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Thomas M.C.,Baker IDI Heart and Diabetes Institute | Groop P.-H.,Baker IDI Heart and Diabetes Institute | Groop P.-H.,Folkhalsan Institute of Genetics | Groop P.-H.,University of Helsinki | Tryggvason K.,Matrix
Current Opinion in Nephrology and Hypertension | Year: 2012

Purpose of review: The burden of nephropathy is unequally shared across patients with diabetes. The majority of the variability in incident nephropathy remains unaccounted for by conventional risk factors. There appears to be an inherited predisposition for diabetic nephropathy, but this does not follow simple Mendelian rules. Any inherited predisposition for nephropathy is far more complicated. This article reviews the recent advances in understanding of the genetics and epigenetics of diabetic nephropathy. Recent findings: A few candidate genes have been reproducibly associated with diabetic nephropathy, and recent genome-wide linkage studies have also identified chromosomal loci for susceptibility genes, including 3q, 7q, 10p, 14q and 18q. Unbiased, genome-wide linkage studies have identified specific loci and genome-wide association studies a number of new loci. However, any roles of those genes in the molecular pathobiology remain to be established. Moreover, their individual contribution to the variability in incident nephropathy in diabetes appears to be small. Summary: New genome-wide approaches offer new opportunities to identify genes associated with diabetic nephropathy. However, such approaches have key limitations. Upto the present time, genetic testing has failed to identify a gene or combination of genes that will substantially identify those patients most at risk for diabetic nephropathy. It may be that epigenetic regulation of gene expression may represent a more important contributor to an inherited predisposition to diabetic nephropathy. Nonetheless, genetic studies may provide valuable information regarding the pathobiology of nephropathy and potential targets for its treatment. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Lukashevich V.,Novartis | Schweizer A.,Novartis | Shao Q.,Novartis | Groop P.-H.,University of Helsinki | And 2 more authors.
Diabetes, Obesity and Metabolism | Year: 2011

Aim: Assess safety/tolerability and efficacy of the DPP-4 inhibitor vildagliptin in 515 patients with type 2 diabetes mellitus (T2DM) and moderate or severe renal impairment (RI). Methods: Double-blind, randomized, parallel-group, placebo-controlled, 24-week clinical trial assessing safety and efficacy of vildagliptin (50 mg qd) added to current antidiabetic therapy, in patients with T2DM and moderate or severe RI (GFR ≥ 30 to <50 or <30 ml/min/1.73 m2). Results: The study population comprised of 165 and 129 patients with moderate RI and 124 and 97 patients with severe RI randomized to vildagliptin and placebo, respectively, with most patients receiving background insulin therapy (68 and 81% for moderate and severe RI, respectively). After 24 weeks, the between-treatment difference in the adjusted mean change in A1C was -0.5 ± 0.1% (p < 0.0001) in moderate RI (baseline A1C = 7.9%) and -0.6 ± 0.1% (p < 0.0001) in severe RI (baseline A1C = 7.7%). In patients with moderate RI, similar proportions of those receiving vildagliptin or placebo experienced any AE (68 vs. 73%), any SAE (9 vs. 9%), any AE leading to discontinuation (3 vs. 5%) or death (1 vs. 1%). This was also true for patients with severe RI: AEs (73 vs. 74%), SAEs (19 vs. 21%), AEs leading to discontinuation (9 vs. 6%) and death (2 vs. 4%). Conclusions: In this 24-week study of 515 patients with T2DM and moderate or severe RI, vildagliptin added to ongoing antidiabetic therapy had a safety profile similar to placebo. Further, relative to placebo, vildagliptin elicited a statistically and clinically significant decrease in A1C in patients with moderate or severe RI. © 2011 Blackwell Publishing Ltd.


Fellman J.,Folkhalsan Institute of Genetics | Eriksson A.W.,Folkhalsan Institute of Genetics
Twin Research and Human Genetics | Year: 2013

Numerous papers have investigated the distribution of birth weight. This interest arises from the association between birth weight and the future health condition of the child. Birth weight distribution commonly differs slightly from the Gaussian distribution. The distribution is typically split into two components: a predominant Gaussian distribution and an unspecified 'residual' distribution. In this study, we consider birth weight data from the Åland Islands (Finland) for the period 1885-1998. We compare birth weight between males and females and among singletons and twins. Our study confirms that, on average, birth weight was highest among singletons, medium among twins, and lowest among triplets. A marked difference in the mean birth weight between singleton males and females was found. For singletons, the distribution of birth weight differed significantly from the normal distribution, but for twins the normal distribution held. © 2013 The Authors.


Groop P.-H.,Folkhalsan Institute of Genetics | Groop P.-H.,University of Helsinki | Groop P.-H.,Baker IDI Heart and Diabetes Institute | Cooper M.E.,Baker IDI Heart and Diabetes Institute | And 4 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-Preclinical data suggest that linagliptin, a dipeptidyl peptidase-4 inhibitor, may lower urinary albumin excretion. The ability of linagliptin to lower albuminuria on top of reninangiotensin- aldosterone system(RAAS) inhibition in humans was analyzed by pooling data from four similarly designed, 24-week, randomized, double-blind, placebo-controlled, phase III trials. RESEARCH DESIGN AND METHODSdA pooled analysis of four completed studies identified 217 subjects with type 2 diabetes and prevalent albuminuria (defined as a urinary albumin-to-creatinine ratio [UACR] of 3023,000mg/g creatinine) while receiving stable doses of RAAS inhibitors. Participants were randomized to either linagliptin 5 mg/day (n = 162) or placebo (n = 55). The primary end point was the percentage change in geometric mean UACR from baseline to week 24. RESULTS-UACR at week 24 was reduced by 32% (95% CI 242 to 221; P < 0.05) with linagliptin compared with 6% (95% CI 227 to +23) with placebo, with a between-group difference of 28% (95% CI 247 to 22; P = 0.0357). The between-group difference in the change in HbA1c from baseline to week 24 was 20.61% (26.7 mmol/mol) in favor of linagliptin (95% CI 20.88 to 20.34% [29.6 to 23.7 mmol/mol]; P < 0.0001). The albuminuria-lowering effect of linagliptin, however, was not influenced by race or HbA1c and systolic blood pressure (SBP) values at baseline or after treatment. CONCLUSIONS-Linagliptin administered in addition to stable RAAS inhibitors led to a significant reduction in albuminuria in patients with type 2 diabetes and renal dysfunction. This observation was independent of changes in glucose level or SBP. Further research to prospectively investigate the renal effects of linagliptin is underway. © 2013 by the American Diabetes Association.


Fellman J.,Folkhalsan Institute of Genetics | Eriksson A.W.,Folkhalsan Institute of Genetics
Biodemography and Social Biology | Year: 2011

Attempts have been made to identify factors influencing the number of males per 100 females at birth, also called the secondary sex ratio. It has been proposed to vary inversely with the frequency of prenatal losses, but available data lend at best only weak support for this hypothesis. Statistical analyses have shown that comparisons between secondary sex ratios demand large data sets. Variations in the secondary sex ratio that have been reliably identified in family data have mostly been slight and without a notable influence on national birth registers. For Sweden, 1751-1950, the secondary sex ratio among all births and live births revealed increasing trends. The Swedish results are compared with available findings for live births in Finland, Norway, Denmark, and the small Icelandic population. For Norway and Denmark, the secondary sex ratio increased during 1801-1950. A similar, but stronger pattern was observed for Finland (1751-1950) and Iceland (1838-1950). During the latter half of the twentieth century, marked decreases were observed in all countries. Attempts to identify reliable associations between secondary sex ratios and stillbirth rates have been made, but no consistent results have emerged. Copyright © 2011 Society for the Study of Social Biology.


Unverricht-Lundborg type progressive myoclonus epilepsy (EPM1, OMIM 254800) is an autosomal recessive disorder characterized by onset at the age of 6 to 16 years, incapacitating stimulus-sensitive myoclonus and tonic-clonic epileptic seizures. It is caused by mutations in the gene encoding cystatin B. Previously, widespread white matter changes and atrophy has been detected both in adult EPM1 patients and in 6-month-old cystatin B-deficient mice, a mouse model for the EPM1 disease. In order to elucidate the spatiotemporal dynamics of the brain atrophy and white matter changes in EPM1, we conducted longitudinal in vivo magnetic resonance imaging and ex vivo diffusion tensor imaging accompanied with tract-based spatial statistics analysis to compare volumetric changes and fractional anisotropy in the brains of 1 to 6 months of age cystatin B-deficient and control mice. The results reveal progressive but non-uniform volume loss of the cystatin B-deficient mouse brains, indicating that different neuronal populations possess distinct sensitivity to the damage caused by cystatin B deficiency. The diffusion tensor imaging data reveal early and progressive white matter alterations in cystatin B-deficient mice affecting all major tracts. The results also indicate that the white matter damage in the cystatin B-deficient brain is most likely secondary to glial activation and neurodegenerative events rather than a primary result of CSTB deficiency. The data also show that diffusion tensor imaging combined with TBSS analysis provides a feasible approach not only to follow white matter damage in neurodegenerative mouse models but also to detect fractional anisotropy changes related to normal white matter maturation and reorganisation.


Fellman J.,Folkhalsan Institute of Genetics | Eriksson A.W.,Folkhalsan Institute of Genetics
Twin Research and Human Genetics | Year: 2010

Attempts have been made to identify factors influencing the sex ratio at birth (number of males per 100 females). Statistical analyses have shown that comparisons between sex ratios demand large data sets. The secondary sex ratio has been believed to vary inversely with the frequency of prenatal losses. This hypothesis suggests that the ratio is highest among singletons, medium among twins and lowest among triplets. Birth data in Sweden for the period 1869-2004 showed that among live births the secondary sex ratio was on average 105.9 among singletons, 103.2 among twins and 99.1 among triplets. The secondary sex ratio among stillbirths for both singletons and twins started at a high level, around 130, in the 1860s, but approached live birth values in the 1990s. This trend is associated with the decrease and convergence of stillbirth rates among males and females. For detailed studies, we considered data for Sweden in 1869-1878 and in 1901-1967. Marital status or place of residence (urban or rural) had no marked influence on the secondary sex ratio among twins. For triplets, the sex ratio showed large random fluctuations and was on average low. During the period 1901-1967, 20 quadruplet, two quintuplet and one sextuplet set were registered. The sex ratio was low, around 92.0.


Pussinen P.J.,University of Helsinki | Havulinna A.S.,Finnish National Institute for Health and Welfare | Lehto M.,Folkhalsan Institute of Genetics | Lehto M.,University of Helsinki | And 2 more authors.
Diabetes Care | Year: 2011

OBJECTIVE - Diabetes is accompanied with a chronic low-grade inflammation, which may in part be mediated by endotoxins derived from Gram-negative bacteria. RESEARCH DESIGN AND METHODS - We investigated in a population-based cohort whether endotoxemia is associated with clinically incident diabetes. The serum endotoxin activity was measured by limulus assay from the FINRISK97 cohort comprising 7,169 subjects aged 25-74 years and followed up for 10 years. RESULTS - Both the subjects with prevalent diabetes (n = 537) and those with incident diabetes (n = 462) had higher endotoxin activity than the nondiabetic individuals (P < 0.001). The endotoxin activity was significantly associated with increased risk for incident diabetes with a hazard ratio 1.004 (95% CI 1.001-1.007; P = 0.019) per unit increase resulting in a 52% increased risk (P = 0.013) in the highest quartile comparedwith the lowest one. The association was independent of diabetes risk factors: serum lipids, γ-glutamyl transferase, C-reactive protein, BMI, and blood glucose. Furthermore, the association of endotoxemia with an increased risk of incident diabetes was independent of the metabolic syndrome as defined either by the National Cholesterol Educational Program-Adult Treatment Panel III or the International Diabetes Federation. Endotoxin activity was linearly related (P < 0.001) to the number of components of the metabolic syndrome. CONCLUSIONS - Both prevalent and incident diabetes were associated with endotoxemia, which may link metabolic disorders to inflammation. The results suggest that microbes play a role in the pathogenesis of diabetes. © 2011 by the American Diabetes Association.


Ahola A.J.,Folkhalsan Institute of Genetics
Diabetic medicine : a journal of the British Diabetic Association | Year: 2013

People with diabetes hold major responsibility for the day-to-day management of their chronic condition. The management that, amongst others, includes blood glucose monitoring, medication taking, diet and physical activity, aims at normalizing blood glucose levels. In many individuals, the level of glycaemia, however, frequently exceeds the recommendations. This observation, together with patients' and practitioners' reports, suggests that active self-management is suboptimal. Various reasons, both individual and environment related, contribute to the suboptimal concordance with treatment regimen. The aim of this review is to discuss some of the barriers to optimal diabetes self-management. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.


Kollmann K.,University of Hamburg | Uusi-Rauva K.,Folkhalsan Institute of Genetics | Uusi-Rauva K.,Finnish National Institute for Health and Welfare | Scifo E.,University of Helsinki | And 3 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2013

Neuronal ceroid lipofuscinoses (NCL) comprise a group of inherited lysosomal disorders with variable age of onset, characterized by lysosomal accumulation of autofluorescent ceroid lipopigments, neuroinflammation, photoreceptor- and neurodegeneration. Most of the NCL-related genes encode soluble and transmembrane proteins which localize to the endoplasmic reticulum or to the endosomal/lysosomal compartment and directly or indirectly regulate lysosomal function. Recently, exome sequencing led to the identification of four novel gene defects in NCL patients and a new NCL nomenclature currently comprising CLN1 through CLN14. Although the precise function of most of the NCL proteins remains elusive, comprehensive analyses of model organisms, particularly mouse models, provided new insight into pathogenic mechanisms of NCL diseases and roles of mutant NCL proteins in cellular/subcellular protein and lipid homeostasis, as well as their adaptive/compensatorial regulation at the transcriptional level. This review summarizes the current knowledge on the expression, function and regulation of NCL proteins and their impact on lysosomal integrity. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease. © 2013 Elsevier B.V.

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