Johan Svensson

The gut microbiota is associated with human health and disease. Here we conducted a genome-wide association study of host genetic factors influencing gut microbiota composition in 12,652 individuals from the Trøndelag Health Study (HUNT), with replication in Nordic cohorts ( n = 16,017–21,976). We identified 12 reproducible SNP–species associations across six genomic loci, including known ( LCT , ABO ) and novel ( HLA-DQB1 , MUC12 , SLC37A2 , FUT2 ) regions. Additionally, we detected genetic signals associated with gut microbiota functional modules at three loci ( LCT , ABO , FUT2 ). Follow-up analyses suggest that these host–microbiota associations are linked to the pathogenesis of celiac disease and hemorrhoidal disease. Mendelian randomization analyses provided evidence supporting a causal effect of body mass index on gut microbiota composition. These findings highlight the interplay between host genetics and gut microbiota for human health and disease.

Background: Markers of synaptic degeneration and neuroinflammation have been investigated in memory clinic cohorts, but less is known about their role in community-dwelling subjects. Objective: To investigate baseline cerebrospinal fluid (CSF) levels of neurogranin and YKL-40 in community-dwelling subjects with mild cognitive impairment (MCI) who had not yet sought help for their cognitive decline. Methods: We recruited and characterized 107 subjects, who at the clinical baseline examination were found to have MCI. Based on the clinical progression at a 3-year follow-up, the individuals were classified as MCI-Alzheimer's disease (MCI-AD, n = 40), MCI-vascular dementia (MCI-VaD, n = 25), and stable MCI (sMCI, n = 42). Results: Baseline CSF neurogranin level was elevated in the MCI-AD group compared with the MCI-VaD and sMCI groups (p = 0.02 and p < 0.001, respectively), and baseline CSF YKL-40 level was higher in the MCI-AD group than in the sMCI group (p = 0.01). Neurogranin, and to a lesser extent YKL-40, correlated positively with CSF levels of total tau and phosphorylated tau ₁₈₁ in all study groups. However, in receiver operator characteristics analyses, neurogranin and YKL-40 used alone or in combination had a moderate diagnostic accuracy that was lower than that of the core AD biomarkers (amyloid-β ₄₂ , total tau, and phosphorylated tau ₁₈₁ ). Conclusions: This study shows that neurogranin and YKL-40 in CSF are elevated in MCI-AD compared with sMCI, and neurogranin was also higher in MCI-AD than in MCI-VaD. Neurogranin and YKL-40 had a moderate diagnostic accuracy, but they could still be of value to characterize the clinical consequences of postsynaptic dysfunction and neuroinflammation.

Background: It is unclear whether thyroid hormone levels are associated with the risk of mortality, cardiovascular disease (CVD) events, or cancer in men with normal TSH. Objectives: We analyzed if serum free T4 (FT4) or TSH is associated with the risk of mortality, incident CVD events, or cancer in Swedish men. Methods: Elderly men (n = 1801; mean age 75 years) in the Gothenburg and Malmö subcohorts of the prospective, population-based Osteoporotic Fractures in Men Study-Sweden study were followed for median 12.2 years regarding all-cause mortality [1207 (67%) died] and for median 5.1 years regarding incident CVD events (n = 338) and cancer (n = 249). The statistical analyses included Cox proportional hazards regression with adjustment for covariates including prevalent atrial fibrillation (AF). Results: Serum FT4 (per SD increase) was associated with increased risk of mortality [men with normal TSH: fully adjusted hazard ratio (HR) 1.23, 95% confidence interval (CI): 1.11-1.35] and incident CVD events (HR 1.25, 95% CI: 1.05-1.48) but not with the risk of cancer. The association between FT4 and CVD events was mainly due to increased risk of cerebrovascular (CBV) events (HR 1.56, 95% CI: 1.24-1.96). Finally, TSH was not associated with the risk of mortality, CVD events, or cancer. Conclusion: FT4, but not TSH, is a predictor of mortality risk in elderly men. The association between FT4 and elevated risk of CVD events was mostly due to increased risk of CBV events, which remained significant also after adjustment for prevalent AF.

Both high serum insulin-like growth factor-binding protein-1 (s-IGFBP-1) and insulin resistance (IR) are associated with poor functional outcome poststroke, whereas overweight body mass index (BMI; 25–30) is related to fewer deaths and favorable functional outcome in a phenomenon labeled “the obesity paradox”. Furthermore, IGFBP-1 is inversely related to BMI, in contrast to the linear relation between IR and BMI. Here, we investigated s-IGFBP-1 and IR concerning BMI and 7-year poststroke functional outcome. We included 451 stroke patients from the Sahlgrenska Study on Ischemic Stroke (SAHLSIS) with baseline measurements of s-IGFBP1, homeostasis model assessment of IR (HOMA-IR), BMI (categories: normal-weight (8.5–25), overweight (25–30), and obesity (>30)), and high-sensitivity C-reactive protein (hs-CRP) as a measure of general inflammation. Associations with poor functional outcome (modified Rankin scale [mRS] score: 3–6) after 7 years were evaluated using multivariable binary logistic regression, with overweight as reference due to the nonlinear relationship. Both normal-weight (odds-ratio [OR] 2.32, 95% confidence interval [CI] 1.30–4.14) and obese (OR 2.25, 95% CI 1.08–4.71) patients had an increased risk of poor functional outcome, driven by deaths only in the normal-weight. In normal-weight, s-IGFBP-1 modestly attenuated (8.3%) this association. In the obese, the association was instead attenuated by HOMA-IR (22.4%) and hs-CRP (10.4%). Thus, a nonlinear relation between BMI and poor 7-year functional outcome was differently attenuated in the normal-weight and the obese.

Overt and subclinical hyperthyroidism are associated with an increased fracture risk, but whether thyroid hormones are associated with fracture risk in individuals with normal thyroid-stimulating hormone (TSH) has mostly been investigated in women. Therefore, we investigated if serum levels of free thyroxine (FT4) or TSH are associated with fracture risk in Swedish men. We followed (median 12.2 yr) elderly men (n = 1825; mean age 75, range 69–81 yr) participating in the Gothenburg and Malmö subcohorts of the prospective, population-based MrOS-Sweden study. The statistical analyses included Cox proportional hazards regression. Men receiving levothyroxine treatment were excluded. In our total cohort, serum FT4 (per SD increase) was associated with increased risk of major osteoporotic fractures (MOFs; n = 479; fully adjusted hazard ratio [HR] 1.14, 95% CI, 1.05–1.24) and hip fractures (n = 207; HR 1.18, 95% CI, 1.04–1.33). Also, in men with normal TSH (n = 1658), FT4 (per SD increase) was significantly associated with increased risk of MOF and hip fractures. Furthermore, men in the highest FT4 quartile had a 1.5-fold increase in hip fracture risk compared with men in the three lower FT4 quartiles, both in the total population and in men with normal TSH (fully adjusted: HR 1.45, 95% CI, 1.04–2.02 and HR 1.51, 95% CI, 1.07–2.12, respectively). In contrast, the risk of MOF was not statistically different in the highest FT4 quartile compared with the three lower FT4 quartiles. Finally, serum TSH was not associated with fracture risk after full adjustment for covariates. In conclusion, serum FT4, but not serum TSH, is a predictor of hip fracture risk in elderly Swedish men. Additionally, there was an association between FT4 (per SD increase) and the risk of MOF.

Insulin-like growth factor-I (IGF-I) levels, which are reduced by age, and cortical bone dimensions are major determinants of fracture risk in elderly subjects. Inactivation of liver-derived circulating IGF-I results in reduced periosteal bone expansion in young and older mice. In mice with lifelong depletion of IGF-I in osteoblast lineage cells, the long bones display reduced cortical bone width. However, it has not previously been investigated whether inducible inactivation of IGF-I locally in bone in adult/old mice affects the bone phenotype. Adult tamoxifen-inducible inactivation of IGF-I using a CAGG-CreER mouse model (inducible IGF-I^KO mice) substantially reduced IGF-I expression in bone (−55%) but not in liver. Serum IGF-I and body weight were unchanged. We used this inducible mouse model to assess the effect of local IGF-I on the skeleton in adult male mice, avoiding confounding developmental effects. After tamoxifen-induced inactivation of the IGF-I gene at 9 months of age, the skeletal phenotype was determined at 14 months of age. Computed tomography analyses of tibia revealed that the mid-diaphyseal cortical periosteal and endosteal circumferences and calculated bone strength parameters were decreased in inducible IGF-I^KO mice compared with controls. Furthermore, 3-point bending showed reduced tibia cortical bone stiffness in inducible IGF-I^KO mice. In contrast, the tibia and vertebral trabecular bone volume fraction was unchanged. In conclusion, inactivation of IGF-I in cortical bone with unchanged liver-derived IGF-I in older male mice resulted in reduced radial growth of cortical bone. This suggests that not only circulating IGF-I but also locally derived IGF-I regulates the cortical bone phenotype in older mice.

Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates insulin-like growth factor-I (IGF-I) bioactivity, and is a central player in normal growth, metabolism, and stroke recovery. However, the role of serum IGFBP-1 (s-IGFBP-1) after ischemic stroke is unclear. We determined whether s-IGFBP-1 is predictive of poststroke outcome. The study population comprised patients (n = 470) and controls (n = 471) from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). Functional outcome was evaluated after 3 months, 2, and 7 years using the modified Rankin Scale (mRS). Survival was followed for a minimum of 7 years or until death. S-IGFBP-1 was increased after 3 months (p < 0.01), but not in the acute phase after stroke, compared with the controls. Higher acute s-IGFBP-1 was associated with poor functional outcome (mRS score > 2) after 7 years [fully adjusted odds ratio (OR) per log increase 2.9, 95% confidence interval (CI): 1.4-5.9]. Moreover, higher s-IGFBP-1 after 3 months was associated with a risk of poor functional outcome after 2 and 7 years (fully adjusted: OR 3.4, 95% CI: 1.4–8.5 and OR 5.7, 95% CI: 2.5–12.8, respectively) and with increased mortality risk (fully adjusted: HR 2.0, 95% CI: 1.1–3.7). Thus, high acute s-IGFBP-1 was only associated with poor functional outcome after 7 years, whereas s-IGFBP-1 after 3 months was an independent predictor of poor long-term functional outcome and poststroke mortality.