Simon D. Rees

Replication of 13 genome-wide association (GWA)-validated risk variants for type 2 diabetes in Pakistani populations

Aims/hypothesisRecent genome-wide association (GWA) studies and subsequent replication studies have greatly increased the number of validated type 2 diabetes susceptibility variants, but most of these have been conducted in European populations. Despite the high prevalence of the disease in South Asians, studies investigating GWA-validated type 2 diabetes risk variants in this ethnic group are limited. We investigated 30 single nucleotide polymorphisms (SNPs), predominantly derived from recent GWA studies, to determine if and to what extent these variants affect type 2 diabetes risk in two Punjabi populations, originating predominantly from the District of Mirpur, Pakistan.MethodsThirty SNPs were genotyped in 1,678 participants with type 2 diabetes and 1,584 normoglycaemic control participants from two populations; one resident in the UK and one indigenous to the District of Mirpur.ResultsSNPs in or near PPARG, TCF7L2, FTO, CDKN2A/2B, HHEX/IDE, IGF2BP2, SLC30A8, KCNQ1, JAZF1, IRS1, KLF14, CHCHD9 and DUSP9 displayed significant (p < 0.05) associations with type 2 diabetes, with similar effect sizes to those seen in European populations. A constructed genetic risk score was associated with type 2 diabetes (p = 5.46 × 10−12), BMI (p = 2.25 × 10−4) and age at onset of diabetes (p = 0.002).Conclusions/interpretationWe have demonstrated that 13 variants confer an increased risk of type 2 diabetes in our Pakistani populations; to our knowledge this is the first time that SNPs in or near KCNQ1, JAZF1, IRS1, KLF14, CHCHD9 and DUSP9 have been significantly associated with the disease in South Asians. Large-scale studies and meta-analyses of South Asian populations are needed to further confirm the effect of these variants in this ethnic group.

An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference

Diabet. Med. 28, 673–680 (2011)

Significant effect of APOE Epsilon 4 Genotype on the risk of dementia in Alzheimer's disease and mortality in persons with Down Syndrome

Virtually all adults with Down syndrome (DS) have neuropathological manifestations of Dementia in Alzheimers disease (DAD) but not all develop clinical psychopathology. The effect of allelic variants of Apolipoprotein (APOE) gene in development and progression of DAD and mortality in persons with DS is examined.

Circadian gene variants and susceptibility to type 2 diabetes: A pilot study

Background Disruption of endogenous circadian rhythms has been shown to increase the risk of developing type 2 diabetes, suggesting that circadian genes might play a role in determining disease susceptibility. We present the results of a pilot study investigating the association between type 2 diabetes and selected single nucleotide polymorphisms (SNPs) in/near nine circadian genes. The variants were chosen based on their previously reported association with prostate cancer, a disease that has been suggested to have a genetic link with type 2 diabetes through a number of shared inherited risk determinants. Methodology/Principal Findings The pilot study was performed using two genetically homogeneous Punjabi cohorts, one resident in the United Kingdom and one indigenous to Pakistan. Subjects with (N = 1732) and without (N = 1780) type 2 diabetes were genotyped for thirteen circadian variants using a competitive allele-specific polymerase chain reaction method. Associations between the SNPs and type 2 diabetes were investigated using logistic regression. The results were also combined with in silico data from other South Asian datasets (SAT2D consortium) and white European cohorts (DIAGRAM+) using meta-analysis. The rs7602358G allele near PER2 was negatively associated with type 2 diabetes in our Punjabi cohorts (combined odds ratio [OR] = 0.75 [0.66–0.86], p = 3.18×10−5), while the BMAL1 rs11022775T allele was associated with an increased risk of the disease (combined OR = 1.22 [1.07–1.39], p = 0.003). Neither of these associations was replicated in the SAT2D or DIAGRAM+ datasets, however. Meta-analysis of all the cohorts identified disease associations with two variants, rs2292912 in CRY2 and rs12315175 near CRY1, although statistical significance was nominal (combined OR = 1.05 [1.01–1.08], p = 0.008 and OR = 0.95 [0.91–0.99], p = 0.015 respectively). Conclusions/significance None of the selected circadian gene variants was associated with type 2 diabetes with study-wide significance after meta-analysis. The nominal association observed with the CRY2 SNP, however, complements previous findings and confirms a role for this locus in disease susceptibility.

Common variants of the TCF7L2 gene are associated with increased risk of type 2 diabetes mellitus in a UK-resident South Asian population

BackgroundRecent studies have implicated variants of the transcription factor 7-like 2 (TCF7L2) gene in genetic susceptibility to type 2 diabetes mellitus in several different populations. The aim of this study was to determine whether variants of this gene are also risk factors for type 2 diabetes development in a UK-resident South Asian cohort of Punjabi ancestry.MethodsWe genotyped four single nucleotide polymorphisms (SNPs) of TCF7L2 (rs7901695, rs7903146, rs11196205 and rs12255372) in 831 subjects with diabetes and 437 control subjects.ResultsThe minor allele of each variant was significantly associated with type 2 diabetes; the greatest risk of developing the disease was conferred by rs7903146, with an allelic odds ratio (OR) of 1.31 (95% CI: 1.11 – 1.56, p = 1.96 × 10-3). For each variant, disease risk associated with homozygosity for the minor allele was greater than that for heterozygotes, with the exception of rs12255372. To determine the effect on the observed associations of including young control subjects in our data set, we reanalysed the data using subsets of the control group defined by different minimum age thresholds. Increasing the minimum age of our control subjects resulted in a corresponding increase in OR for all variants of the gene (p ≤ 1.04 × 10-7).ConclusionOur results support recent findings that TCF7L2 is an important genetic risk factor for the development of type 2 diabetes in multiple ethnic groups.

Effects of 16 Genetic Variants on Fasting Glucose and Type 2 Diabetes in South Asians: ADCY5 and GLIS3 Variants May Predispose to Type 2 Diabetes

Background The Meta-Analysis of Glucose and Insulin related traits Consortium (MAGIC) recently identified 16 loci robustly associated with fasting glucose, some of which were also associated with type 2 diabetes. The purpose of our study was to explore the role of these variants in South Asian populations of Punjabi ancestry, originating predominantly from the District of Mirpur, Pakistan. Methodology/Principal Findings Sixteen single nucleotide polymorphisms (SNPs) were genotyped in 1678 subjects with type 2 diabetes and 1584 normoglycaemic controls from two Punjabi populations; one resident in the UK and one indigenous to the District of Mirpur. In the normoglycaemic controls investigated for fasting glucose associations, 12 of 16 SNPs displayed β values with the same direction of effect as that seen in European studies, although only the SLC30A8 rs11558471 SNP was nominally associated with fasting glucose (β = 0.063 [95% CI: 0.013, 0.113] p = 0.015). Of interest, the MTNR1B rs10830963 SNP displayed a negative β value for fasting glucose in our study; this effect size was significantly lower than that seen in Europeans (p = 1.29×10−4). In addition to previously reported type 2 diabetes risk variants in TCF7L2 and SLC30A8, SNPs in ADCY5 (rs11708067) and GLIS3 (rs7034200) displayed evidence for association with type 2 diabetes, with odds ratios of 1.23 (95% CI: 1.09, 1.39; p = 9.1×10−4) and 1.16 (95% CI: 1.05, 1.29; p = 3.49×10−3) respectively. Conclusions/Significance Although only the SLC30A8 rs11558471 SNP was nominally associated with fasting glucose in our study, the finding that 12 out of 16 SNPs displayed a direction of effect consistent with European studies suggests that a number of these variants may contribute to fasting glucose variation in individuals of South Asian ancestry. We also provide evidence for the first time in South Asians that alleles of SNPs in GLIS3 and ADCY5 may confer risk of type 2 diabetes.

Association of variants within APOE, SORL1, RUNX1, BACE1 and ALDH18A1 with dementia in Alzheimer's disease in subjects with Down syndrome.

BACKGROUND Down syndrome (DS) is caused by either complete or partial triplication of chromosome 21, affecting approximately 1/1000 live births, and it is widely accepted that individuals with DS are more likely to develop dementia of Alzheimers disease (DAD) compared with the general population. Many studies have investigated genetic susceptibility to AD in the general population, resulting in a number of potential candidate genes that may influence the development of DAD. The majority of these variants, however, have not been investigated in subjects with DS. AIM The aim of this study was to determine whether genetic variants previously associated with AD in the general population, were also associated with DAD in individuals with DS. METHODS Genotyping of 43 SNPs within 28 genes was undertaken in 187 individuals with Down syndrome with and without dementia of Alzheimers disease, using the SNPlex platform. RESULTS Significant associations of SNPs in five genes with DAD in DS were found, namely APOE, SORL1, BACE1, RUNX1 and ALDH18A1. As expected, the most strongly associated SNP was the APOE ɛ4 rs429358 variant (HR=2.47 [1.58, 3.87], p=7.52×10(-5)), although variants within the more recently implicated SORL1 and RUNX1 genes were also strongly associated with DAD in DS (HR=0.54 [0.37, 0.80], p=0.002 and HR=1.61 [1.15, 2.26], p=0.006 respectively). CONCLUSIONS Our study demonstrates that a number of variants previously associated with AD in the general population are also associated with DAD in DS. To enable us to determine whether these variants, as well as other more recently revealed AD susceptibility variants, truly contribute to the development of DAD in DS, further multi-centre collaborative studies comprising large number of individuals with DS are needed.

The promoter polymorphism -232C/G of the PCK1 gene is associated with type 2 diabetes in a UK-resident South Asian population

BackgroundThe PCK1 gene, encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), has previously been implicated as a candidate gene for type 2 diabetes (T2D) susceptibility. Rodent models demonstrate that over-expression of Pck1 can result in T2D development and a single nucleotide polymorphism (SNP) in the promoter region of human PCK1 (-232C/G) has exhibited significant association with the disease in several cohorts. Within the UK-resident South Asian population, T2D is 4 to 6 times more common than in indigenous white Caucasians. Despite this, few studies have reported on the genetic susceptibility to T2D in this ethnic group and none of these has investigated the possible effect of PCK1 variants. We therefore aimed to investigate the association between common variants of the PCK1 gene and T2D in a UK-resident South Asian population of Punjabi ancestry, originating predominantly from the Mirpur area of Azad Kashmir, Pakistan.MethodsWe used TaqMan assays to genotype five tagSNPs covering the PCK1 gene, including the -232C/G variant, in 903 subjects with T2D and 471 normoglycaemic controls.ResultsOf the variants studied, only the minor allele (G) of the -232C/G SNP demonstrated a significant association with T2D, displaying an OR of 1.21 (95% CI: 1.03 - 1.42, p = 0.019).ConclusionThis study is the first to investigate the association between variants of the PCK1 gene and T2D in South Asians. Our results suggest that the -232C/G promoter polymorphism confers susceptibility to T2D in this ethnic group.Trial RegistrationUKADS Trial Registration: ISRCTN38297969

Genetic variants conferring susceptibility to Alzheimer's disease in the general population; do they also predispose to dementia in Down's syndrome

BackgroundDown’s syndrome (DS) is caused by either complete or partial triplication of chromosome 21, affecting approximately 1/1000 live births, and it is widely accepted that individuals with DS are more likely to develop dementia of Alzheimer’s disease (DAD) compared with the general population. Recent collaborative genome-wide association studies of large case control data sets of individuals with and without Alzhemier’s disease (AD) have revealed new risk variants for dementia, as well as confirming previously identified risk variants. In this study, nine AD-derived SNPs, near or within the CR1 (rs3818361), BIN1 (rs744373), CD2AP (rs9349407), EPHA1 (rs11767557), CLU (rs1532278), MS4A6A/4A (rs610932), PICALM (rs561655), ABCA7 (rs3764650) and CD33 (rs3865444) genes were genotyped in 295 individuals with DS.ResultsThere were no significant associations between these nine GWAS-derived SNPs and DAD in British Caucasian individuals with DS. Interestingly the CR1 rs3818361 variant appeared to be associated with mortality in our cohort, particularly in the subjects without dementia. To our knowledge, this is the first time that this variant has been implicated as a determinant of mortality and the finding warrants further investigation in other cohorts with DS.ConclusionsThis study shows negative associations of nine AD-derived SNPs with DAD in DS. This may be due to the modest size of our cohort, which may indicate that our study is insufficiently powered to pick up such associations. We cannot conclusively exclude a role for these SNPs in DAD in DS. Clearly, efforts to investigate genetic variants with small effects on disease risk require a much larger cohort of individuals with DS. In fact, we hypothesize that a sample size of 4465 individuals with DS would be needed to determine the role in DAD in DS of the nine AD-derived SNPs investigated in this study. We therefore recommend that all national and international clinics with access to individuals with DS should contribute DNA samples to form DS consortia.

Genetic structure of the Black Bog Ant (Formica picea Nylander) in the United Kingdom

Social Hymenoptera have been relatively little studied in terms of conservation genetics even though their sociality and complementary sex determination potentially influence the interaction of genetics with extinction risk. Using microsatellite markers, we investigated the social and genetic structure of nests and populations of the Black Bog Ant Formica picea at four sites in the UK, where this habitat specialist has a localized and fragmented range. Nests were weakly polygynous (effective queen number, 4–27 per nest) with low worker relatedness. Isolation by distance tended to be present within sites, indicating limited dispersal, but inbreeding was rare. The four study sites fell into three main populations (two in South Wales, one in southern England). We conclude that, although UK F. picea populations are not at immediate risk from genetic factors, their limited dispersal abilities at both within- and between-site scales should inform conservation management decisions.