PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-9 (9)
 

Clipboard (0)
None
Journals
Year of Publication
Document Types
1.  Evaluation of Common Type 2 Diabetes Risk Variants in a South Asian Population of Sri Lankan Descent 
PLoS ONE  2014;9(6):e98608.
Introduction
Most studies seeking common variant associations with type 2 diabetes (T2D) have focused on individuals of European ancestry. These discoveries need to be evaluated in other major ancestral groups, to understand ethnic differences in predisposition, and establish whether these contribute to variation in T2D prevalence and presentation. This study aims to establish whether common variants conferring T2D-risk in Europeans contribute to T2D-susceptibility in the South Asian population of Sri Lanka.
Methodology
Lead single nucleotide polymorphism (SNPs) at 37 T2D-risk loci attaining genome-wide significance in Europeans were genotyped in 878 T2D cases and 1523 normoglycaemic controls from Sri Lanka. Association testing was performed by logistic regression adjusting for age and sex and by the Cochran-Mantel-Haenszel test after stratifying according to self-identified ethnolinguistic subgroup. A weighted genetic risk score was generated to examine the combined effect of these SNPs on T2D-risk in the Sri Lankan population.
Results
Of the 36 SNPs passing quality control, sixteen showed nominal (p<0.05) association in Sri Lankan samples, fifteen of those directionally-consistent with the original signal. Overall, these association findings were robust to analyses that accounted for membership of ethnolinguistic subgroups. Overall, the odds ratios for 31 of the 36 SNPs were directionally-consistent with those observed in Europeans (p = 3.2×10−6). Allelic odds ratios and risk allele frequencies in Sri Lankan subjects were not systematically different to those reported in Europeans. Genetic risk score and risk of T2D were strongly related in Sri Lankans (per allele OR 1.10 [95%CI 1.08–1.13], p = 1.2×10−17).
Conclusion
Our data indicate that most T2D-risk variants identified in Europeans have similar effects in South Asians from Sri Lanka, and that systematic difference in common variant associations are unlikely to explain inter-ethnic differences in prevalence or presentation of T2D.
doi:10.1371/journal.pone.0098608
PMCID: PMC4057178  PMID: 24926958
2.  Family-based analysis of tumor necrosis factor and lymphotoxin-α tag polymorphisms with type 1 diabetes in the population of South Croatia 
Human immunology  2009;70(3):195-199.
Tumor necrosis factor (TNF) and lymphotoxin-α (LTA) are cytokines with a wide range of inflammatory and immunomodulatory activities. Type 1 diabetes is an autoimmune disease characterized by destruction of insulin-producing pancreatic β cells. The aim of the present study was to evaluate the association of polymorphisms in the TNF/LTA gene region with susceptibility to type 1 diabetes. We investigated 11 TNF/LTA tag polymorphisms, designed to capture the majority of common variation in the region, in 160 trio families from South Croatia. We observed overtransmission of alleles from parents to affected child at five variants: (rs909253, allele C, p = 1.2×10−4; rs1041981, allele A, p = 1.1×10−4; rs1800629 (G-308A), allele A, p = 1.2×10−4; rs361525(G-238A), allele G, p = 8.2×10−3 and rs3093668, allele G, p = 0.014). We also identified overtransmission of the rs 1800629(G-308A)-rs361525(G-238A) A-G haplotype, p = 2.384×10−5. The present study found an association of the TNF/LTA gene region with type 1 diabetes. A careful assessment of TNF/LTA variants adjusted for linkage disequilibrium with HLA loci is needed to further clarify the role of these genes in type 1 diabetes susceptibility in the population of South Croatia.
doi:10.1016/j.humimm.2008.12.010
PMCID: PMC2709221  PMID: 19167443
Type 1 diabetes; Tumor necrosis factor; Lymphotoxin alpha; TDT; Tag polymorphism
3.  Low Frequency Variants in the Exons Only Encoding Isoform A of HNF1A Do Not Contribute to Susceptibility to Type 2 Diabetes 
PLoS ONE  2009;4(8):e6615.
Background
There is considerable interest in the hypothesis that low frequency, intermediate penetrance variants contribute to the proportion of Type 2 Diabetes (T2D) susceptibility not attributable to the common variants uncovered through genome-wide association approaches. Genes previously implicated in monogenic and multifactorial forms of diabetes are obvious candidates in this respect. In this study, we focussed on exons 8–10 of the HNF1A gene since rare, penetrant mutations in these exons (which are only transcribed in selected HNF1A isoforms) are associated with a later age of diagnosis of Maturity onset diabetes of the young (MODY) than mutations in exons 1–7. The age of diagnosis in the subgroup of HNF1A-MODY individuals with exon 8–10 mutations overlaps with that of early multifactorial T2D, and we set out to test the hypothesis that these exons might also harbour low-frequency coding variants of intermediate penetrance that contribute to risk of multifactorial T2D.
Methodology and Principal Findings
We performed targeted capillary resequencing of HNF1A exons 8–10 in 591 European T2D subjects enriched for genetic aetiology on the basis of an early age of diagnosis (≤45 years) and/or family history of T2D (≥1 affected sibling). PCR products were sequenced and compared to the published HNF1A sequence. We identified several variants (rs735396 [IVS9−24T>C], rs1169304 [IVS8+29T>C], c.1768+44C>T [IVS9+44C>T] and rs61953349 [c.1545G>A, p.T515T] but no novel non-synonymous coding variants were detected.
Conclusions and Significance
We conclude that low frequency, nonsynonymous coding variants in the terminal exons of HNF1A are unlikely to contribute to T2D-susceptibility in European samples. Nevertheless, the rationale for seeking low-frequency causal variants in genes known to contain rare, penetrant mutations remains strong and should motivate efforts to screen other genes in a similar fashion.
doi:10.1371/journal.pone.0006615
PMCID: PMC2720540  PMID: 19672314
4.  BMI-Associated Alleles Do Not Constitute Risk Alleles for Polycystic Ovary Syndrome Independently of BMI: A Case-Control Study 
PLoS ONE  2014;9(1):e87335.
Introduction
Polycystic Ovary Syndrome (PCOS) has a strong genetic background and the majority of patients with PCOS have elevated BMI levels. The aim of this study was to determine to which extent BMI-increasing alleles contribute to risk of PCOS when contemporaneous BMI is taken into consideration.
Methods
Patients with PCOS and controls were recruited from the United Kingdom (563 cases and 791 controls) and The Netherlands (510 cases and 2720 controls). Cases and controls were of similar BMI. SNPs mapping to 12 BMI-associated loci which have been extensively replicated across different ethnicities, i.e., BDNF, FAIM2, ETV5, FTO, GNPDA2, KCTD15, MC4R, MTCH2, NEGR1, SEC16B, SH2B1, and TMEM18, were studied in association with PCOS within each cohort using the additive genetic model followed by a combined analysis. A genetic allelic count risk score model was used to determine the risk of PCOS for individuals carrying increasing numbers of BMI-increasing alleles.
Results
None of the genetic variants, including FTO and MC4R, was associated with PCOS independently of BMI in the meta-analysis. Moreover, no differences were observed between cases and controls in the number of BMI-risk alleles present and no overall trend across the risk score groups was observed.
Conclusion
In this combined analysis of over 4,000 BMI-matched individuals from the United Kingdom and the Netherlands, we observed no association of BMI risk alleles with PCOS independent of BMI.
doi:10.1371/journal.pone.0087335
PMCID: PMC3909077  PMID: 24498077
5.  Meta-Analysis Investigating Associations Between Healthy Diet and Fasting Glucose and Insulin Levels and Modification by Loci Associated With Glucose Homeostasis in Data From 15 Cohorts 
American Journal of Epidemiology  2012;177(2):103-115.
Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 US and European cohort studies comprising 51,289 persons without diabetes to test whether genotype and diet interact to influence FG or FI concentration. We constructed a diet score using study-specific quartile rankings for intakes of whole grains, fish, fruits, vegetables, and nuts/seeds (favorable) and red/processed meats, sweets, sugared beverages, and fried potatoes (unfavorable). We used linear regression within studies, followed by inverse-variance-weighted meta-analysis, to quantify 1) associations of diet score with FG and FI levels and 2) interactions of diet score with 16 FG-associated loci and 2 FI-associated loci. Diet score (per unit increase) was inversely associated with FG (β = −0.004 mmol/L, 95% confidence interval: −0.005, −0.003) and FI (β = −0.008 ln-pmol/L, 95% confidence interval: −0.009, −0.007) levels after adjustment for demographic factors, lifestyle, and body mass index. Genotype variation at the studied loci did not modify these associations. Healthier diets were associated with lower FG and FI concentrations regardless of genotype at previously replicated FG- and FI-associated loci. Studies focusing on genomic regions that do not yield highly statistically significant associations from main-effect genome-wide association studies may be more fruitful in identifying diet-gene interactions.
doi:10.1093/aje/kws297
PMCID: PMC3707424  PMID: 23255780
diabetes; dietary pattern; gene-environment interaction; glucose; insulin
6.  Multiple type 2 diabetes susceptibility genes following genome-wide association scan in UK samples 
Science (New York, N.Y.)  2007;316(5829):1336-1341.
The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1,924 diabetic cases and 2,938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3,757 additional cases and 5,346 controls, and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insights into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.
doi:10.1126/science.1142364
PMCID: PMC3772310  PMID: 17463249
7.  Linkage Disequilibrium Mapping of the Replicated Type 2 Diabetes Linkage Signal on Chromosome 1q 
Diabetes  2009;58(7):1704-1709.
OBJECTIVE
Linkage of the chromosome 1q21–25 region to type 2 diabetes has been demonstrated in multiple ethnic groups. We performed common variant fine-mapping across a 23-Mb interval in a multiethnic sample to search for variants responsible for this linkage signal.
RESEARCH DESIGN AND METHODS
In all, 5,290 single nucleotide polymorphisms (SNPs) were successfully genotyped in 3,179 type 2 diabetes case and control subjects from eight populations with evidence of 1q linkage. Samples were ascertained using strategies designed to enhance power to detect variants causal for 1q linkage. After imputation, we estimate ∼80% coverage of common variation across the region (r 2 > 0.8, Europeans). Association signals of interest were evaluated through in silico replication and de novo genotyping in ∼8,500 case subjects and 12,400 control subjects.
RESULTS
Association mapping of the 23-Mb region identified two strong signals, both of which were restricted to the subset of European-descent samples. The first mapped to the NOS1AP (CAPON) gene region (lead SNP: rs7538490, odds ratio 1.38 [95% CI 1.21–1.57], P = 1.4 × 10−6, in 999 case subjects and 1,190 control subjects); the second mapped within an extensive region of linkage disequilibrium that includes the ASH1L and PKLR genes (lead SNP: rs11264371, odds ratio 1.48 [1.18–1.76], P = 1.0 × 10−5, under a dominant model). However, there was no evidence for association at either signal on replication, and, across all data (>24,000 subjects), there was no indication that these variants were causally related to type 2 diabetes status.
CONCLUSIONS
Detailed fine-mapping of the 23-Mb region of replicated linkage has failed to identify common variant signals contributing to the observed signal. Future studies should focus on identification of causal alleles of lower frequency and higher penetrance.
doi:10.2337/db09-0081
PMCID: PMC2699860  PMID: 19389826
8.  Type 2 Diabetes Risk Alleles Are Associated With Reduced Size at Birth 
Diabetes  2009;58(6):1428-1433.
OBJECTIVE
Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight.
RESEARCH DESIGN AND METHODS
We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring.
RESULTS
We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11–31], P = 2 × 10−5, and 14 g [4–23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39–120) lighter at birth than the 8% carrying none (Ptrend = 5 × 10−7). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus.
CONCLUSIONS
Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.
doi:10.2337/db08-1739
PMCID: PMC2682672  PMID: 19228808
9.  Common Variation in the LMNA Gene (Encoding Lamin A/C) and Type 2 Diabetes 
Diabetes  2007;56(3):879-883.
Mutations in the LMNA gene (encoding lamin A/C) underlie familial partial lipodystrophy, a syndrome of monogenic insulin resistance and diabetes. LMNA maps to the well-replicated diabetes-linkage region on chromosome 1q, and there are reported associations between LMNA single nucleotide polymorphisms (SNPs) (particularly rs4641; H566H) and metabolic syndrome components. We examined the relationship between LMNA variation and type 2 diabetes (using six tag SNPs capturing >90% of common variation) in several large datasets. Analysis of 2,490 U.K. diabetic case and 2,556 control subjects revealed no significant associations at either genotype or haplotype level: the minor allele at rs4641 was no more frequent in case subjects (allelic odds ratio [OR] 1.07 [95% CI 0.98-1.17], P = 0.15). In 390 U.K. trios, family-based association analyses revealed nominally significant overtransmission of the major allele at rs12063564 (P = 0.01), which was not corroborated in other samples. Finally, genotypes for 2,817 additional subjects from the International 1q Consortium revealed no consistent case-control or family-based associations with LMNA variants. Across all our data, the OR for the rs4641 minor allele approached but did not attain significance (1.07 [0.99-1.15], P = 0.08). Our data do not therefore support a major effect of LMNA variation on diabetes risk. However, in a meta-analysis including other available data, there is evidence that rs4641 has a modest effect on diabetes susceptibility (1.10 [1.04-1.16], P = 0.001).
doi:10.2337/db06-0930
PMCID: PMC2672988  PMID: 17327460

Results 1-9 (9)