Robert A. Scott

Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases

Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m2) compared to obese cases (BMI≥30 Kg/m2). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m2) or 4,123 obese cases (BMI≥30 kg/m2), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (Pu200a=u200a8.4×10−9, ORu200a=u200a1.13 [95% CI 1.09–1.18]), and this association was stronger than that in obese cases (Pu200a=u200a0.04, ORu200a=u200a1.03 [95% CI 1.00–1.06]). A variant in HMG20A—previously identified in South Asians but not Europeans—was associated with type 2 diabetes in obese cases (Pu200a=u200a1.3×10−8, ORu200a=u200a1.11 [95% CI 1.07–1.15]), although this association was not significantly stronger than that in lean cases (Pu200a=u200a0.02, ORu200a=u200a1.09 [95% CI 1.02–1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial Pu200a=u200a0.0002). In the lean analysis, we observed a weighted per-risk allele ORu200a=u200a1.13 [95% CI 1.10–1.17], Pu200a=u200a3.2×10−14. This was larger than the same model fitted in the obese analysis where the ORu200a=u200a1.06 [95% CI 1.05–1.08], Pu200a=u200a2.2×10−16. This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.

Demographic characteristics of elite Kenyan endurance runners

Abstract Kenyan athletes have dominated international distance running in recent years. Explanations for their success include favourable physiological characteristics, which could include favourable genetic endowment, and advantageous environmental conditions. The aim of this study was to compare the demographic characteristics of elite Kenyan runners with those of the general Kenyan population. Questionnaires, administered to 404 elite Kenyan runners specializing in distances ranging from the 800 m to the marathon and 87 Kenyan controls, obtained information on place of birth, language, and distance and method of travel to school. Athletes were separated into two groups according to athletic success: those who competed in international competition and those who competed in national competition. The athletes differed from controls in regional distribution, language, and distance and method of travel to school; athletes also differed from each other with the exception of method of travel to school. Most national and international athletes came from the Rift Valley province (controls 20%, national athletes 65%, international athletes 81%), belonged to the Kalenjin ethnic group (controls 8%, national athletes 49%, international athletes 76%) and Nandi sub-tribe (controls 5%, national athletes 25%, international athletes 44%), and spoke languages of Nilotic origin (controls 21%, national athletes 60%, international athletes 79%). A higher proportion of all athletes ran to school each day (controls 22%, national athletes 73%, international athletes 81%) and covered greater distances. In conclusion, Kenyan runners are from a distinctive environmental background in terms of geographical distribution, ethnicity and travelled further to school, mostly by running. These findings highlight the importance of environmental and social factors in the success of Kenyan runners.

ACTN3 and ACE genotypes in elite Jamaican and US sprinters

UNLABELLEDnThe angiotensin-converting enzyme (ACE) and the alpha-actinin-3 (ACTN3) genes are two of the most studied performance genes and both have been associated with sprint/power phenotypes and elite performance.nnnPURPOSEnTo investigate the association between the ACE and the ACTN3 genotypes and sprint athlete status in elite Jamaican and US African American sprinters.nnnMETHODSnThe ACTN3 R577X and the ACE I/D and A22982G (rs4363) genotype distributions of elite Jamaican (J-A; N = 116) and US sprinters (US-A; N = 114) were compared with controls from the Jamaican (J-C; N = 311) and US African American (US-C; N = 191) populations. Frequency differences between groups were assessed by exact test.nnnRESULTSnFor ACTN3, the XX genotype was found to be at very low frequency in both athlete and control cohorts (J-C = 2%, J-A = 3%, US-C = 4%, US-A = 2%). Athletes did not differ from controls in ACTN3 genotype distribution (J, P = 0.87; US, P = 0.58). Similarly, neither US nor Jamaican athletes differed from controls in genotype at ACE I/D (J, P = 0.44; US, P = 0.37). Jamaican athletes did not differ from controls for A22982G genotype (P = 0.28), although US sprinters did (P = 0.029), displaying an excess of heterozygotes relative to controls but no excess of GG homozygotes (US-C = 22%, US-A = 18%).nnnCONCLUSIONSnGiven that ACTN3 XX genotype is negatively associated with elite sprint athlete status, the underlying low frequency in these populations eliminates the possibility of replicating this association in Jamaican and US African American sprinters. The finding of no excess in ACE DD or GG genotypes in elite sprint athletes relative to controls suggests that ACE genotype is not a determinant of elite sprint athlete status.

The link between family history and risk of type 2 diabetes is not explained by anthropometric, lifestyle or genetic risk factors: The EPIC-InterAct study

Although a family history of type 2 diabetes is a strong risk factor for the disease, the factors mediating this excess risk are poorly understood. In the InterAct case-cohort study, we investigated the association between a family history of diabetes among different family members and the incidence of type 2 diabetes, as well as the extent to which genetic, anthropometric and lifestyle risk factors mediated this association. A total of 13,869 individuals (including 6,168 incident cases of type 2 diabetes) had family history data available, and 6,887 individuals had complete data on all mediators. Country-specific Prentice-weighted Cox models were fitted within country, and HRs were combined using random effects meta-analysis. Lifestyle and anthropometric measurements were performed at baseline, and a genetic risk score comprising 35 polymorphisms associated with type 2 diabetes was created. A family history of type 2 diabetes was associated with a higher incidence of the condition (HR 2.72, 95% CI 2.48, 2.99). Adjustment for established risk factors including BMI and waist circumference only modestly attenuated this association (HR 2.44, 95% CI 2.03, 2.95); the genetic score alone explained only 2% of the family history-associated risk of type 2 diabetes. The greatest risk of type 2 diabetes was observed in those with a biparental history of type 2 diabetes (HR 5.14, 95% CI 3.74, 7.07) and those whose parents had been diagnosed with diabetes at a younger age (<50xa0years; HR 4.69, 95% CI 3.35, 6.58), an effect largely confined to a maternal family history. Prominent lifestyle, anthropometric and genetic risk factors explained only a marginal proportion of the excess risk associated with family history, highlighting the fact that family history remains a strong, independent and easily assessed risk factor for type 2 diabetes. Discovering factors that will explain the association of family history with type 2 diabetes risk will provide important insight into the aetiology of type 2 diabetes.Aims/hypothesisAlthough a family history of type 2 diabetes is a strong risk factor for the disease, the factors mediating this excess risk are poorly understood. In the InterAct case-cohort study, we investigated the association between a family history of diabetes among different family members and the incidence of type 2 diabetes, as well as the extent to which genetic, anthropometric and lifestyle risk factors mediated this association.MethodsA total of 13,869 individuals (including 6,168 incident cases of type 2 diabetes) had family history data available, and 6,887 individuals had complete data on all mediators. Country-specific Prentice-weighted Cox models were fitted within country, and HRs were combined using random effects meta-analysis. Lifestyle and anthropometric measurements were performed at baseline, and a genetic risk score comprising 35 polymorphisms associated with type 2 diabetes was created.ResultsA family history of type 2 diabetes was associated with a higher incidence of the condition (HR 2.72, 95% CI 2.48, 2.99). Adjustment for established risk factors including BMI and waist circumference only modestly attenuated this association (HR 2.44, 95% CI 2.03, 2.95); the genetic score alone explained only 2% of the family history-associated risk of type 2 diabetes. The greatest risk of type 2 diabetes was observed in those with a biparental history of type 2 diabetes (HR 5.14, 95% CI 3.74, 7.07) and those whose parents had been diagnosed with diabetes at a younger age (<50xa0years; HR 4.69, 95% CI 3.35, 6.58), an effect largely confined to a maternal family history.Conclusions/interpretationProminent lifestyle, anthropometric and genetic risk factors explained only a marginal proportion of the excess risk associated with family history, highlighting the fact that family history remains a strong, independent and easily assessed risk factor for type 2 diabetes. Discovering factors that will explain the association of family history with type 2 diabetes risk will provide important insight into the aetiology of type 2 diabetes.

FTO genotype and adiposity in children: physical activity levels influence the effect of the risk genotype in adolescent males

Studies of the fat mass and obesity-associated (FTO) gene provide compelling evidence of genetic variation in the general population that influences fat levels and obesity risk. Studies of the interaction between genetic and environmental factors such as physical activity (PA) will promote the understanding of how lifestyle can modulate genetic contributions to obesity. In this study, we investigated the effect of FTO genotype, and interactions with PA or energy intake, in young children and adolescents. In all, 1–5-year-old children from the Growth, Exercise and Nutrition Epidemiological Study in preSchoolers (GENESIS) study (N=1980) and 11–18-year-old Greek adolescents (N=949) were measured for adiposity-related phenotypes and genotyped at the FTO single-nucleotide polymorphism (SNP) marker, rs17817449. Adolescents were classified as physically active or inactive based on self-reported levels of PA. In adolescents, FTO genotype influenced weight (P=0.001) and BMI (P=0.007). There was also a significant SNP*PA*gender interaction (P=0.028) on BMI, which reflected the association between FTO genotype and BMI in males (P=0.016), but not females (P=0.15), and significant SNP*PA interaction in males (P=0.007), but not females (P=0.74). The FTO genotype effect was more pronounced in inactive than active males. Inactive males homozygous for the G allele had a mean BMI 3u2009kg/m2 higher than T carriers (P=0.008). In the GENESIS study, no significant association between FTO genotype and adiposity was found. The present findings highlight PA as an important factor modifying the effect of FTO genotype.

Genotypes and distance running : clues from Africa.

A look at the medal podium in almost any international sporting competition reveals that some athletes and certain countries enjoy regular success in particular events. While environmental influences such as training and diet are important, it is likely that there is also some genetic component to elite athletic performance. One of the most compelling examples of athletic domination is that of east African runners in international distance running competition. This phenomenon has led to the suggestion that east Africans possess some inherent genetic advantage predisposing them to superior athletic performances. The concurrent success of athletes of west African ancestry in sprint events also appears to have augmented this belief given their similar skin colour. A growing body of evidence suggests that genetic variation does influence athletic performance, yet despite the speculation that African athletes have a genetic advantage for physical performance, there is no genetic evidence to suggest that this is the case. The only available genetic studies of elite African athletes do not find that these athletes possess a unique genetic makeup; rather, they serve to highlight the high degree of genetic diversity in east African populations and also among elite east African athletes.

Impact of peroxisome proliferator–activated receptors γ and δ on adiposity in toddlers and preschoolers in the GENESIS study

Peroxisome proliferator–activated receptor γ (PPAR γ) and peroxisome proliferator–activated receptor δ (PPAR δ) are promising candidate genes for obesity. Associations between adiposity‐related phenotypes and genetic variation in PPAR γ (Pro12Ala and C1431T), as well as PPAR δ (T+294C) were assessed in 2,102 Greek children aged 1–6 years, as part of a large‐scale epidemiological study (Growth, Exercise and Nutrition Epidemiological Study In preSchoolers). In girls aged 3–4 years, the Ala12 allele was associated with higher mid‐upper arm (P = 0.010) and hip (P = 0.005) circumferences, as well as subscapular (P = 0.008) and total skinfolds (P = 0.011) that explained 2.0, 3.7, 2.1, and 1.9% of the phenotypic variance, respectively, while the T1431 allele was associated with higher mean values for waist circumference (P = 0.018) and suprailiac skinfold (P = 0.017), genotype accounting for 1.6% of the variance in both phenotypes. No significant effects of PPAR δ T+294C polymorphism or the interaction of the PPAR δ and PPAR γ variants on adiposity‐related phenotypes were observed in any age group or gender. Haplotype‐based analysis including both PPAR γ polymorphisms revealed that in girls aged 3–4 years, the Ala‐T haplotype was associated with higher waist (P = 0.014) and hip (P = 0.007) circumferences compared to the common Pro‐C haplotype. The PPAR γ Pro12Ala and C1431T polymorphisms are associated with increased adiposity during early childhood in a gender‐ and age‐specific manner and independently of the PPAR δ T+294C polymorphism.

DNA yield and quality of saliva samples and suitability for large scale epidemiological studies in children

Objective:To evaluate two saliva collection methods for DNA yield and quality as applied to a large, integrated, multicentre, European project involving the collection of biological material from children.Design:Cross-sectional multicentre comparative study in young children.Methods:Saliva samples were collected from 14u2009019 children aged 2–9 years from eight European countries participating in the IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) study. This involved either the collection of 2u2009ml of saliva from children who were able to spit, or using a sponge to collect whole saliva and buccal mucosal cells from the inside of the mouth of younger children unable to spit. Samples were assembled centrally in each participating centre and subsequently despatched for DNA extraction and biobanking to the University of Glasgow. A subgroup of 4678 samples (∼33% of sampled individuals) were chosen for DNA extraction before genotyping.Results:The whole-saliva collection method resulted in a higher DNA yield than the sponge collection method (mean±s.d.; saliva: 20.95±2.35u2009μg, sponge: 9.13±2.25u2009μg; P<0.001). DNA quality as measured by A 260/A 280 was similar for the two collection methods. A minimum genotype calling success rate of 95% showed that both methods provide good-quality DNA for genotyping using TaqMan allelic discrimination assays.Conclusions:Our results showed higher DNA yield from the whole-saliva collection method compared with the assisted sponge collection. However, both collection methods provided DNA of sufficient quantity and quality for large-scale genetic epidemiological studies.

The Impact of ACE Genotype on Serum ACE Activity in a Black South African Male Population

The strong association between the angiotensin I‐converting enzyme (ACE) gene I/D polymorphism with serum ACE activity appears lacking in Nigerians and Kenyans, but has not previously been well assessed in others of African origin. This study addressed this issue in an ethnically well defined black South African population. A putative association for the A22982G ACE gene variant, a QTL likely to impact on serum ACE activity, was also sought.

Y chromosome haplogroups of elite Ethiopian endurance runners

Favourable genetic endowment has been proposed as part of the explanation for the success of East African endurance athletes, but no evidence has yet been presented. The Y chromosome haplogroup distribution of elite Ethiopian athletes (n=62) was compared with that of the general Ethiopian population (n=95) and a control group from Arsi (a region producing a disproportionate number of athletes; n=85). Athletes belonged to three groups: marathon runners (M; n=23), 5–km to 10–km runners (5–10K; n=21) and other track and field athletes (TF; n=18). DNA was extracted from buccal swabs and haplogroups were assigned after the typing of binary markers in multiplexed minisequencing reactions. Frequency differences between groups were assessed by using contingency exact tests and showed that Y chromosome haplogroups are not distributed amongst elite Ethiopian endurance runners in the same proportions as in the general population, with statistically significant (P<0.05) differences being found in four of the individual haplogroups. The geographical origins and languages of the athletes and controls suggest that these differences are less likely to be a reflection of population structure and that Y chromosome haplogroups may play a significant role in determining Ethiopian endurance running success.