Novel genes and sex differences in COVID-19 severity.

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

Beneficial effects of liraglutide on adipocytokines, insulin sensitivity parameters and cardiovascular risk biomarkers in patients with Type 2 diabetes: a prospective study.

AIMS: To evaluate the effects of liraglutide after 14 weeks of treatment on serum adipokines, insulin resistance index and cardiovascular risk biomarkers in overweight or obese T2DM patients unable to achieve glycemic control with metformin alone or in association with a sulfonylurea in daily clinical practice. METHODS: Prospective study in 59 consecutive overweight or obese (BMI≥25kg/m(2)) T2DM patients unable to achieve glycemic control (HbA1c>7%, 53mmol/mol) with metformin alone or in association with sulfonylurea that require initiation of liraglutide in progressive dose increase up to 1.8mg/day subcutaneously. Weight, body composition, blood pressure, glucose, HbA1c, C-peptide, insulin, plasma lipids, adipokines (leptin, adiponectin, resistin and visfatin) as well as cardiovascular biomarkers (IL-6 and TNF-a) levels were measured fasting at baseline and 14 weeks after liraglutide initiation. RESULTS: 14 weeks of liraglutide treatment significantly reduced HbA1c, BMI and total body fat mass by 0.9%, 1.4kg/m(2) and 0.5% respectively. Statistically significant lower insulin resistance and higher insulin secretion was found by HOMA-IR 8.4 (1.6) vs 4.6 (0.9)molmIU/L(2) and HOMA-B 48.2 (9.0) vs 87.6 (16.3)µIU/mmol. Statistically significantly higher levels of visfatin 6.3 (2.1) vs 6.8 (2.1)ng/ml and resistin 3.6 (2.0) vs 4.3 (2.3)ng/ml were also observed after treatment. Baseline visfatin was negatively correlated with basal fasting plasma glucose r=-0.360 (p<0.05). CONCLUSIONS: Liraglutide treatment for 14 weeks in daily clinical practice led to reduction of BMI and improvement of glucose control and insulin sensitivity and resistance parameters. Additionally, circulating levels of adipokines and pro-inflammatory factors could play an important role in GLP-1 treatment response.

Relation of -55CT polymorphism of uncoupling protein 3 gene with fat mass and insulin resistance in morbidly obese patients.

Some studies have pointed to a role of uncoupling protein 3 (UCP3) in the regulation of whole-body energy homoeostasis and regulation of fat distribution. The aim of our study was to investigate the influence of -55CT polymorphism of UCP3 gene on fat mass and insulin resistance in morbidly obese patients. A population of 47 obese subjects (body mass index [BMI] >40 kg/m(2)) was selected randomly in a prospective way. A nutritional evaluation was performed. Dietary intake and exercise were recorded. The mean age was 48.2 +/- 15.4 years; and the BMI was 44.7 +/- 4.7 kg/m(2), with 10 men (21.3%) and 37 women (78.7%). Thirty-two (68.1%) had the genotype -55CC (wild-type group), and 15 patients (31.9%) had -55CT (mutant-type group). In the mutant-type group, insulin (20.6+/-10.8 vs 31.2 +/- 17.4 mIU/L, P < .05), homeostasis model assessment (5.3 +/- 2.7 vs 8.7 6.6, P < .05), weight (114.1 +/- 17.3 vs 122.8+/-19.1 kg, P < .05), BMI (44.1 +/- 4.6 vs 45.7 +/- 6.3 kg/m(2), P < .05), fat mass (56.3 +/- 11.4 vs 61.4 +/- 15.1 kg, P < .05), and waist circumference (124.8 +/- 12.5 vs 128.3 +/- 9.1 cm, P < .05) were higher than those in the wild-type group. Adiponectin levels were higher in wild-type group than mutant-type group (70.3 +/- 26.1 vs 30.5 +/- 32.5 ng/mL, P < .05). In conclusion, mutant-type group of -55CC UCP3 gene patients had higher weight, fat mass, and insulin resistance than wild-type group.