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We compare patterns of linkage disequilibrium (LD) for 633 SNPs in two regions between samples collected in two Australian states and HapMap samples collected from Utah residents of Northern and Western (NW) European ancestry (CEU). Patterns of LD in the Australian and HapMap samples are similar, and tag SNPs chosen using HapMap genotypes perform almost as well on Australian samples as tags chosen using Australian genotypes.

Aims/hypothesis: Uncoupling proteins are mitochondrial transmembrane carriers implicated in the regulation of energy balance. Dysfunction of UCP3 (the predominant uncoupling protein in skeletal muscle) might therefore be expected to reduce thermogenic capacity, alter energy homeostasis and influence predisposition to obesity and Type II (non-insulin-dependent) diabetes mellitus. A variant in the putative promoter region of UCP3 (-55 c-->t) has recently been identified, and an association with obesity reported in French subjects. Our aim was to study the pathophysiological role of this variant in diabetes-related and obesity-related traits using two distinct ethnic populations., Methods: The -55 c-->t variant was genotyped in 85 South Indian and 150 European parent-offspring trios ascertained through Type II diabetic probands and in 455 South Indian subjects initially recruited to an urban survey into the prevalence of diabetes., Results: In South Indian and European parent-offspring trios there was no preferential transmission of either allele at the -55 c-->t polymorphism to diabetic offspring (South Indians, p = 0.60; Europeans, p = 0.15). When family members were analysed for intermediate traits, the t-allele was associated with increased waist-to-hip ratio but only in females (South Indian mothers p = 0.036, daughters p = 0.032: European mothers p = 0.037, daughters p = 0.14). These findings were replicated in South Indian females from the population-based survey (p = 0.039)., Conclusion/interpretation: The consistent association between the t-allele at this locus and increased waist-to-hip ratio in women from three separate data sets indicates that variation at this polymorphism (or another locus with which it is in linkage disequilibrium) influences fat distribution but that this effect is restricted to females.

Variation at the variable number tandem repeat (VNTR) minisatellite 5' of the insulin gene (INS) is associated with several phenotypes, including type 1 diabetes, polycystic ovary syndrome, and birth weight. Case-control studies have suggested that class III VNTR alleles are also associated with type 2 diabetes, but results have been inconsistent and may reflect population stratification. To explore further the role of the INS-VNTR in type 2 diabetes susceptibility, we used family-based association methods in 155 parent-offspring trios from the British Diabetic Association-Warren Trios repository, each ascertained via a Europid proband with type 2 diabetes. Overall, there was no significant association between diabetes and the INS-VNTR genotype, with 65 of 119 heterozygous parents (55%) transmitting class III and 54 class I (P = 0.16, one-sided). However, whereas maternal transmissions followed Mendelian expectation, there was a marked excess of class III transmission from the 49 heterozygous fathers (34 [69%] vs. 15, P = 0.003 vs. 50% expectation, P = 0.003 vs. maternal transmission). These results confirm that variation within the TH-INS-IGF2 locus, most plausibly at the VNTR itself, influences type 2 diabetes susceptibility. By demonstrating that this effect is mediated exclusively by the paternally derived allele, these findings implicate imprinted genes in the pathogenesis of type 2 diabetes.

Aims: To elucidate the relationship between the human insulin gene INS VNTR regulatory polymorphism and insulin secretion. The polymorphism arises from tandem repetition of 14-15 bp oligonucleotides. In Caucasians, repeat number varies from 26 to over 200, with two main and discrete allele size classes: class I (26-63 repeats) and class III (141-209 repeats). Class I allele homozygosity is associated with elevated risk of developing Type 1 diabetes, while the class III allele has been associated with increased risk of Type 2 diabetes, polycystic ovary syndrome (PCOS) and with larger size at birth, which may influence development of adult disease., Methods: Thirty-one healthy adult subjects with normal glucose tolerance, underwent an intravenous glucose tolerance test with one minute sampling. Seventeen subjects were homozygous for class I alleles (14 excluding individuals carrying alleles associated with parent-of-origin effects and heterogeneity in allele transmission) and 14 homozygous for class III alleles. The groups were well matched., Results: No significant differences in amount or rate of insulin secretion, or beta cell function were detected between the two groups. There was a difference in pattern of pulsatile insulin secretion with more 9-minute oscillations in class I homozygotes (P<0.026). The after-load glucose concentration was also higher in subjects with class I alleles (P<0.03)., Conclusions: These results warrant further analysis of possible association between allelic variation of the INS VNTR and the pulsatility of insulin secretion.

Size at birth is an important determinant of perinatal survival and has also been associated with the risk for cardiovascular disease and type 2 diabetes in adult life. Common genetic variation that regulates fetal growth could therefore influence perinatal survival and predispose to the development of adult disease. We have tested the insulin gene (INS) variable number of tandem repeats (VNTR) locus, which in Caucasians has two main allele sizes (class I and class III; ref. 3), as a functional candidate polymorphism for association with size at birth, as it has been shown to influence transcription of INS (refs 3-5). In a cohort of 758 term singletons (Avon Longitudinal Study of Pregnancy and Childhood; ALSPAC) followed longitudinally from birth to 2 years, we detected significant genetic associations with size at birth: class III homozygotes had larger mean head circumference (P=0.004) than class I homozygotes. These associations were amplified in babies who did not show postnatal realignment of growth (45%), and were also evident for length (P=0.015) and weight (P=0.009) at birth. The INS VNTR III/II genotype might have bestowed a perinatal survival during human history by conferring larger size at birth. Common genetic variation of this kind may contribute to reported associations between birth size and adult disease.