Use of postmenopausal hormone therapy and risk of Alzheimer's disease in Finland: nationwide case-control study

OBJECTIVESTo compare the use of hormone therapy between Finnish postmenopausal women with and without a diagnosis for Alzheimer's disease.DESIGNNationwide case-control study.SETTINGFinnish national population and drug register, between 1999 and 2013.PARTICIPANTSAll postmenopausal women (n= 84 739) in Finland who, between 1999 and 2013, received a diagnosis of Alzheimer's disease from a neurologist or geriatrician, and who were identified from a national drug register. Control women without a diagnosis (n= 84 739), matched by age and hospital district, were traced from the Finnish national population register.INTERVENTIONSData on hormone therapy use were obtained from the Finnish national drug reimbursement register.MAIN OUTCOME MEASURESOdds ratios and 95% confidence intervals for Alzheimer's disease, calculated with conditional logistic regression analysis.RESULTSIn 83 688 (98.8%) women, a diagnosis for Alzheimer's disease was made at the age of 60 years or older, and 47 239 (55.7%) women had been over 80 years of age at diagnosis. Use of systemic hormone therapy was associated with a 9-17% increased risk of Alzheimer's disease. The risk of the disease did not differ significantly between users of estradiol only (odds ratio 1.09, 95% confidence interval 1.05 to 1.14) and those of oestrogen-progestogen (1.17, 1.13 to 1.21). The risk increases in users of oestrogen-progestogen therapy were not related to different progestogens (noreth isterone acetate, medroxyprogesterone acetate, or other progestogens); but in women younger than 60 at hormone therapy initiation, these risk increases were associated with hormone therapy exposure over 10 years. Furthermore, the age at initiation of systemic hormone therapy was not a decisive determinant for the increase in risk of Alzheimer's disease. The exclusive use of vaginal estradiol did not affect the risk of the disease (0.99, 0.96 to 1.01).CONCLUSIONSLong term use of systemic hormone therapy might be accompanied with an overall increased risk of Alzheimer's disease, which is not related to the type of progestogen or the age at initiation of systemic hormone therapy. By contrast, use of vaginal estradiol shows no such risk. Even though the absolute risk increase for Alzheimer's disease is small, our data should be implemented into information for present and future users of hormone therapy

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Mining the human phenome using allelic scores that index biological intermediates

J. Kaprio ja M-L. Lokki työryhmien jäseniä.It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.Peer reviewe

Average demands and most demanding passages of national-level female soccer matches : do small- and large-sided games replicate match demands?

Introduction: This study aims to (1) determine the average and most demanding passage (MDP) load of national-level female soccer matches and (2) evaluate the relationship between average and MDP load during small-sided games (SSGs), large-sided games (LSGs), and matches. Methods: A total of 37 national-level female soccer players from a single club senior team and the U18 team participated. The average and 1-, 3-, and 5-min MDP external (total, high-speed, and very-high-speed running distances, acceleration and deceleration distances, average metabolic power, and high-metabolic load distance) and internal loads (average heart rate, rate of perceived exertion) of the 29 league matches, ten 4 vs. 4 + goalkeepers SSGs, and six 8 vs. 8 + goalkeepers LSGs were analyzed by the Polar Team Pro player tracking system. Results: In matches, the external load variables during 1-, 3-, and 5-min MDPs were 167%–1,165%, 135%–504%, and 126%–359%, of match average values, respectively. In LSGs, all external load variables reached higher average values compared with those during matches, except for the very-high-speed running distance; however, no variable reached higher values of 1-min MDP compared with those during the matches. In SSGs, the average acceleration and deceleration distances were higher compared with those during the matches. Discussion: The findings from the present study suggest that LSGs and SSGs can be used to overload the average values of the selected external load variables compared with those during the matches; however, other training options must be explored to overload 1-min match MDPs.peerReviewe

Image1_Average demands and most demanding passages of national-level female soccer matches: do small- and large-sided games replicate match demands?.jpeg

IntroductionThis study aims to (1) determine the average and most demanding passage (MDP) load of national-level female soccer matches and (2) evaluate the relationship between average and MDP load during small-sided games (SSGs), large-sided games (LSGs), and matches.MethodsA total of 37 national-level female soccer players from a single club senior team and the U18 team participated. The average and 1-, 3-, and 5-min MDP external (total, high-speed, and very-high-speed running distances, acceleration and deceleration distances, average metabolic power, and high-metabolic load distance) and internal loads (average heart rate, rate of perceived exertion) of the 29 league matches, ten 4 vs. 4 + goalkeepers SSGs, and six 8 vs. 8 + goalkeepers LSGs were analyzed by the Polar Team Pro player tracking system.ResultsIn matches, the external load variables during 1-, 3-, and 5-min MDPs were 167%–1,165%, 135%–504%, and 126%–359%, of match average values, respectively. In LSGs, all external load variables reached higher average values compared with those during matches, except for the very-high-speed running distance; however, no variable reached higher values of 1-min MDP compared with those during the matches. In SSGs, the average acceleration and deceleration distances were higher compared with those during the matches.DiscussionThe findings from the present study suggest that LSGs and SSGs can be used to overload the average values of the selected external load variables compared with those during the matches; however, other training options must be explored to overload 1-min match MDPs.</p

Image2_Average demands and most demanding passages of national-level female soccer matches: do small- and large-sided games replicate match demands?.jpeg

IntroductionThis study aims to (1) determine the average and most demanding passage (MDP) load of national-level female soccer matches and (2) evaluate the relationship between average and MDP load during small-sided games (SSGs), large-sided games (LSGs), and matches.MethodsA total of 37 national-level female soccer players from a single club senior team and the U18 team participated. The average and 1-, 3-, and 5-min MDP external (total, high-speed, and very-high-speed running distances, acceleration and deceleration distances, average metabolic power, and high-metabolic load distance) and internal loads (average heart rate, rate of perceived exertion) of the 29 league matches, ten 4 vs. 4 + goalkeepers SSGs, and six 8 vs. 8 + goalkeepers LSGs were analyzed by the Polar Team Pro player tracking system.ResultsIn matches, the external load variables during 1-, 3-, and 5-min MDPs were 167%–1,165%, 135%–504%, and 126%–359%, of match average values, respectively. In LSGs, all external load variables reached higher average values compared with those during matches, except for the very-high-speed running distance; however, no variable reached higher values of 1-min MDP compared with those during the matches. In SSGs, the average acceleration and deceleration distances were higher compared with those during the matches.DiscussionThe findings from the present study suggest that LSGs and SSGs can be used to overload the average values of the selected external load variables compared with those during the matches; however, other training options must be explored to overload 1-min match MDPs.</p