Aims/hypothesis
We conducted genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) analyses to identify and characterise risk loci for type 2 diabetes in ...Mexican-Americans from Starr County, TX, USA.
Method
Using 1.8 million directly interrogated and imputed genotypes in 837 unrelated type 2 diabetes cases and 436 normoglycaemic controls, we conducted Armitage trend tests. To improve power in this population with high disease rates, we also performed ordinal regression including an intermediate class with impaired fasting glucose and/or glucose tolerance. These analyses were followed by meta-analysis with a study of 967 type 2 diabetes cases and 343 normoglycaemic controls from Mexico City, Mexico.
Result
The top signals (unadjusted
p
value <1 × 10
−5
) included 49 single nucleotide polymorphisms (SNPs) in eight gene regions (
PER3
,
PARD3B
,
EPHA4
,
TOMM7
,
PTPRD
,
HNT
also known as
RREB1
,
LOC729993
and
IL34
) and six intergenic regions. Among these was a missense polymorphism (rs10462020; Gly639Val) in the clock gene
PER3
, a system recently implicated in diabetes. We also report a second signal (minimum
p
value 1.52 × 10
−6
) within
PTPRD
, independent of the previously implicated SNP, in a population of Han Chinese. Top meta-analysis signals included known regions
HNF1A
and
KCNQ1
. Annotation of top association signals in both studies revealed a marked excess of
trans
-acting eQTL in both adipose and muscle tissues.
Conclusions/Interpretation
In the largest study of type 2 diabetes in Mexican populations to date, we identified modest associations of novel and previously reported SNPs. In addition, in our top signals we report significant excess of SNPs that predict transcript levels in muscle and adipose tissues.
Evidence from human and animal research indicates that choline metabolic pathways may be activated during a variety of diseases, including cancer. We report results of a case-control study of 2821 ...lung cancer cases and 2923 controls that assessed associations of choline and betaine dietary intakes with lung cancer. Using multivariable logistic regression analyses, we report a significant association between higher betaine intake and lower lung cancer risk that varied by smoking status. Specifically, no significant association was observed between betaine intake and lung cancer among never-smokers. However, higher betaine intake was significantly associated with reduced lung cancer risk among smokers, and the protective effect was more evident among current than former smokers: for former and current smokers, the ORs (95% CI) of lung cancer for individuals with highest as compared to lowest quartiles of intake were 0.70(0.55-0.88) and 0.51(0.39-0.66) respectively. Significant linear trend of higher betaine intake and lower lung cancer risk was observed among both former (p(trend) = 0.002) and current (p(trend)<0.0001) smokers. A similar protective effect was also observed with choline intake both in overall analysis as well as among current smokers, with p-values for chi-square tests being 0.001 and 0.004 respectively, but the effect was less evident, as no linear trend was observed. Our results suggest that choline and betaine intake, especially higher betaine intake, may be protective against lung cancer through mitigating the adverse effect of smoking.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To investigate possible age-related changes in associations between polymorphisms in the fat mass and obesity-associated (FTO) gene and higher body mass index (BMI).
Multilevel mixed regression ...models were used to examine associations between four FTO variants and longitudinal BMI profiles in non-Hispanic white and African American children and adolescents 8-17 years of age from two different longitudinal cohort studies, the Bogalusa Heart Study (BHS) and Project HeartBeat! (PHB). In the BHS, there were 1551 examinations of 478 African Americans and 3210 examinations of 1081 non-Hispanic whites; in PHB, there were 971 examinations of 131 African Americans and 4458 examinations of 505 non-Hispanic whites.
In African Americans, no significant FTO associations with BMI were found. In non-Hispanic whites, linkage disequilibrium among all four variants made haplotype analysis superfluous, so we focused on the single-nucleotide polymorphism, rs9939609. In longitudinal multilevel models, the A/A genotype of rs9939609 was associated with higher BMI in non-Hispanic whites in both cohorts at all ages. A significant age-by-genotype interaction found only in the BHS cohort predicted that in those with the A/A genotype, BMI would be ∼0.7 kg m(-2) higher at age 8 and ∼1.6 kg m(-2) higher at age 17 than in those with A/T or T/T genotypes. The design of PHB limited follow-up of any single individual to 4 years, and may have reduced the ability to detect any age-by-genotype interaction in this cohort.
The A/A genotype of rs9939609 in the FTO gene is associated with higher longitudinal BMI profiles in non-Hispanic whites from two different cohorts. The association may change with age, with the A/A genotype being associated with a larger BMI difference in late adolescence than in childhood, though this was observed only in the BHS cohort and requires verification.
The epidemiology and outcomes of multiple organ dysfunction syndrome (MODS) are incompletely characterized in the pediatric population due to small sample size and conflicting diagnoses of organ ...failure. We sought to describe the epidemiology and outcomes of early MODS in a large clinical database of pediatric intensive care unit (PICU) patients based on consensus definitions of organ failure.
Retrospective analysis of a contemporaneously collected clinical PICU database.
Virtual Pediatric Intensive Care Unit Performance System database patient admissions from January 2004 to December 2005 for 35 U.S. children's hospitals.
: We evaluated 63,285 consecutive PICU admissions from January 2004 to December 2005 in the Virtual Pediatric Intensive Care Unit Performance System database. We excluded patients younger than 1 month or older than 18 years of age, and hospitals with >10% missing values for MODS variables. We identified day 1 MODS by International Pediatric Sepsis Consensus Conference criteria with day 1 laboratory and vital sign values. We evaluated functional status using Pediatric Overall Performance Category and Pediatric Cerebral Performance Category scores from PICU admission and discharge.
Student's t test, chi-square test, Mann-Whitney rank sum, Kruskal-Wallis, and linear and logistic regression.
We analyzed 44,693 admissions from 28 hospitals meeting inclusion criteria. Overall PICU mortality was 2.8%. We identified day 1 MODS in 18.6% of admissions. Patients with day 1 MODS had higher mortality (10.0% vs. 1.2%, p < .001), longer PICU length of stay (3.6 vs. 1.3 days, p < .001), and larger change from baseline Pediatric Overall Performance Category and Pediatric Cerebral Performance Category scores at time of PICU discharge (p < .001). Infants had the highest incidence of day 1 MODS (25.2% vs. 16.5%, p < .001) compared with other age groups.
Using the largest clinical dataset to date and consensus definitions for organ failure, we found that children with MODS present on day 1 of intensive care unit admission have worse functional outcomes, higher mortality, and longer PICU length of stay than children who do not have MODS on day 1. Infants are disproportionally affected by MODS.
Genome-Wide Linkage and Admixture Mapping of Type 2 Diabetes in African American Families From the American Diabetes Association
GENNID (Genetics of NIDDM) Study Cohort
Steven C. Elbein 1 2 ,
Swapan ...K. Das 1 2 ,
D. Michael Hallman 3 ,
Craig L. Hanis 3 and
Sandra J. Hasstedt 4
1 Division of Endocrinology, Department of Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little
Rock, Arkansas
2 Research and Medical Services, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
3 Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, Texas
4 Department of Human Genetics, University of Utah Health Sciences Center, Salt Lake City, Utah
Corresponding author: Steven C. Elbein, elbeinstevenc{at}uams.edu
Abstract
OBJECTIVE— We used a single nucleotide polymorphism (SNP) map in a large cohort of 580 African American families to identify regions
linked to type 2 diabetes, age of type 2 diabetes diagnosis, and BMI.
RESEARCH DESIGN AND METHODS— After removing outliers and problematic samples, we conducted linkage analysis using 5,914 SNPs in 1,344 individuals from
530 families. Linkage analysis was conducted using variance components for type 2 diabetes, age of type 2 diabetes diagnosis,
and BMI and nonparametric linkage analyses. Ordered subset analyses were conducted ranking on age of type 2 diabetes diagnosis,
BMI, waist circumference, waist-to-hip ratio, and amount of European admixture. Admixture mapping was conducted using 4,486
markers not in linkage disequilibrium.
RESULTS— The strongest signal for type 2 diabetes (logarithm of odds LOD 4.53) was a broad peak on chromosome 2, with weaker linkage
to age of type 2 diabetes diagnosis (LOD 1.82). Type 2 diabetes and age of type 2 diabetes diagnosis were linked to chromosome
13p (3–22 cM; LOD 2.42 and 2.46, respectively). Age of type 2 diabetes diagnosis was linked to 18p (66 cM; LOD 2.96). We replicated
previous reports on chromosome 7p (79 cM; LOD 2.93). Ordered subset analysis did not overlap with linkage of unselected families.
The best admixture score was on chromosome 12 (90 cM; P = 0.0003).
CONCLUSIONS— The linkage regions on chromosomes 7 (27–78 cM) and 18p overlap prior reports, whereas regions on 2p and 13p linkage are novel.
Among potential candidate genes implicated are TCF7L1 , VAMP5, VAMP8, CDK8 , INSIG2 , IPF1 , PAX8 , IL18R1 , members of the IL1 and IL1 receptor families, and MAP4K4 . These studies provide a complementary approach to genome-wide association scans to identify causative genes for African
American diabetes.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 7 October 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted September 29, 2008.
Received July 10, 2008.
DIABETES
OBJECTIVE:--Diabetic retinopathy is a major cause of blindness. To determine whether retinopathy itself or only its severity aggregates in families, we examined the occurrence and severity of ...diabetic retinopathy in Mexican-American siblings with type 2 diabetes. RESEARCH DESIGN AND METHODS--Using stereoscopic fundus photography of seven standard fields, we measured retinopathy in 656 type 2 diabetic patients from 282 Mexican-American families from Starr County, Texas. Retinopathy severity was scored using the Early Treatment of Diabetic Retinopathy Study system and classified as no retinopathy, early nonproliferative diabetic retinopathy (NPDR-E), moderate-to-severe nonproliferative diabetic retinopathy (NPDR-S), or proliferative diabetic retinopathy (PDR). RESULTS:--Of 249 siblings of randomly selected probands with retinopathy, 169 (67.9%) had retinopathy, compared with 95 of 125 siblings of unaffected probands (76.0%; P = 0.11). Proband retinopathy class was associated (P = 0.03) with sibling retinopathy class, with significant odds ratios (ORs) for NPDR-E versus no retinopathy (OR 0.57 95% CI 0.35-0.93) and PDR versus NPDR-E (2.02 1.13-3.63); the contrast of NPDR-S versus NPDR-E approached significance (1.78 0.99-3.20). With the more severe classes (PDR and NPDR-S) combined in one group and the less severe ones (none and NPDR-E) in another, more severe proband retinopathy was associated with more severe sibling retinopathy (1.72 1.03-2.88). CONCLUSIONS:--More severe diabetic retinopathy showed evidence of familial aggregation, but the occurrence of diabetic retinopathy per se did not. The factors involved in the onset of diabetic retinopathy may differ from those involved in its progression to more severe forms.
A Genome-Wide Linkage Scan for Diabetic Retinopathy Susceptibility Genes in Mexican Americans With Type 2 Diabetes From Starr
County, Texas
D. Michael Hallman 1 ,
Eric Boerwinkle 1 ,
Victor H. ...Gonzalez 2 ,
Barbara E. K. Klein 3 ,
Ronald Klein 3 and
Craig L. Hanis 1
1 Human Genetics Center, University of Texas Health Science Center at Houston School of Public Health, Houston, Texas
2 Valley Retina Institute, McAllen, Texas
3 Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison Medical School, Madison, Wisconsin
Address correspondence and reprint requests to Craig L. Hanis, University of Texas Health, Science Center at Houston, P.O.
Box 20186, Houston, TX 77225. E-mail: craig.l.hanis{at}uth.tmc.edu
Abstract
We conducted a genome-wide linkage scan for genes contributing to retinopathy risk using 794 diabetes case subjects from 393
Mexican-American families from Starr County, Texas, having at least two diabetic siblings. The sample included 567 retinopathy
case subjects comprising 282 affected sibling pairs. Retinopathy was classified as none, early nonproliferative, moderate-to-severe
nonproliferative, or proliferative. Using 360 polymorphic markers (average spacing 9.4 cM), we conducted nonparametric linkage
analysis followed by ordered-subset analysis (OSA) ranking families by average age of diabetes diagnosis. For any retinopathy,
the highest LOD scores including all families were on chromosomes 3 (2.41 at 117 cM) and 12 (2.47 at 15.5). OSA logarithm
of odds (LOD) scores >2 for any retinopathy occurred on chromosomes 12 (4.47 at 13.2 cM), 15 (3.65 at 100.6), and 20 (2.67
at 54.1). Scores >2 for either moderate-to-severe nonproliferative or proliferative retinopathy occurred on chromosomes 5
(2.53 at 11.2 cM), 6 (2.28 at 30.6), and 19 (2.21 at 100.6). Thus, unconditional linkage analysis revealed suggestive evidence
of linkage with retinopathy on two chromosomes, whereas OSA revealed strong evidence of linkage on two chromosomes, and suggestive
evidence on four. Candidate genes were identified in most implicated regions.
LOD, logarithm of odds
OSA, ordered-subset analysis
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 24 January 2007. DOI: 10.2337/db06-1373.
Additional information can be found in an online appendix at http://dx.doi.org/10.2337/db06-1373 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted January 9, 2007.
Received October 2, 2006.
DIABETES
Specific mutations in the gene for proprotein convertase, subtilisin-kexin type 9 (PCSK9), that are associated with lower coronary heart disease risk may produce lifelong decreases in low-density ...lipoprotein (LDL) cholesterol levels, but data on their effects in younger subjects are lacking. We analyzed associations of 1 missense (R46L) and 2 nonsense (Y142X and C679X) PCSK9 mutations with serum LDL cholesterol in 478 African-Americans and 1,086 whites, 4 to 38 years of age, examined 3 to 8 times in the Bogalusa Heart Study. L46 allele frequency in whites was 0.017 ± 0.003; the combined frequency of X142 or X679 alleles in African-Americans was 0.016 ± 0.005. In whites, LDL cholesterol was lower in L46 carriers (78.9 ± 21.8 mg/dl) than in noncarriers (89.7 ± 24.9 mg/dl, p = 0.027) at their first examination (mean age 9.4 ± 3.2 years). African-Americans carrying the X142 or X679 allele had lower LDL cholesterol levels than did noncarriers (77.3 ± 15.1 vs 91.4 ± 23.9 mg/dl, p = 0.043) at their first examination (mean age 9.0 ± 3.0 years). Longitudinal LDL cholesterol profiles were significantly lower in whites with the L46 allele and in African-Americans with the X142 or X679 allele. In conclusion, our results show that these PCSK9 variants are associated with significantly lower LDL cholesterol levels starting in childhood.
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