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ABSTRACT: OBJECTIVE
The Old Order Amish (OOA) is a conservative Christian sect of European origin living in Pennsylvania. Diabetes is rare in adult OOA despite a mean BMI rivaling that in the general U.S. non-Hispanic white population. The current study examines childhood factors that may contribute to the low prevalence of diabetes in the OOA by comparing OOA children aged 8 to 19 years with National Health and Nutrition Examination Survey (NHANES) data and children from Maryland's Eastern Shore (ES), a nearby, non-Amish, rural community. We hypothesized that pediatric overweight is less common in OOA children, that physical activity (PA) and BMI are inversely correlated, and that OOA children are more physically active than ES children.RESEARCH DESIGN AND METHODS
We obtained anthropometric data in 270 OOA children and 229 ES children (166 non-Hispanic white, 60 non-Hispanic black, 3 Hispanic). PA was measured by hip-worn accelerometers in all ES children and in 198 OOA children. Instrumentation in 43 OOA children was identical to ES children.RESULTSOOA children were approximately 3.3 times less likely than non-Hispanic white ES children and NHANES estimates to be overweight (BMI ≥85th percentile, Centers for Disease Control and Prevention). Time spent in moderate/vigorous PA (MVPA) was inversely correlated to BMI z score (r = -0.24, P = 0.0006). PA levels did not differ by ethnicity within the ES group, but OOA children spent an additional 34 min/day in light activity (442 ± 56 vs. 408 ± 75, P = 0.005) and, impressively, an additional 53 min/day in MVPA (106 ± 54 vs. 53 ± 32, P < 0.0001) compared with ES children. In both groups, boys were more active than girls but OOA girls were easily more active than ES boys.CONCLUSIONS
We confirmed all three hypotheses. Together with our previous data, the study implies that the OOA tend to gain their excess weight relatively late in life and that OOA children are very physically active, both of which may provide some long-term protection against diabetes.
Diabetes care 10/2012; · 8.09 Impact Factor
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Kristine Yaffe,
Karla Lindquist,
Molly Kluse,
Richard Cawthon,
Tamara Harris, Wen-Chi Hsueh,
Eleanor M Simonsick,
Lewis Kuller,
Rongling Li,
Hilsa N Ayonayon,
Susan M Rubin,
Steven R Cummings
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ABSTRACT: Telomere shortening is a marker of cellular aging and has been associated with risk of Alzheimer's disease. Few studies have determined if telomere length is associated with cognitive decline in non-demented elders. We prospectively studied 2734 non-demented elders (mean age: 74 years). We measured cognition with the Modified Mini-Mental State Exam (3MS) and Digit Symbol Substitution Test (DSST) repeatedly over 7 years. Baseline telomere length was measured in blood leukocytes and classified by tertile as "short", "medium", or "long". At baseline, longer telomere length was associated with better DSST score (36.4, 34.9 and 34.4 points for long, medium and short, p<0.01) but not for change in score. However, 7-year 3MS change scores were less among those with longer telomere length (-1.7 points vs. -2.5 and -2.9, p=0.01). Findings were similar after multivariable adjustment for age, gender, race, education, assay batch, and baseline score. There was a borderline statistically significant interaction for telomere length and APOE e4 on 3MS change score (p=0.06). Thus, telomere length may serve as a biomarker for cognitive aging.
Neurobiology of aging 11/2011; 32(11):2055-60. · 5.94 Impact Factor
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ABSTRACT: We sought to evaluate the contribution of genetic and non-genetic factors on habitual sleep/wake patterns in a community-dwelling agrarian population using a physical activity monitoring device, the Actical.
Cross-sectional population-based study of healthy Old Order Amish enrolled in the Heredity and Phenotype Intervention (HAPI) Heart Study.
Lancaster County, PA, USA.
723 healthy adults (54% men) with a mean age of 43.3 ± 13.8 years (range: 20-80). 96% of the subjects were connected into one 5-generation pedigree.
N/A.
Participants wore Actical accelerometers 24 hours/day for 7 days to determine physical activity level, as well as habitual wake time, bedtime, and sleep duration. Participants completed the Horne-Östberg Morningness-Eveningness Questionnaire (MEQ), a modified Epworth Sleepiness Scale (ESS), and a lifestyle questionnaire. A sub-study of 164 participants kept sleep diaries.
Habitual wake time and bedtime determined by Actical were highly correlated with results from sleep diaries (r = 0.82 for wake time and 0.72 for bedtime, both P < 0.0001). After adjustment for age, sex, occupation, and season, higher activity level was associated with earlier wake time but not with bedtime, and correspondingly with shorter sleep duration. After adjustment for the aforementioned factors and the effects of a shared household, habitual wake time, MEQ score, and ESS score showed significant heritability (wake time h(2) = 0.20, MEQ h(2) = 0.21, and ESS h(2) = 0.17).
Objectively measured wake time, self-reported morningness-eveningness preference, and daytime sleepiness appear heritable and wake time may be associated with physical activity level.
Sleep 05/2011; 34(5):661-9. · 5.05 Impact Factor
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Michael M Swarbrick,
Daniel S Evans,
Maria I Valle,
Hélène Favre,
Shi-Hsuan Wu,
Omer T Njajou,
Rongling Li,
Joseph M Zmuda,
Iva Miljkovic,
Tamara B Harris,
Pui-Yan Kwok,
Christian Vaisse, Wen-Chi Hsueh
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ABSTRACT: Haplo-insufficiency of the bHLH (basic helix-loop-helix) transcription factor single-minded 1 (SIM1) causes severe obesity in mice and humans. We hypothesized that common genetic variations in/near SIM1 could exert more subtle effects on its function and associate with human adiposity. First, SIM1 coding regions were sequenced in severely obese subjects, and two common nonsynonymous single-nucleotide polymorphisms (nsSNPs) in complete linkage disequilibrium (LD) were identified: Pro352Thr (rs3734354) and Ala371Val (rs3734355). We next carried out a SNP association study of five adiposity traits (BMI, % body fat, abdominal visceral and subcutaneous fat, and leptin concentrations) in 1,699 whites and 1,173 blacks. TagSNPs covering SIM1 and nearby conserved regions, and the only common nsSNP in SIM1's binding partner aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) (Gly679Ser/rs4072568), were investigated. The effects of rs3734355/4 on SIM1 activity were tested using an in vitro reporter assay. We replicated previous observations that homozygosity for the 371Val allele was associated with higher BMI in white males (P = 0.003). Together with previous findings in white males (combined n = 3,479), BMI was increased by 1.10 kg/m(2) in 371Val homozygotes (95% confidence interval (CI): 0.25-1.95 kg/m(2), P = 0.01). In vitro, the 352Thr-371Val haplotype impaired SIM1 transcriptional activity by 22% (P < 0.0001). TagSNP analysis of SIM1 revealed two SNPs in the 3' region (rs9390322 and rs7746743) and another in intron 5 (rs3734353) to be significantly associated with various adiposity measures in ethnicity- and sex-specific manners after multiple testing correction. In white males, rs4072568 in ARNT2 was also associated with BMI (P = 9 × 10(-4)) and % body fat (P = 0.001). Our findings implicate heritable defects of the SIM1-ARNT2 axis in the predisposition to human obesity.
Obesity 04/2011; 19(12):2394-403. · 4.28 Impact Factor
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Jason L Sanders,
Alessandro Iannaccone,
Robert M Boudreau,
Yvette P Conley,
Patricia L Opresko, Wen-Chi Hsueh,
Steven R Cummings,
Richard M Cawthon,
Tamara B Harris,
Michael A Nalls,
Steven B Kritchevsky,
Anne B Newman
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ABSTRACT: Lens transparency, or the magnitude of cataract severity, is a potential in vivo marker of aging distinguishable from diagnosed cataract. To explore lens transparency as a marker of aging, we determined its association with leukocyte telomere length (LTL) measured with quantitative polymerase chain reaction. Cataract severity was directly measured in 259 participants, and prevalent cataract and incident cataract surgery were ascertained in 2,750 participants of the Health, Aging, and Body Composition Study. LTL was unassociated with clinical cataract outcomes. Six of 259 had successfully aged lenses and a mean LTL of 5,700 bp, whereas 253/259 with poorly aged lenses had a mean LTL of 4,770 bp. Participants with a 1,000 bp greater mean LTL had nearly half the odds of any cataract (odds ratio = 0.47, 95% confidence interval 0.22-1.02) after adjustment. Lens transparency might be associated with longer LTL in community-dwelling older adults and should be investigated further as a possible biomarker of aging.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 03/2011; 66(6):639-45. · 4.60 Impact Factor
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Aoife O'Donovan,
Matthew S Pantell,
Eli Puterman,
Firdaus S Dhabhar,
Elizabeth H Blackburn,
Kristine Yaffe,
Richard M Cawthon,
Patricia L Opresko, Wen-Chi Hsueh,
Suzanne Satterfield,
Anne B Newman,
Hilsa N Ayonayon,
Susan M Rubin,
Tamara B Harris,
Elissa S Epel
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ABSTRACT: Leukocyte telomere length (LTL) is an emerging marker of biological age. Chronic inflammatory activity is commonly proposed as a promoter of biological aging in general, and of leukocyte telomere shortening in particular. In addition, senescent cells with critically short telomeres produce pro-inflammatory factors. However, in spite of the proposed causal links between inflammatory activity and LTL, there is little clinical evidence in support of their covariation and interaction.
To address this issue, we examined if individuals with high levels of the systemic inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) had increased odds for short LTL. Our sample included 1,962 high-functioning adults who participated in the Health, Aging and Body Composition Study (age range: 70-79 years). Logistic regression analyses indicated that individuals with high levels of either IL-6 or TNF-α had significantly higher odds for short LTL. Furthermore, individuals with high levels of both IL-6 and TNF-α had significantly higher odds for short LTL compared with those who had neither high (OR = 0.52, CI = 0.37-0.72), only IL-6 high (OR = 0.57, CI = 0.39-0.83) or only TNF-α high (OR = 0.67, CI = 0.46-0.99), adjusting for a wide variety of established risk factors and potential confounds. In contrast, CRP was not associated with LTL.
Results suggest that cumulative inflammatory load, as indexed by the combination of high levels of IL-6 and TNF-α, is associated with increased odds for short LTL. In contrast, high levels of CRP were not accompanied by short LTL in this cohort of older adults. These data provide the first large-scale demonstration of links between inflammatory markers and LTL in an older population.
PLoS ONE 01/2011; 6(5):e19687. · 4.09 Impact Factor
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ABSTRACT: Parental diabetes history is a well-known risk factor for type 2 diabetes and considered strong evidence for a genetic basis of type 2 diabetes. Whether this relationship is affected by other known risk factors, specifically obesity, remains unclear, possibly due to a relative paucity of lean diabetic patients.
This issue was investigated using data from a high-risk population from Mexico (National Health Survey 2000, n = 27,349), with observations replicated using U.S. citizens of Mexican descent from the National Health and Nutrition Examination Survey 2001-2002 and 2003-2004 (n = 1,568).
As expected, positive parental diabetes was a significant risk factor for type 2 diabetes, regardless of age, sex, or adiposity level. However, positive parental diabetes conferred greater risk in leaner individuals than in their overweight peers (P = 0.001). In other words, the effect of BMI on type 2 diabetes risk was smaller in the presence of parental diabetes history.
These findings suggest that parental diabetes is a stronger risk factor for type 2 diabetes in the absence of obesity. Thus, studies in lean diabetic patients could help identify type 2 diabetes susceptibility genes. This study reinforces the concept that parental diabetes and BMI are independent type 2 diabetes risk factors and suggests that glycemic screening may be helpful in assessing type 2 diabetes risk in individuals with parental diabetes history, regardless of their overweight status.
Diabetes care 10/2010; 33(10):2260-5. · 8.09 Impact Factor
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ABSTRACT: The target of rapamycin (TOR) signal transduction network monitors intra- and extracellular conditions that favor cell growth. Research during the last decade has revealed a modular structure of the TOR signaling network. Each signaling module senses a particular set of signals from the cellular milieu and exerts regulatory control towards TOR activity. The TOR pathway responds to growth factor signals, nutrient availability, and cellular stresses like hypoxia and energy stress. The signaling modules and their molecular components constituting the TOR network are remarkably conserved in both sequence and function across species. In yeast, roundworms, flies, and mice, the TOR pathway has been shown to regulate lifespan. Correspondingly, genetic, dietary or pharmacological manipulation of individual signaling modules as well as TOR activity itself extends lifespan in these model organisms. We discuss the potential impact of manipulating TOR activity for human health and lifespan.
Ageing research reviews 04/2010; 10(2):225-37. · 5.62 Impact Factor
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Omer T Njajou,
Elizabeth H Blackburn,
Ludmila Pawlikowska,
Massimo Mangino,
Coleen M Damcott,
Pui-Yan Kwok,
Timothy D Spector,
Anne B Newman,
Tamara B Harris,
Steven R Cummings,
Richard M Cawthon,
Alan R Shuldiner,
Ana M Valdes, Wen-Chi Hsueh
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ABSTRACT: Telomeres shorten as cells divide. This shortening is compensated by the enzyme telomerase. We evaluated the effect of common variants in the telomerase RNA component (TERC) gene on telomere length (TL) in the population-based Health Aging and Body Composition (Health ABC) Study and in two replication samples (the TwinsUK Study and the Amish Family Osteoporosis Study, AFOS).
Five variants were identified in the TERC region by sequence analysis and only one SNP was common (rs2293607, G/A). The frequency of the G allele was 0.26 and 0.07 in white and black, respectively. Testing for association between TL and rs2293607 was performed using linear regression models or variance component analysis conditioning on relatedness among subjects.
The adjusted mean TL was significantly shorter in 665 white carriers of the G allele compared to 887 non-carriers from the Health ABC Study (4.69±0.05 kbp vs. 4.86±0.04 kbp, measured by quantitative PCR, p = 0.005). This association was replicated in another white sample from the TwinsUK Study (6.90±0.03 kbp in 301 carriers compared to 7.06±0.03 kbp in 395 non-carriers, measured by Southern blots, p = 0.009). A similar pattern of association was observed in whites from the family-based AFOS and blacks from the Health ABC cohort, although not statistically significant, possibly due to the lower allele frequency in these populations. Combined analysis using 2,953 white subjects from 3 studies showed a significant association between TL and rs2293607 (β = -0.19±0.04 kbp, p = 0.001).
Our study shows a significant association between a common variant in TERC and TL in humans, suggesting that TERC may play a role in telomere homeostasis.
PLoS ONE 01/2010; 5(9):e13048. · 4.09 Impact Factor
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ABSTRACT: Accumulating evidence suggests a cross-sectional association between oxidative stress and type 2 diabetes (T2D). Systemic oxidative stress, as measured by oxidized LDL (oxLDL), has been correlated with visceral fat. We examined the relationship between oxLDL, and T2D- and obesity-related traits in a bi-racial sample of 2985 subjects at baseline and after 7 years of follow-up.
We examined six T2D-related traits (T2D status, HbA(1c), fasting glucose, insulin, adiponectin and HOMA-IR) as well as six obesity-related traits (obesity status, BMI, leptin, % body fat, visceral and subcutaneous fat mass) using logistic and linear regression models.
In all subjects at baseline, oxLDL was positively associated with T2D (OR = 1.3, 95% CI:1.1-1.5), fasting glucose (ss = 0.03 +/- 0.006), HbA(1c) (ss = 0.02 +/- 0.004), fasting insulin (ss = 0.12 +/- 0.02), HOMA-IR (ss = 0.13 +/- 0.02) and negatively with adiponectin (ss = -0.16 +/- 0.03), (all p < 0.001). The strength and magnitude of these associations did not differ much between blacks and whites. In both blacks and whites, oxLDL was also associated with obesity (OR = 1.3, 95% CI:1.1-1.4) and three of its related traits (ss = 0.60 +/- 0.14 for BMI, ss = 0.74 +/- 0.17 for % body fat, ss = 0.29 +/- 0.06 for visceral fat; all p < 0.001). Furthermore, of four traits measured after 7 years of follow-up (fasting glucose, HbA1c, BMI and % fat), their relationship with oxLDL was similar to baseline observations. No significant association was found between oxLDL and incident T2D. Interestingly, oxLDL was significantly associated with % change in T2D- and obesity-related traits in whites but not in blacks.
Our data suggest that systemic oxidative stress may be a novel risk factor for T2D and obesity.
Diabetes/Metabolism Research and Reviews 09/2009; 25(8):733-9. · 3.37 Impact Factor
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Donglei Hu,
Ludmila Pawlikowska,
Alka Kanaya, Wen-Chi Hsueh,
Lisa Colbert,
Anne B Newman,
Suzanne Satterfield,
Clifford Rosen,
Steven R Cummings,
Tamara B Harris,
Elad Ziv
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ABSTRACT: To evaluate the relationship between serum insulin-like growth factor 1 (IGF-1), IGF-1 binding protein 1 (IGFBP-1), and IGF-1 binding protein 2 (IGFBP-2) and fasting insulin, fasting glucose, adiposity, and mortality in older adults.
A prospective cohort study with mean follow-up of 6.2 years.
Participants were recruited and followed at two centers affiliated with academic medical institutions.
Six hundred twenty-five men and women aged 70 and older and in good health at the time of enrollment.
Serum IGF-1, IGFBP-1, and IGFBP-2; fasting serum insulin; fasting serum glucose; visceral fat; and total percent fat.
Higher IGFBP-1 and higher IGFBP-2 were significantly associated with lower fasting insulin, lower fasting glucose, and lower adiposity, but higher IGFBP-1 and IGFBP-2 were associated with greater mortality. In multivariate adjusted models, the hazard ratio for all-cause mortality was 1.48 (95% confidence interval (CI)=1.14-1.92) per standard deviation (SD) increase in IGFBP-2 and 1.34 (95% CI=1.01-1.76) per SD increase in IGFBP-1. No association was found between IGF-1 and all-cause mortality.
Higher IGFBP-1 and IGFBP-2 are associated with lower adiposity and decreased glucose tolerance but also with greater all-cause mortality. Higher levels of serum IGF-1 binding protein (IGFBP) may indicate greater IGF-1 activity and thus represent an association between higher IGF-1 activity and mortality in humans.
Journal of the American Geriatrics Society 08/2009; 57(7):1213-8. · 3.74 Impact Factor
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M L Scherer,
M A Nalls,
L Pawlikowska,
E Ziv,
G Mitchell,
S Huntsman,
D Hu,
K Sutton-Tyrrell,
E G Lakatta, W-C Hsueh,
A B Newman,
A Tandon,
L Kim,
P-Y Kwok,
A Sung,
R Li,
B Psaty,
A P Reiner,
T Harris
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ABSTRACT: Peripheral arterial disease (PAD) is associated with significant morbidity and mortality, and has a higher prevalence in African Americans than Caucasians. Ankle-arm index (AAI) is the ratio of systolic blood pressure in the leg to that in the arm, and, when low, is a marker of PAD.
The authors used an admixture mapping approach to search for genetic loci associated with low AAI. Using data from 1040 African American participants in the observational, population based Health, Aging, and Body Composition Study who were genotyped at 1322 single nucleotide polymorphisms (SNPs) that are informative for African versus European ancestry and span the entire genome, we estimated genetic ancestry in each chromosomal region and then tested the association between AAI and genetic ancestry at each locus.
The authors found a region of chromosome 11 that reaches its peak between 80 and 82 Mb associated with low AAI (p<0.001 for rs12289502 and rs9665943, both within this region). 753 African American participants in the observational, population based Cardiovascular Health Study were genotyped at rs9665943 to test the reproducibility of this association, and this association was also statistically significant (odds ratio (OR) for homozygous African genotype 1.59, 95% confidence interval (CI) 1.12 to 2.27). Another candidate SNP (rs1042602) in the same genomic region was tested in both populations, and was also found to be significantly associated with low AAI in both populations (OR for homozygous African genotype 1.89, 95% CI 1.29 to 2.76).
This study identifies a novel region of chromosome 11 representing an area with a potential candidate gene associated with PAD in African Americans.
Journal of Medical Genetics 08/2009; 47(1):1-7. · 6.36 Impact Factor
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Ludmila Pawlikowska,
Donglei Hu,
Scott Huntsman,
Andrew Sung,
Catherine Chu,
Justin Chen,
Alexander H. Joyner,
Nicholas J. Schork, Wen-Chi Hsueh,
Alexander P. Reiner,
Bruce M. Psaty,
Gil Atzmon,
Nir Barzilai,
Steven R. Cummings,
Warren S. Browner,
Pui-Yan Kwok,
Elad Ziv,
for the Study of Osteoporotic Fractures
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ABSTRACT: The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long-lived cases (lifespan ≥ 92 years (y), mean ± standard deviation (SD) = 95.3 ± 2.2y) and 603 average-lifespan controls (lifespan ≤ 79y, mean = 75.7 ± 2.6y). Variants were selected for genotyping using a haplotype-tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78 95%CI = 0.68–0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95%CI = 1.15–1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan.
Aging cell 07/2009; 8(4):460 - 472. · 7.55 Impact Factor
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ABSTRACT: Although telomere length (TL) is known to play a critical role in cellular senescence, the relationship of TL to aging and longevity in humans is not well understood. In a large biracial population-based cohort, we tested the hypotheses that elderly persons with shorter TL in peripheral white blood cells have poorer survival, shorter life span, and fewer years of healthy life (YHL). Associations were evaluated using Cox proportional hazard models and linear regression analyses where appropriate. TL (in kilo base pairs) was not associated with overall survival (hazard ratio 1.0; 95% confidence interval 0.9-1.1) or death from any specific underlying cause including infectious diseases, cancer, or cardiac and cerebrovascular diseases. TL, however, was positively associated with more YHL (beta = 0.08 +/- 0.04, p = .03). Findings suggest that TL may not be a strong biomarker of survival in older individuals, but it may be an informative biomarker of healthy aging.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 06/2009; 64(8):860-4. · 4.60 Impact Factor
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Ching-Yu Cheng,
W H Linda Kao,
Nick Patterson,
Arti Tandon,
Christopher A Haiman,
Tamara B Harris,
Chao Xing,
Esther M John,
Christine B Ambrosone,
Frederick L Brancati, [......],
Rongling Li,
Giske Ursin,
Leslie Bernstein,
Kristin Ardlie,
Herman A Taylor,
Eric Boerwinckle,
Joseph M Zmuda,
Brian E Henderson,
James G Wilson,
David Reich
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ABSTRACT: The prevalence of obesity (body mass index (BMI) > or =30 kg/m(2)) is higher in African Americans than in European Americans, even after adjustment for socioeconomic factors, suggesting that genetic factors may explain some of the difference. To identify genetic loci influencing BMI, we carried out a pooled analysis of genome-wide admixture mapping scans in 15,280 African Americans from 14 epidemiologic studies. Samples were genotyped at a median of 1,411 ancestry-informative markers. After adjusting for age, sex, and study, BMI was analyzed both as a dichotomized (top 20% versus bottom 20%) and a continuous trait. We found that a higher percentage of European ancestry was significantly correlated with lower BMI (rho = -0.042, P = 1.6x10(-7)). In the dichotomized analysis, we detected two loci on chromosome X as associated with increased African ancestry: the first at Xq25 (locus-specific LOD = 5.94; genome-wide score = 3.22; case-control Z = -3.94); and the second at Xq13.1 (locus-specific LOD = 2.22; case-control Z = -4.62). Quantitative analysis identified a third locus at 5q13.3 where higher BMI was highly significantly associated with greater European ancestry (locus-specific LOD = 6.27; genome-wide score = 3.46). Further mapping studies with dense sets of markers will be necessary to identify the alleles in these regions of chromosomes X and 5 that may be associated with variation in BMI.
PLoS Genetics 05/2009; 5(5):e1000490. · 8.69 Impact Factor
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ABSTRACT: Determining the long-range haplotypes in a diploid individual is a major technical challenge. Here we report a method of molecular haplotyping by directly imaging multiple polymorphic sites on individual human DNA molecules simultaneously. We demonstrate the utility of this technology by accurately determining the haplotypes consisting of up to 16 single-nucleotide polymorphisms in genomic regions up to 50 kilobases.
Nature Methods 03/2009; 6(3):199-201. · 19.28 Impact Factor
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David Reich,
Michael A Nalls,
W H Linda Kao,
Ermeg L Akylbekova,
Arti Tandon,
Nick Patterson,
James Mullikin, Wen-Chi Hsueh,
Ching-Yu Cheng,
Josef Coresh, [......],
Rongling Li,
Tennille S Leak,
Lynette Ekunwe,
Joe C Files,
Cheryl L Hardy,
Joseph M Zmuda,
Herman A Taylor,
Elad Ziv,
Tamara B Harris,
James G Wilson
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ABSTRACT: Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8 x 10(-5)), establishing a novel phenotype for this genetic variant.
PLoS Genetics 02/2009; 5(1):e1000360. · 8.69 Impact Factor
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ABSTRACT: Serum insulin levels are altered in insulin resistance and insulin deficiency, states that are associated with the development of type 2 diabetes. The goal of our study was to identify chromosomal regions that are likely to harbor genetic determinants of these traits.
We conducted a series of genetic analyses, including genome-wide and fine-mapping linkage studies, based on insulin levels measured during an oral glucose tolerance test (OGTT) in 552 nondiabetic participants in the Amish Family Diabetes Study. Indices of insulin secretion included the insulinogenic index and insulin at 30 min postglucose load (insulin 30), while indices of insulin resistance included homeostasis model assessment of insulin resistance (HOMA-IR) and fasting insulin. Insulin area under the curve, a measure of both insulin secretion and insulin resistance, was also examined.
All traits were modestly heritable, with heritability estimates ranging from 0.1 to 0.4 (all P < 0.05). There was significant genetic correlation between fasting insulin and HOMA-IR (rho(G) > 0.86, P < 0.05), as well as insulin 30 and insulinogenic index (rho(G) = 0.81, P < 0.0001), suggesting that common genes influence variation in these pairs of traits. Suggestive linkage signals in the genome scan were to insulin 30 on chromosome 15q23 (logarithm of odds [LOD] 2.53, P = 0.00032) and to insulinogenic index on chromosome 2p13 (LOD 2.51, P = 0.00034). Fine-mapping study further refined our signal for insulin 30 on chromosome 15 (LOD 2.38 at 68 cM).
These results suggest that there may be different genes influencing variation in OGTT measures of insulin secretion and insulin resistance.
Diabetes 11/2007; 56(10):2643-8. · 8.29 Impact Factor
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ABSTRACT: Telomere length (TL) is emerging as a biomarker for aging and survival. To evaluate factors influencing this trait, we measured TL in a large homogeneous population, estimated the heritability (h(2)), and tested for parental effects on TL variation. Our sample included 356 men and 551 women, aged 18-92 years, from large Amish families. Mean TL in leukocytes was measured by quantitative PCR (mean: 6,198 +/- 1,696 bp). The h(2) of TL was 0.44 +/- 0.06 (P < 0.001), after adjusting for age, sex, and TL assay batch. As expected, TL was negatively correlated with age (r = -0.40; P < 0.001). There was no significant difference in TL between men and women, consistent with our previous findings that Amish men lived as long as Amish women. There was a stronger and positive correlation and association between TL in the offspring and paternal TL (r = 0.46, P < 0.001; beta = 0.22, P = 0.006) than offspring and maternal TL (r = 0.18, P = 0.04; beta = -0.02, P = 0.4). Furthermore, we observed a positive correlation and association between daughter's TL and paternal lifespan (r = 0.20, P < 0.001; beta = 0.21, P = 0.04), but not between daughter's TL and maternal lifespan (r = -0.01, beta = 0.04; both P = not significant). Our data, which are based on one of the largest family studies of human TL, support a link between TL and aging and lifespan and suggest a strong genetic influence, possibly via an imprinting mechanism, on TL regulation.
Proceedings of the National Academy of Sciences 08/2007; 104(29):12135-9. · 9.68 Impact Factor
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Christina L Wassel Fyr,
Alka M Kanaya,
Steve R Cummings,
David Reich, Wen-Chi Hsueh,
Alexander P Reiner,
Tamara B Harris,
Susan Moffett,
Rongling Li,
Jingzhong Ding,
Iva Miljkovic-Gacic,
Elad Ziv
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ABSTRACT: Adipocytokines are a subset of cytokines produced by adipose tissue and are associated with risk of type II diabetes and atherosclerosis. Levels of adipocytokines differ between Black and White Americans, even after adjustment for differences in adiposity, diseases associated with adipocytokines including type 2 diabetes and cardiovascular disease, and general socioeconomic status indicators such as income. We used a series of ancestry informative markers to estimate genetic ancestry in a population-based study of older Black Americans, and examined the association between genetic ancestry and adipocytokines and soluble receptors to help determine which of these may be most amenable to admixture mapping. We typed 35 ancestry informative markers in 1,241 self-reported Black Americans with available DNA from the Health, Aging, and Body Composition (Health ABC) study with available DNA and used a maximum likelihood approach to estimate percent European ancestry. We used linear regression models to determine the association between these adipocytokines and percent ancestry, and staged models to examine whether adiposity or other measures affected the associations of genetic ancestry and adipocytokines. Mean European ancestry was 22.3+/-15.9%. In multivariate adjusted models, the strongest associations observed were between higher European ancestry and interleukin-6 soluble receptor (IL-6 SR), C-reactive protein (CRP), and adiponectin levels, with interleukin-2 soluble receptor (IL-2 SR) and soluble tumor necrosis factor receptor II (TNF-alpha SR II) also showing more modest but significant associations. The association with adiponectin became stronger after adjustment for adiposity. These novel findings suggest that admixture mapping may identify genetic factors influencing the levels of IL-6 SR, CRP, IL-2 SR, and adiponectin.
Human Genetics 06/2007; 121(5):615-24. · 5.07 Impact Factor
