Frans van der Ouderaa

A Genomewide Association Study of Skin Pigmentation in a South Asian Population

We have conducted a multistage genomewide association study, using 1,620,742 single-nucleotide polymorphisms to systematically investigate the genetic factors influencing intrinsic skin pigmentation in a population of South Asian descent. Polymorphisms in three genes--SLC24A5, TYR, and SLC45A2--yielded highly significant replicated associations with skin-reflectance measurements, an indirect measure of melanin content in the skin. The associations detected in these three genes, in an additive manner, collectively account for a large fraction of the natural variation of skin pigmentation in a South Asian population. Our study is the first to interrogate polymorphisms across the genome, to find genetic determinants of the natural variation of skin pigmentation within a human population.

The case for strategic international alliances to harness nutritional genomics for public and personal health

Nutrigenomics is the study of how constituents of the diet interact with genes, and their products, to alter phenotype and, conversely, how genes and their products metabolise these constituents into nutrients, antinutrients, and bioactive compounds. Results from molecular and genetic epidemiological studies indicate that dietary unbalance can alter gene-nutrient interactions in ways that increase the risk of developing chronic disease. The interplay of human genetic variation and environmental factors will make identifying causative genes and nutrients a formidable, but not intractable, challenge. We provide specific recommendations for how to best meet this challenge and discuss the need for new methodologies and the use of comprehensive analyses of nutrient-genotype interactions involving large and diverse populations. The objective of the present paper is to stimulate discourse and collaboration among nutrigenomic researchers and stakeholders, a process that will lead to an increase in global health and wellness by reducing health disparities in developed and developing countries.

Why Some Women Look Young for Their Age

The desire of many to look young for their age has led to the establishment of a large cosmetics industry. However, the features of appearance that primarily determine how old women look for their age and whether genetic or environmental factors predominately influence such features are largely unknown. We studied the facial appearance of 102 pairs of female Danish twins aged 59 to 81 as well as 162 British females aged 45 to 75. Skin wrinkling, hair graying and lip height were significantly and independently associated with how old the women looked for their age. The appearance of facial sun-damage was also found to be significantly correlated to how old women look for their age and was primarily due to its commonality with the appearance of skin wrinkles. There was also considerable variation in the perceived age data that was unaccounted for. Composite facial images created from women who looked young or old for their age indicated that the structure of subcutaneous tissue was partly responsible. Heritability analyses of the appearance features revealed that perceived age, pigmented age spots, skin wrinkles and the appearance of sun-damage were influenced more or less equally by genetic and environmental factors. Hair graying, recession of hair from the forehead and lip height were influenced mainly by genetic factors whereas environmental factors influenced hair thinning. These findings indicate that women who look young for their age have large lips, avoid sun-exposure and possess genetic factors that protect against the development of gray hair and skin wrinkles. The findings also demonstrate that perceived age is a better biomarker of skin, hair and facial aging than chronological age.

Perceived age as clinically useful biomarker of ageing: cohort study.

Objective To determine whether perceived age correlates with survival and important age related phenotypes. Design Follow-up study, with survival of twins determined up to January 2008, by which time 675 (37%) had died. Setting Population based twin cohort in Denmark. Participants 20 nurses, 10 young men, and 11 older women (assessors); 1826 twins aged ≥70. Main outcome measures Assessors: perceived age of twins from photographs. Twins: physical and cognitive tests and molecular biomarker of ageing (leucocyte telomere length). Results For all three groups of assessors, perceived age was significantly associated with survival, even after adjustment for chronological age, sex, and rearing environment. Perceived age was still significantly associated with survival after further adjustment for physical and cognitive functioning. The likelihood that the older looking twin of the pair died first increased with increasing discordance in perceived age within the twin pair—that is, the bigger the difference in perceived age within the pair, the more likely that the older looking twin died first. Twin analyses suggested that common genetic factors influence both perceived age and survival. Perceived age, controlled for chronological age and sex, also correlated significantly with physical and cognitive functioning as well as with leucocyte telomere length. Conclusion Perceived age—which is widely used by clinicians as a general indication of a patient’s health—is a robust biomarker of ageing that predicts survival among those aged ≥70 and correlates with important functional and molecular ageing phenotypes.

Effects of a web-based intervention on physical activity and metabolism in older adults: randomized controlled trial.

Background Lack of physical activity leads to detrimental changes in body composition and metabolism, functional decline, and increased risk of disease in old age. The potential of Web-assisted interventions for increasing physical activity and improving metabolism in older individuals holds great promise but to our knowledge it has not been studied. Objective The goal of our study was to assess whether a Web-based intervention increases physical activity and improves metabolic health in inactive older adults. Methods We conducted a 3-month randomized, waitlist-controlled trial in a volunteer sample of 235 inactive adults aged 60-70 years without diabetes. The intervention group received the Internet program Philips DirectLife, which was directed at increasing physical activity using monitoring and feedback by accelerometer and digital coaching. The primary outcome was relative increase in physical activity measured objectively using ankle- and wrist-worn accelerometers. Secondary outcomes of metabolic health included anthropometric measures and parameters of glucose metabolism. Results In total, 226 participants (97%) completed the study. At the ankle, activity counts increased by 46% (standard error [SE] 7%) in the intervention group, compared to 12% (SE 3%) in the control group (P difference<.001). Measured at the wrist, activity counts increased by 11% (SE 3%) in the intervention group and 5% (SE 2%) in the control group (P difference=.11). After processing of the data, this corresponded to a daily increase of 11 minutes in moderate-to-vigorous activity in the intervention group versus 0 minutes in the control group (P difference=.001). Weight decreased significantly more in the intervention group compared to controls (−1.5 kg vs −0.8 kg respectively, P=.046), as did waist circumference (−2.3 cm vs −1.3 cm respectively, P=.036) and fat mass (−0.6% vs 0.07% respectively, P=.025). Furthermore, insulin and HbA1c levels were significantly more reduced in the intervention group compared to controls (both P<.05). Conclusions This was the first study to show that in inactive older adults, a 3-month Web-based physical activity intervention was effective in increasing objectively measured daily physical activity and improving metabolic health. Such Web-based interventions provide novel opportunities for large scale prevention of metabolic deregulation in our rapidly aging population. Trial Registration Dutch Trial Registry: NTR 3045; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3045 (Archived by WebCite at http://www.webcitation.org/6KPw52dCc).

Lipoprotein Particle Profiles Mark Familial and Sporadic Human Longevity

Background Genetic and biochemical studies have indicated an important role for lipid metabolism in human longevity. Ashkenazi Jewish centenarians and their offspring have large low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles as compared with control individuals. This profile also coincided with a lower prevalence of disease. Here, we investigate whether this observation can be confirmed for familial longevity in an outbred European population and whether it can be extended to sporadic longevity in the general population. Methods and Findings NMR-measured lipoprotein profiles were analyzed in 165 families from the Leiden Longevity Study, consisting of 340 long-lived siblings (females >91 y, males >89 y), 511 of their offspring, and 243 partners of the offspring. Offspring had larger (21.3 versus 21.1 nm; p = 0.020) and fewer (1,470 versus 1,561 nmol/l; p = 0.011) LDL particles than their same-aged partners. This effect was even more prominent in the long-lived siblings (p < 10−3) and could be pinpointed to a reduction specifically in the concentration of small LDL particles. No differences were observed for HDL particle phenotypes. The mean LDL particle sizes in 259 90-y-old singletons from a population-based study were similar to those in the long-lived siblings and thus significantly larger than in partners of the offspring, suggesting that the relevance of this phenotype extends beyond familial longevity. A low concentration of small LDL particles was associated with better overall health among both long-lived siblings (p = 0.003) and 90-y-old singletons (p = 0.007). Conclusions Our study indicates that LDL particle profiles mark both familial and sporadic human longevity already in middle age.

Ambulant 24-h glucose rhythms mark calendar and biological age in apparently healthy individuals

Glucose metabolism marks health and disease and is causally inferred in the aging process. Ambulant continuous glucose monitoring provides 24‐h glucose rhythms under daily life conditions. We aimed to describe ambulant 24‐h glucose rhythms measured under daily life condition in relation to calendar and biological age in apparently healthy individuals. In the general population and families with propensity for longevity, we studied parameters from 24‐h glucose rhythms; glucose levels; and its variability, obtained by continuous glucose monitoring. Participants were 21 young (aged 22–37 years), 37 middle‐aged (aged 44–72 years) individuals from the general population, and 26 middle‐aged (aged 52–74 years) individuals with propensity for longevity. All were free of diabetes. Compared with young individuals, middle‐aged individuals from the general population had higher mean glucose levels (5.3 vs. 4.7 mmol L−1, P < 0.001), both diurnally (P < 0.001) and nocturnally (P = 0.002). Glucose variability was higher in the middle‐aged compared with the young (standard deviation 0.70 vs. 0.57 mmol L−1, P = 0.025). Compared with middle‐aged individuals from the general population, middle‐aged individuals with propensity for longevity had lower overall mean glucose levels (5.2 vs. 5.4 mmol L−1, P = 0.047), which were more different nocturnally (4.8 vs. 5.2 mmol L−1, P = 0.003) than diurnally (5.3 vs. 5.5 mmol L−1, P = 0.14). There were no differences in glucose variability between these groups. Results were independent of body mass index. Among individuals without diabetes, we observed significantly different 24‐h glucose rhythms depending on calendar and biological age.

An Internet-Based Physical Activity Intervention to Improve Quality of Life of Inactive Older Adults: A Randomized Controlled Trial

Background Increasing physical activity is a viable strategy for improving both the health and quality of life of older adults. Objective The aim of this study was to assess if an Internet-based intervention aimed to increase physical activity was effective in improving quality of life of inactive older adults. In addition, we analyzed the effect of the intervention on quality of life among those participants who successfully reached their individually targeted increase in daily physical activity as indicated by the intervention program, as well as the dose-response effect of increasing physical activity on quality of life. Methods The intervention was tested in a randomized controlled trial and was comprised of an Internet program—DirectLife (Philips)—aimed at increasing physical activity using monitoring and feedback by accelerometry and feedback by digital coaching (n=119). The control group received no intervention (n=116). Participants were inactive 60-70-year-olds and were recruited from the general population. Quality of life and physical activity were measured at baseline and after 3 months using the Research ANd Development 36-item health survey (RAND-36) and wrist-worn triaxial accelerometer, respectively. Results After 3 months, a significant improvement in quality of life was seen in the intervention group compared to the control group for RAND-36 subscales on emotional and mental health (2.52 vs -0.72, respectively; P=.03) and health change (8.99 vs 2.03, respectively; P=.01). A total of 50 of the 119 participants (42.0%) in the intervention group successfully reached their physical activity target and showed a significant improvement in quality of life compared to the control group for subscales on emotional and mental health (4.31 vs -0.72, respectively; P=.009) and health change (11.06 vs 2.03, respectively; P=.004). The dose-response analysis showed that there was a significant association between increase in minutes spent in moderate-to-vigorous physical activity (MVPA) and increase in quality of life. Conclusions Our study shows that an Internet-based physical activity program was effective in improving quality of life in 60-70-year-olds after 3 months, particularly in participants that reached their individually targeted increase in daily physical activity. Trial Registration Nederlands Trial Register: NTR 3045; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3045 (Archived by WebCite at http://www.webcitation.org/6fobg2sjJ)

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach.

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17 000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P<1 × 10−4). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an ‘extreme genetics’ approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may, therefore, not lead to significant gains in statistical power.

Vitaliteit en de ambities, opinies en wensen van 55 plussers

SamenvattingAan het begin van de 21e eeuw doen zich onder de invloed van de gestegen levensverwachting van 50plussers drie belangrijke tendensen voor. Dit zijn de verschuiving in de verhouding van werkenden tot niet-werkenden en het daarmee gepaard gaande verwachte verlies aan expertise en productiviteit, grotere aantallen met aanspraak op de AOW en problemen van pensioenfondsen met betrekking tot hun kapitaalspositie en de snel stijgende kosten voor de zorg (nu meer dan 12% van GDP). Vanwege de publiciteit over deze wat negatieve tendensen wordt vaak vergeten dat de verdubbeling van de levensverwachting in de laatste 200 jaar één van de grootste successen is van onze samenleving.