The Trp64Arg allele of the beta 3-adrenergic receptor is associated with abdominal obesity and resistance to insulin and may contribute to the early onset of NIDDM:

Non-insulin dependent diabetes mellitus (NIDDM) affects more than 100 million people worldwide and is associated with severe metabolic defects, including peripheral insulin resistance, elevated hepatic glucose production, and inappropriate insulin secretion. Family studies point to a major genetic component, but specific susceptibility genes have not yet been identified-except for rare early-onset forms with monogenic or mitochondrial inheritance. We have screened over 4,000 individuals from a population isolate in western Finland, identified 26 families (comprising 217 individuals) enriched for NIDDM and performed a genome-wide scan using non-parametric linkage analysis. We found no significant evidence for linkage when the families were analysed together, but strong evidence for linkage when families were classified according to mean insulin levels in affecteds (in oral glucose tolerance tests). Specifically, families with the lowest insulin levels showed linkage (P = 2 x 10(-6)) to chromosome 12 near D12S1349. Interestingly, this region contains the gene causing the rare, dominant, early-onset form of diabetes MODY3. Unlike MODY3 families, the Finnish families with low insulin have an age-of-onset typical for NIDDM (mean = 58 years). We infer the existence of a gene NIDDM2 causing NIDDM associated with low insulin secretion, and suggest that NIDDM2 and MODY3 may represent different alleles of the same gene.

Maturity-onset diabetes of the young (MODY) type 3 is a dominantly inherited form of diabetes, which is often misdiagnosed as non-insulin-dependent diabetes mellitus (NIDDM) or insulin-dependent diabetes mellitus (IDDM). Phenotypic analysis of members from four large Finnish MODY3 kindreds (linked to chromosome 12q with a maximum lod score of 15) revealed a severe impairment in insulin secretion, which was present also in those normoglycemic family members who had inherited the MODY3 gene. In contrast to patients with NIDDM, MODY3 patients did not show any features of the insulin resistance syndrome. They could be discriminated from patients with IDDM by lack of glutamic acid decarboxylase antibodies (GAD-Ab). Taken

Type 2 diabetes mellitus is a heterogeneous inherited disorder characterized by chronic hyperglycemia resulting from pancreatic beta-cell dysfunction and insulin resistance. Although the pathogenic mechanisms are not fully understood, manifestation of the disease most likely requires interaction between both environmental and genetic factors. In the search for such susceptibility genes, we have performed a genomewide scan in 58 multiplex families (comprising 440 individuals, 229 of whom were affected) from the Botnia region in Finland. Initially, linkage between chromosome 12q24 and impaired insulin secretion had been reported, by Mahtani et al., in a subsample of 26 families. In the present study, we extend the initial genomewide scan to include 32 additional families, update the affectation status, and fine map regions of interest, and we try to replicate the initial stratification analysis. In our analysis of all 58 families, we identified suggestive linkage to one region, chromosome 9p13-q21 (nonparametric linkage [NPL] score 3.9; P<.0002). Regions with nominal P values <.05 include chromosomes 2p11 (NPL score 2.0 [P<.03]), 3p24-p22 (NPL score 2.2 [P<.02]), 4q32-q33 (NPL score 2.5 [P<.01]), 12q24 (NPL score 2.1 [P<.03]), 16p12-11 (NPL score 1.7 [P<.05]), and 17p12-p11 (NPL score 1.9 [P<.03]). When chromosome 12q24 was analyzed in only the 32 additional families, a nominal P value <.04 was observed. Together with data from other published genomewide scans, these findings lend support to the hypothesis that regions on chromosome 9p13-q21 and 12q24 may harbor susceptibility genes for type 2 diabetes.

A specific mutation termed FH-North Karelia [FH-NK] accounts for almost 90% of familial hypercholesterolemia [FH] cases in the Finnish North Karelia, with a population of about 180,000. Extensive search for its presence in the entire North Karelia province revealed 340 carriers of this mutation. Other mutations of the LDL receptor [LDLR] gene accounted for 67 cases of heterozygous FH. This gives a minimum FH prevalence of 1 in 441 inhabitants in North Karelia, with the highest density of patients in the Polvijärvi commune (1 in 143 inhabitants). Old parish records, confirmation records, and tax records were used to track a common ancestor for most of the present-day North Karelian FH-NK patients in the village of Puso, located within an area where the FH prevalence today is the highest. DNA analysis indicated that 2% of the subjects aged 1 to 25 years would have been diagnosed as false-negative and 7% as false-positive FH patients on the basis of LDL cholesterol [LDL-C] determinations alone. Common genetic variations of apolipoprotein E [apoE], XbaI, polymorphism of apolipoprotein B [apoB], and PvuII polymorphism of the intact LDLR allele contributed little to serum lipid variation in established carriers of the FH-NK allele, although apoE2/4 genotype and the presence of the PvuII restriction site tended to be associated with relatively low LDL-C levels. Coronary heart disease (CHD) was present in 65 (30%) out of the 179 FH gene carriers aged > or = 25 years, and 19 individuals had a previous history of acute myocardial infarction (AMI). The average age (mean +/- SD) at onset of CHD was 42 +/- 7 years for males and 48 +/- 11 years for females (P < .05). In stepwise logistic regression analysis carried out in carriers of the FH-NK allele, age, gender, smoking, and apoE allele E2 all emerged as independent determinants of risk of CHD or AMI. It may be concluded that the relatively high prevalence of FH patients in North Karelia province provides a unique founder population in which genetic and nongenetic factors modifying the course of FH can be effectively investigated.