), fat percentage (-3.3% [1.0%]; P = 3.7 × 10-4), fasting triglyceride (-0.27 [0.07] mmol/L; P = 2.3 × 10-6), and remnant cholesterol (-0.11 [0.03] mmol/L; P = 4.2 × 10-5). Further analyses suggested that this was likely mediated partly by higher circulating levels of acetate observed in homozygous carriers (ß [standard error], 0.056 [0.002] mmol/L; P = 2.1 × 10-26), and partly by reduced sucrose uptake, but not lower caloric intake. These findings were verified in Sis-KO mice, which, compared with wild-type mice, were leaner on a sucrose-containing diet, despite similar caloric intake, had significantly higher plasma acetate levels in response to a sucrose gavage, and had lower plasma glucose level in response to a sucrose-tolerance test. CONCLUSIONS: These results suggest that sucrase-isomaltase constitutes a promising drug target for improvement of metabolic health, and that the health benefits are mediated by reduced dietary sucrose uptake and possibly also by higher levels of circulating acetate.

Outcomes following SARS-CoV-2 infection in individuals with and without solid organ transplantation-A Danish nationwide cohort study.

The risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hospitalization and death, and the effects of SARS-CoV-2 vaccines in solid organ transplant recipients (SOTRs) is still debated. We performed a nationwide, population-based, matched cohort study, including all Danish SOTRs (n = 5184) and a matched cohort from the general population (n = 41 472). Cox regression analyses were used to calculate incidence rate ratios (IRRs). SOTRs had a slightly increased risk of SARS-CoV-2 infection and were vaccinated earlier than the general population. The overall risk of hospital contact with COVID-19, severe COVID-19, need for assisted respiration, and hospitalization followed by death was substantially higher in SOTRs (IRR: 32.8 95%CI [29.0-37.0], 9.2 [6.7-12.7], 12.5 [7.6-20.8], 12.4 [7.9-12.7]). The risk of hospitalization and death after SARS-CoV-2 infection decreased substantially in SOTRs after the emergence of the Omicron variant (IRR: 0.45 [0.37-0.56], 0.17 [0.09-0.30]). Three vaccinations reduced the risk of SARS-CoV-2 infection only marginally compared to two vaccinations, but SOTRs with three vaccinations had a lower risk of death (IRR: 022 [0.16-0.35]). We conclude that SOTRs have a risk of SARS-CoV-2 infection comparable to the general population, but substantially increased the risk of hospitalization and death following SARS-CoV-2 infection. A third vaccination only reduces the risk of SARS-CoV2 infection marginally, but SOTRs vaccinated 3 times have reduced mortality.

Molecular epidemiology of the SARS-CoV-2 variant Omicron BA.2 sub-lineage in Denmark, 29 November 2021 to 2 January 2022.

Following emergence of the SARS-CoV-2 variant Omicron in November 2021, the dominant BA.1 sub-lineage was replaced by the BA.2 sub-lineage in Denmark. We analysed the first 2,623 BA.2 cases from 29 November 2021 to 2 January 2022. No epidemiological or clinical differences were found between individuals infected with BA.1 versus BA.2. Phylogenetic analyses showed a geographic east-to-west transmission of BA.2 from the Capital Region with clusters expanding after the Christmas holidays. Mutational analysis shows distinct differences between BA.1 and BA.2.

Epidemiological characterisation of the first 785 SARS-CoV-2 Omicron variant cases in Denmark, December 2021.

By 9 December 2021, 785 SARS-CoV-2 Omicron variant cases have been identified in Denmark. Most cases were fully (76%) or booster-vaccinated (7.1%); 34 (4.3%) had a previous SARS-CoV-2 infection. The majority of cases with available information reported symptoms (509/666; 76%) and most were infected in Denmark (588/644; 91%). One in five cases cannot be linked to previous cases, indicating widespread community transmission. Nine cases have been hospitalised, one required intensive care and no deaths have been registered.

Efficacy and safety of semaglutide 2.4 mg according to antidepressant use at baseline: A post hoc subgroup analysis.

OBJECTIVE: To explore the efficacy and safety of semaglutide 2.4 mg in people with overweight/obesity who were also being treated with antidepressants (ADs). METHODS: Across the Semaglutide Treatment Effect for People with obesity (STEP) 1-3 and 5 trials, adults with overweight/obesity and type 2 diabetes (STEP 2 only) were enrolled. People with severe major depressive disorder within 2 years prior to screening or with a patient health questionnaire-9 score ≥15 at screening were excluded. Participants were categorized into subgroups according to baseline AD status (on/off ADs) in this post hoc exploratory analysis of the STEP trials. RESULTS: Of 3683 participants randomized, 539 were on ADs at baseline. Mean body weight change from baseline to week 68 was greater for semaglutide versus placebo, regardless of baseline AD use. In STEP 1, for participants on ADs at baseline, mean change from baseline was -15.7% with semaglutide versus -0.2% with placebo and -14.7% versus -2.8% for those not on ADs at baseline. Similar patterns were seen in STEP 2, 3, and 5. The prevalence of adverse events (AEs) was generally similar between semaglutide and placebo in participants on ADs at baseline. CONCLUSIONS: In adults with overweight/obesity, semaglutide provided clinically meaningful weight loss regardless of baseline AD use, with an AE profile consistent with previous studies.

Psychiatric Safety of Semaglutide for Weight Management in People Without Known Major Psychopathology: Post Hoc Analysis of the STEP 1, 2, 3, and 5 Trials.

Importance: Obesity is associated with numerous psychosocial complications, making psychiatric safety a consideration for treating people with obesity. Few studies have investigated the psychiatric safety of newly available antiobesity medications. Objective: To evaluate the psychiatric safety of subcutaneous semaglutide, 2.4 mg, once weekly in people without known major psychopathology. Design, Setting, and Participants: This post hoc analysis of pooled data from the randomized, double-blind, placebo-controlled, multicenter phase 3a STEP 1, 2, and 3 trials (68 weeks; 2018-2020) and phase 3b STEP 5 trial (104 weeks; 2018-2021) included adults with overweight or obesity; STEP 2 participants also had type 2 diabetes. Trial designs have been published previously. Interventions: Semaglutide, 2.4 mg, vs placebo. Main Outcomes and Measures: Depressive symptoms and suicidal ideation/behavior were assessed using the Patient Health Questionnaire (PHQ-9) and Columbia-Suicide Severity Rating Scale, respectively. Psychiatric and nervous system disorder adverse events were investigated. Results: This analysis included 3377 participants in the STEP 1, 2, and 3 trials (2360 women [69.6%]; mean [SD] age, 49 [13] years) and 304 participants in STEP 5 (236 women [77.6%]; mean [SD] age, 47 [11] years). In the STEP 1, 2, and 3 trials, mean (SD) baseline PHQ-9 scores for the semaglutide, 2.4 mg, and placebo groups were 2.0 (2.3) and 1.8 (2.3), respectively, indicating no/minimal symptoms of depression. PHQ-9 scores at week 68 were 2.0 (2.9) and 2.4 (3.3), respectively; the estimated treatment difference (95% CI) between groups was -0.56 (-0.81 to -0.32) (P < .001). Participants treated with semaglutide vs placebo were less likely to shift (from baseline to week 68) to a more severe category of PHQ-9 depression (odds ratio, 0.63; 95% CI, 0.50-0.79; P < .001). Based on the Columbia-Suicide Severity Rating Scale, 1% or fewer of participants reported suicidal ideation/behavior during treatment, with no differences between semaglutide, 2.4 mg, and placebo. Psychiatric disorder adverse events were generally balanced between groups. Similar results were observed in STEP 5. Conclusions and Relevance: The results of this post hoc analysis suggest that treatment with semaglutide, 2.4 mg, did not increase the risk of developing symptoms of depression or suicidal ideation/behavior vs placebo and was associated with a small but statistically significant reduction in depressive symptoms (not considered clinically meaningful). People with obesity should be monitored for mental health concerns so they can receive appropriate support and care. Trial Registration: ClinicalTrials.gov Identifiers: STEP 1 (NCT03548935), 2 (NCT03552757), 3 (NCT03611582), and 5 (NCT03693430).

The effect of diabetes and the diabetogenic TBC1D4 p.Arg684ter variant on kidney function in Inuit in Greenland.

The aim of this study was to examine the effect of diabetes and the diabetogenic TBC1D4 variant on kidney function in Greenland in a population-based setting. Health survey data and TBC1D4 genotypes from 5,336 Greenlanders were used to estimate odds ratios (ORs) of albuminuria (>30 mg/g creatinine) and chronic kidney disease (CKD, eGFR <60 ml/min/1.73m2), comparing individuals with and without diabetes, including the effect of TBC1D4 variant. Of the 3,909 participants with complete data, 9.3% had diabetes. Albuminuria was found in 27.6% and 9.5% and CKD was found in 10.8% and 6.3% among those with and without diabetes, respectively. Diabetes was cross-sectionally associated with an increased risk of albuminuria (OR (95% CI) = 2.37 (1.69,3.33); p < 0.001) and the TBC1D4 variant protected against albuminuria (OR (95% CI) = 0.44 (0.22,0.90); p = 0.02) in a multivariable model. Neither diabetes nor the TBC1D4 variant significantly associated with CKD. The presence/absence of diabetes did not predict changes in eGFR and UACR in longitudinal analyses. Diabetes conferred an increased risk of albuminuria, and the TBC1D4 variant was associated with a decreased risk of albuminuria, but neither was associated with CKD. The potential renoprotective association of the TBC1D4 variant on albuminuria calls for further studies.

Household transmission of SARS-CoV-2 Omicron variant of concern subvariants BA.1 and BA.2 in Denmark.

SARS coronavirus 2 (SARS-CoV-2) continues to evolve and new variants emerge. Using nationwide Danish data, we estimate the transmission dynamics of SARS-CoV-2 Omicron subvariants BA.1 and BA.2 within households. Among 22,678 primary cases, we identified 17,319 secondary infections among 50,588 household contacts during a 1-7 day follow-up. The secondary attack rate (SAR) was 29% and 39% in households infected with Omicron BA.1 and BA.2, respectively. BA.2 was associated with increased susceptibility of infection for unvaccinated household contacts (Odds Ratio (OR) 1.99; 95%-CI 1.72-2.31), fully vaccinated contacts (OR 2.26; 95%-CI 1.95-2.62) and booster-vaccinated contacts (OR 2.65; 95%-CI 2.29-3.08), compared to BA.1. We also found increased infectiousness from unvaccinated primary cases infected with BA.2 compared to BA.1 (OR 2.47; 95%-CI 2.15-2.84), but not for fully vaccinated (OR 0.66; 95%-CI 0.57-0.78) or booster-vaccinated primary cases (OR 0.69; 95%-CI 0.59-0.82). Omicron BA.2 is inherently more transmissible than BA.1. Its immune-evasive properties also reduce the protective effect of vaccination against infection, but do not increase infectiousness of breakthrough infections from vaccinated individuals.

Household transmission of the SARS-CoV-2 Omicron variant in Denmark.

In late 2021, the Omicron SARS-CoV-2 variant overtook the previously dominant Delta variant, but the extent to which this transition was driven by immune evasion or a change in the inherent transmissibility is currently unclear. We estimate SARS-CoV-2 transmission within Danish households during December 2021. Among 26,675 households (8,568 with the Omicron VOC), we identified 14,140 secondary infections within a 1-7-day follow-up period. The secondary attack rate was 29% and 21% in households infected with Omicron and Delta, respectively. For Omicron, the odds of infection were 1.10 (95%-CI: 1.00-1.21) times higher for unvaccinated, 2.38 (95%-CI: 2.23-2.54) times higher for fully vaccinated and 3.20 (95%-CI: 2.67-3.83) times higher for booster-vaccinated contacts compared to Delta. We conclude that the transition from Delta to Omicron VOC was primarily driven by immune evasiveness and to a lesser extent an inherent increase in the basic transmissibility of the Omicron variant.

An LDLR missense variant poses high risk of familial hypercholesterolemia in 30% of Greenlanders and offers potential of early cardiovascular disease intervention.

The common Arctic-specific LDLR p.G137S variant was recently shown to be associated with elevated lipid levels. Motivated by this, we aimed to investigate the effect of p.G137S on metabolic health and cardiovascular disease risk among Greenlanders to quantify its impact on the population. In a population-based Greenlandic cohort (n = 5,063), we tested for associations between the p.G137S variant and metabolic health traits as well as cardiovascular disease risk based on registry data. In addition, we explored the variant's impact on plasma NMR measured lipoprotein concentration and composition in another Greenlandic cohort (n = 1,629); 29.5% of the individuals in the cohort carried at least one copy of the p.G137S risk allele. Furthermore, 25.4% of the heterozygous and 54.7% of the homozygous carriers had high levels (>4.9 mmol/L) of serum LDL cholesterol, which is above the diagnostic level for familial hypercholesterolemia (FH). Moreover, p.G137S was associated with an overall atherosclerotic lipid profile, and increased risk of ischemic heart disease (HR [95% CI], 1.51 [1.18-1.92], p = 0.00096), peripheral artery disease (1.69 [1.01-2.82], p = 0.046), and coronary operations (1.78 [1.21-2.62], p = 0.0035). Due to its high frequency and large effect sizes, p.G137S has a marked population-level impact, increasing the risk of FH and cardiovascular disease for up to 30% of the Greenlandic population. Thus, p.G137S is a potential marker for early intervention in Arctic populations.

Diet and physical activity in Greenland: genetic interactions and associations with obesity and diabetes.

The Inuit in Greenland have gone through dramatic lifestyle changes during the last half century. More time is spent being sedentary and imported foods replaces traditional foods like seal and whale. The population has also experienced a rapid growth in obesity and metabolic disturbances and diabetes is today common despite being almost unknown few decades ago. In this paper, we describe and discuss the role of lifestyle changes and genetics for Inuit metabolic health. Novelty: Cardiometabolic disease risk has increased in Greenland. Lifestyle changes and possibly gene-lifestyle interactions play a role.

The effect of diabetes and the common diabetogenic TBC1D4 p.Arg684Ter variant on cardiovascular risk in Inuit in Greenland.

Cardiovascular disease (CVD) is a well-known complication of diabetes, but the association has not been studied among Inuit in Greenland. The aim was to examine the association between diabetes and incident CVD among Inuit in Greenland and determine if the common diabetogenic TBC1D4 variant confers increased risk of CVD. We followed an initial study population of 4127 adults in Greenland who had participated in at least one population-based health survey, in national registers. We used Poisson regression to calculate incidence rate ratios (IRR) of cardiovascular endpoints, comparing participants with and without diabetes and comparing homozygous TBC1D4 carriers with heterozygous carriers and non-carriers combined. Close to 10% had diabetes and age range was 18-96 years (45% male). Of the 3924 participants without prior CVD, 362 (~ 9%) had CVD events during a median follow-up of 10 years. Multivariate IRR for the effect of diabetes on CVD was 1.12 (95% CI: 0.80, 1.57) p = 0.50. Using a recessive genetic model, we compared homozygous TBC1D4 carriers with wildtype and heterozygous carriers combined, with a multivariate IRR of 1.20 (95% CI: 0.69, 2.11) p = 0.52. Neither diabetes nor the TBC1D4 variant significantly increased CVD risk among Inuit in Greenland in adjusted models.