Increased Plasma Ferritin Concentration and Low-Grade Inflammation-A Mendelian Randomization Study.

BACKGROUND: It is unknown why increased plasma ferritin concentration predicts all-cause mortality. As low-grade inflammation and increased plasma ferritin concentration are associated with all-cause mortality, we hypothesized that increased plasma ferritin concentration is genetically associated with low-grade inflammation. METHODS: We investigated whether increased plasma ferritin concentration is associated with low-grade inflammation [i.e., increased concentrations of C-reactive protein (CRP) and complement component 3 (C3)] in 62537 individuals from the Danish general population. We also applied a Mendelian randomization approach, using the hemochromatosis genotype C282Y/C282Y as an instrument for increased plasma ferritin concentration, to assess causality. RESULTS: For a doubling in plasma ferritin concentration, the odds ratio (95% CI) for CRP ≥2 vs <2 mg/L was 1.12 (1.09-1.16), with a corresponding genetic estimate for C282Y/C282Y of 1.03 (1.01-1.06). For a doubling in plasma ferritin concentration, odds ratio (95% CI) for complement C3 >1.04 vs ≤1.04 g/L was 1.28 (1.21-1.35), and the corresponding genetic estimate for C282Y/C282Y was 1.06 (1.03-1.12). Mediation analyses showed that 74% (95% CI, 24-123) of the association of C282Y/C282Y with risk of increased CRP and 56% (17%-96%) of the association of C282Y/C282Y with risk of increased complement C3 were mediated through plasma ferritin concentration. CONCLUSIONS: Increased plasma ferritin concentration as a marker of increased iron concentration is associated observationally and genetically with low-grade inflammation, possibly indicating a causal relationship from increased ferritin to inflammation. However, as HFE may also play an immunological role indicating pleiotropy and as incomplete penetrance of C282Y/C282Y indicates buffering mechanisms, these weaknesses in the study design could bias the genetic estimates.

Lactase Persistence, Milk Intake, and Adult Acne: A Mendelian Randomization Study of 20,416 Danish Adults.

Whether there is a causal relationship between milk intake and acne is unknown. We tested the hypothesis that genetically determined milk intake is associated with acne in adults using a Mendelian randomization design. LCT-13910 C/T (rs4988235) is associated with lactase persistence (TT/TC) in Northern Europeans. We investigated the association between milk intake, LCT-13910 C/T (rs4988235), and acne in 20,416 adults (age-range: 20⁻96) from The Danish General Suburban Population Study (GESUS). The adjusted observational odds ratio for acne in any milk intake vs. no milk intake was 0.93(95% confidence interval: 0.48⁻1.78) in females and 0.49(0.22⁻1.08) in males aged 20⁻39 years, and 1.15(95% confidence interval: 0.66⁻1.99) in females and 1.02(0.61⁻1.72) in males above 40 years. The unadjusted odds ratio for acne in TT+TC vs. CC was 0.84(0.43⁻1.62) in the age group 20⁻39 years, and 0.99(0.52⁻1.88) above 40 years. We did not find any observational or genetic association between milk intake and acne in our population of adults.

Dairy Intake and Acne Vulgaris: A Systematic Review and Meta-Analysis of 78,529 Children, Adolescents, and Young Adults.

A meta-analysis can help inform the debate about the epidemiological evidence on dairy intake and development of acne. A systematic literature search of PubMed from inception to 11 December 2017 was performed to estimate the association of dairy intake and acne in children, adolescents, and young adults in observational studies. We estimated the pooled random effects odds ratio (OR) (95% CI), heterogeneity (I²-statistics, Q-statistics), and publication bias. We included 14 studies (n = 78,529; 23,046 acne-cases/55,483 controls) aged 7⁻30 years. ORs for acne were 1.25 (95% CI: 1.15⁻1.36; p = 6.13 × 10-8) for any dairy, 1.22 (1.08⁻1.38; p = 1.62 × 10-3) for full-fat dairy, 1.28 (1.13⁻1.44; p = 8.23 × 10-5) for any milk, 1.22 (1.06⁻1.41; p = 6.66 × 10-3) for whole milk, 1.32 (1.16⁻1.52; p = 4.33 × 10-5) for low-fat/skim milk, 1.22 (1.00⁻1.50; p = 5.21 × 10-2) for cheese, and 1.36 (1.05⁻1.77; p = 2.21 × 10-2) for yogurt compared to no intake. ORs per frequency of any milk intake were 1.24 (0.95⁻1.62) by 2⁻6 glasses per week, 1.41 (1.05⁻1.90) by 1 glass per day, and 1.43 (1.09⁻1.88) by ≥2 glasses per day compared to intake less than weekly. Adjusted results were attenuated and compared unadjusted. There was publication bias (p = 4.71 × 10-3), and heterogeneity in the meta-analyses were explained by dairy and study characteristics. In conclusion, any dairy, such as milk, yogurt, and cheese, was associated with an increased OR for acne in individuals aged 7⁻30 years. However, results should be interpreted with caution due to heterogeneity and bias across studies.

Milk intake is not associated with ischaemic heart disease in observational or Mendelian randomization analyses in 98,529 Danish adults.

BACKGROUND: Observationally, reports on the association between milk intake and risk of ischaemic heart disease (IHD) and myocardial infarction (MI) have produced conflicting results; and no previous large-scale study using the lactase persistent/non-persistent LCT-13910 C/T genotype as a largely unconfounded proxy for milk intake free of reverse causation has been conducted. We tested the hypothesis that milk intake observationally and genetically through the LCT-13910 C/T genotype is associated with risk of IHD and MI in a Mendelian randomization design. METHODS: We included 98,529 White individuals of Danish descent, aged 20-100 years, from three studies of the general population. Information on IHD (N = 10,372) and MI (N = 4188) were obtained from national Danish registries. First, we investigated observational associations between milk intake and incident IHD and MI. Second, we confirmed the association between the rs4988235 genetic variant LCT-13910 C/T, associated with lactase persistence/non-persistence, and milk intake. Finally, we tested whether LCT-13910 C/T genotype was associated with risk of IHD and MI as well as with cardiovascular risk factors. RESULTS: During a mean follow-up time of 5.4 years, the observational hazard ratio for a 1 glass/week higher milk intake was 1.00 [95% confidence interval (CI): 1.00,1.01] for both IHD and MI. Median milk intake was 3 glasses/week (interquartile range: 0-7) in lactase CC non-persistent individuals compared with 5 glasses/week (0-10) in lactase TC/TT persistent individuals (P = 3*10(-60)). In the dominant genetic model comparing lactase TC/TT persistent individuals with lactase CC non-persistent individuals, the odds ratio was 1.00 (0.92,1.09) for IHD and 0.96 (0.84,1.09) for MI. Finally, in the dominant genetic model genotype was not associated convincingly with plasma levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides or glucose, nor with blood pressure. CONCLUSION: Milk intake was not associated with risk of IHD or MI, observationally or genetically.

Milk intake is not associated with low risk of diabetes or overweight-obesity: a Mendelian randomization study in 97,811 Danish individuals.

BACKGROUND: High dairy/milk intake has been associated with a low risk of type 2 diabetes observationally, but whether this represents a causal association is unknown. OBJECTIVE: We tested the hypothesis that high milk intake is associated with a low risk of type 2 diabetes and of overweight-obesity, observationally and genetically. DESIGN: In 97,811 individuals from the Danish general population, we examined the risk of incident type 2 diabetes and of overweight-obesity by milk intake observationally and by LCT-13910 C/T genotype [polymorphism (rs4988235) upstream from the lactase (LCT) gene], where TT and TC genotypes are associated with lactase persistence and CC with nonpersistence. RESULTS: Observationally for any compared with no milk intake, the HR for type 2 diabetes was 1.10 (95% CI: 0.98, 1.24; P = 0.11), whereas the OR for overweight-obesity was 1.06 (1.02, 1.09; P = 0.002). Median milk intake was 5 glasses/wk (IQR: 0-10) for lactase TT/TC persistence and 3 (0-7) for CC nonpersistence. Genetically for lactase TT/TC persistence compared with CC nonpersistence, the OR was 0.96 (0.86, 1.08; P = 0.50) for type 2 diabetes and 1.06 (1.00, 1.12; P = 0.04) for overweight-obesity. In a stratified analysis for type 2 diabetes, corresponding values in those with and without milk intake were 0.88 (0.76, 1.03; P = 0.11) and 1.35 (1.07, 1.70; P = 0.01) (P-interaction: 0.002), whereas no gene-milk interaction on overweight-obesity was found. For a 1-glass/wk higher milk intake, the genetic risk ratio for type 2 diabetes was 0.99 (0.93, 1.06), and the corresponding observational risk was 1.01 (1.00, 1.01). For overweight-obesity, the corresponding values were 1.01 (1.00, 1.02) genetically and 1.00 (1.00, 1.01) observationally. CONCLUSIONS: High milk intake is not associated with a low risk of type 2 diabetes or overweight-obesity, observationally or genetically via lactase persistence. The higher risk of type 2 diabetes in lactase-persistent individuals without milk intake likely is explained by collider stratification bias.

Study design, participation and characteristics of the Danish General Suburban Population Study.

INTRODUCTION: The aim of this article was to describe the study design, participants and baseline characteristics of The Danish General Suburban Population Study (GESUS) and to compare suburban participants with age- and gender-matched urban participants from the Copenhagen General Population Study (CGPS). MATERIAL AND METHODS: Data from questionnaire, health examination, biochemical measurements and public registers were collected. RESULTS: In GESUS the overall participation rate was 49.3% (response n = 10,621 of total n = 21,557). Among people aged 40-79 years, the participation rate was 53.9% (8,797/16,310). Participants were more frequently women, had a higher median age, a higher frequency of marriage/registered partnerships, but had a lower frequency of co-morbidities and death in the follow-up period (January 2010-May 2011 (diseases)/June 2011 (death) than the non-participants. GESUS has sufficient power to study effects of rare and common exposures or genetic variants on the occurrence of common multifactorial diseases. Compared with an age- and gender-matched urban population (n = 10,618, CGPS), participants in GESUS (n = 10,618) were less physically active, smoked less and ingested less alcohol, had higher anthropometric measures, less undiagnosed hypertension but more undiagnosed diabetes, had a lower frequency of elevated total cholesterol and low-density lipoprotein chol-esterol but higher frequency of decreased high-density lipoprotein cholesterol and elevated triglycerides. CONCLUSION: In GESUS, participants had a better health profile than non-participants, and participants in GESUS had a different cardiovascular risk profile than participants in the CGPS. FUNDING: The study received funding from the following: Johan and Lise Boserup Foundation; TrygFonden; Det Kommunale Momsfond; Johannes Fog's Foundation; Region Zealand; Region Zealand Foundation; Naestved Hospital; Naestved Hospital Foundation; The National Board of Health; Danish Agency for Science, Technology and Innovation. TRIAL REGISTRATION: not relevant.