Li et al. (2001) assessed the prevalence of families with both type I and type II diabetes in Finland and studied, in patients with type II diabetes, the association between a family history of type 1 diabetes, GAD ... Li et al. (2001) assessed the prevalence of families with both type I and type II diabetes in Finland and studied, in patients with type II diabetes, the association between a family history of type 1 diabetes, GAD antibodies (GADab), and type I diabetes-associated HLA-DQB1 genotypes. Further, in mixed type I/type II diabetes families, they investigated whether sharing an HLA haplotype with a family member with type I diabetes influenced the manifestation of type II diabetes. Among 695 families with more than 1 patient with type II diabetes, 100 (14%) also had members with type I diabetes. Type II diabetic patients from the mixed families more often had GADab (18% vs 8%) and DQB1*0302/X genotype (25% vs 12%) than patients from families with only type II diabetes; however, they had a lower frequency of DQB1*02/0302 genotype compared with adult-onset type I patients (4% vs 27%). In the mixed families, the insulin response to oral glucose load was impaired in patients who had HLA class II risk haplotypes, either DR3(17)-DQA1*0501-DQB1*02 or DR4*0401/4-DQA1*0301-DQB1*0302, compared with patients without such haplotypes. This finding was independent of the presence of GADab. The authors concluded that type I and type II diabetes cluster in the same families. A shared genetic background with a patient with type I diabetes predisposes type II diabetic patients both to autoantibody positivity and, irrespective of antibody positivity, to impaired insulin secretion. Their findings also supported a possible genetic interaction between type I and type II diabetes mediated by the HLA locus.
Altshuler et al. (2000) confirmed an association of the common pro12-to-ala polymorphism in PPAR-gamma (601487.0002) with type II diabetes. They found a modest but significant increase in diabetes risk associated with the ... - Mutation in PPAR-Gamma Altshuler et al. (2000) confirmed an association of the common pro12-to-ala polymorphism in PPAR-gamma (601487.0002) with type II diabetes. They found a modest but significant increase in diabetes risk associated with the more common proline allele (approximately 85% frequency). Because the risk allele occurs at such high frequency, its modest effect translates into a large population-attributable risk--influencing as much as 25% of type II diabetes in the general population. Savage et al. (2002) described a family, which they referred to as a 'Europid pedigree,' in which several members had severe insulin resistance. The grandparents had typical late-onset type II diabetes with no clinical features of severe insulin resistance. Three of their 6 children and 2 of their grandchildren had acanthosis nigricans, elevated fasting plasma insulin levels. Hypertension was also a feature. By mutation screening, Savage et al. (2002) identified a heterozygous frameshift resulting in a premature stop mutation of the PPARG (601487.0011) gene which was present in the grandfather, all 5 relatives with severe insulin resistance, and 1 other relative with normal insulin levels. Further candidate gene studies revealed a heterozygous frameshift/premature stop mutation in PPP1R3A (600917.0003) which was present in the grandmother, in all 5 individuals with severe insulin resistance, and in 1 other relative. Thus, all 5 family members with severe insulin resistance, and no other family members, were double heterozygotes with respect to frameshift mutations. (Although the article by Savage et al. (2002) originally stated that the affected individuals were compound heterozygotes, they were actually double heterozygotes. Compound heterozygosity is heterozygosity at the same locus for each of 2 different mutant alleles; double heterozygosity is heterozygosity at each of 2 separate loci. The use of an incorrect term in the original publication was the result of a 'copy-editing error that was implemented after the authors returned corrected proofs' (Savage et al., 2002).) - Association with Insulin Receptor Substrate-2 Mammarella et al. (2000) genotyped 193 Italian patients with type II diabetes and 206 control subjects for the insulin receptor substrate-2 G1057D polymorphism (600797.0001). They found evidence for a strong association between type II diabetes and the polymorphism, which appears to be protective against type II diabetes in a codominant fashion. - Association with Adiponectin For a discussion of an association between variation in the ADIPOQ gene (605441) on chromosome 3q27 and type 2 diabetes, see ADIPQTL1 (612556). - Association with Mitochondrial DNA Variation A common mtDNA variant (T16189C) in a noncoding region of mtDNA was positively correlated with blood fasting insulin by Poulton et al. (1998). Poulton et al. (2002) demonstrated a significant association between the 16189 variant and type II diabetes in a population-based case-control study in Cambridgeshire, UK (n = 932, odds ratio = 1.61; 1.0-2.7, P = 0.048), which was greatly magnified in individuals with a family history of diabetes from the father's side (odds ratio = infinity; P less than 0.001). Poulton et al. (2002) demonstrated that the 16189 variant had arisen independently many times and on multiple mitochondrial haplotypes. They speculated that the 16189 variant may alter mtDNA bending and hence could influence interactions with regulatory proteins which control replication or transcription. Mohlke et al. (2005) presented data supporting previous evidence for association of 16189T-C with reduced ponderal index at birth and also showed evidence for association with reduced birth weight but not with diabetes status. This study suggested that mitochondrial genome variants may play at most a modest role in glucose metabolism in the Finnish population studied. Furthermore, the data did not support a reported maternal inheritance pattern of type II diabetes mellitus but instead showed a strong effect of recall bias. Because mitochondria play pivotal roles in both insulin secretion from the pancreatic beta cells and insulin resistance of skeletal muscles, Fuku et al. (2007) performed a large-scale association study to identify mitochondrial haplogroups that may confer resistance against or susceptibility to type II diabetes mellitus. The study population comprised 2,906 unrelated Japanese individuals, including 1,289 patients with type II diabetes mellitus and 1,617 controls, and 1,365 unrelated Korean individuals, including 732 patients with type II diabetes and 633 controls. The genotypes for 25 polymorphisms in the coding region of the mitochondrial genome were determined, and the haplotypes were classified into 10 major haplogroups. Multivariate logistic regression analysis with adjustment for age and sex revealed that the mitochondrial group N9a was significantly associated with resistance against type II diabetes mellitus (P = 0.0002) with an odds ratio of 0.55 (95% confidence interval 0.40-0.75). Even in the modern environment, which is often characterized by satiety and physical inactivity, this haplotype might confer resistance against type II diabetes mellitus. The N9a haplogroup found to be associated with reduced susceptibility to type II diabetes mellitus by Fuku et al. (2007) consisted of a synonymous SNP in ND2 (516001), 5231G-A; a missense change in ND5 (516005), thr8 to ala; and a synonymous change also in ND5, 12372G-A. - Mutation in PAX4 Shimajiri et al. (2001) scanned the PAX4 gene (167413) in 200 unrelated Japanese probands with type 2 diabetes and identified an arg121-to-tyr mutation (R121W; 167413.0001) in 6 heterozygous patients and 1 homozygous patient (mutant allele frequency 2.0%). The mutation was not found in 161 nondiabetic subjects (p = 0.01). Six of 7 patients had a family history of diabetes or impaired glucose tolerance, and 4 of 7 had transient insulin therapy at the onset. One of them, a homozygous carrier, had relatively early-onset diabetes and slowly fell into an insulin-dependent state without an autoimmune-mediated process. - Association with TFAP2B Maeda et al. (2005) performed a genomewide, case-control association study using gene-based SNPs in Japanese patients with type II diabetes and controls and identified several variations within the TFAP2B gene (601601) that were significantly associated with type II diabetes: an intron 1 VNTR (p = 0.0009), intron 1 +774G-T (p = 0.0006), and intron 1 +2093A-C (p = 0.0004). The association of TFAP2B with type II diabetes was also observed in a U.K. population. Maeda et al. (2005) suggested that the TFAP2B gene may confer susceptibility to type II diabetes. - Mutation in ABCC8 Babenko et al. (2006) screened the ABCC8 gene (600509) in 34 patients with permanent neonatal diabetes (606176) or transient neonatal diabetes (see 601410) and identified heterozygosity for 7 missense mutations in 9 patients (see, e.g., 600509.0017-600509.0020). The mutation-positive fathers of 5 of the probands with transient neonatal diabetes developed type II diabetes mellitus in adulthood; Babenko et al. (2006) proposed that mutations of the ABCC8 gene may give rise to a monogenic form of type II diabetes with variable expression and age at onset. - Association with WFS1 Sandhu et al. (2007) conducted a gene-centric association study for type 2 diabetes in multiple large cohorts and identified 2 SNPs located in the WFS1 gene, dbSNP rs10010131 (606201.0021) and dbSNP rs6446482 (602201.0022), that were strongly associated with diabetes risk (P = 1.4 x 10(-7) and P = 3.4 x 10(-7), respectively, in the pooled study set). The risk allele was the major allele for both SNPs, with a frequency of 60% for both. The authors noted that both are intronic, with no obvious evidence for biologic function. - Association with IL6 Mohlig et al. (2004) investigated the IL6 -174C-G SNP (147620.0001) and development of NIDDM. They found that this SNP modified the correlation between BMI and IL6 by showing a much stronger increase of IL6 at increased BMI for CC genotypes compared with GG genotypes. The -174C-G polymorphism was found to be an effect modifier for the impact of BMI regarding NIDDM. The authors concluded that obese individuals with BMI greater than or equal to 28 kg/m2 carrying the CC genotype showed a more than 5-fold increased risk of developing NIDDM compared with the remaining genotypes and, hence, might profit most from weight reduction. Illig et al. (2004) investigated the association of the IL6 SNPs -174C-G and -598A-G on parameters of type 2 diabetes and the metabolic syndrome in 704 elderly participants of the Kooperative Gesundheitsforschung im Raum Augsburg/Cooperative Research in the Region of Augsburg (KORA) Survey 2000. They found no significant associations, although both SNPs exhibited a positive trend towards association with type 2 diabetes. Illig et al. (2004) also found that circulating IL6 levels were not associated with the IL6 polymorphisms; however, significantly elevated levels of the chemokine monocyte chemoattractant protein-1 (MCP1; 158105)/CC chemokine ligand-2 (CKR2; 601267) in carriers of the protective genotypes suggested an indirect effect of these SNPs on the innate immune system. - Association with KCNJ15 Okamoto et al. (2010) identified a synonymous SNP (dbSNP rs3746876, C566T) in exon 4 of the KCNJ15 (602106) that showed significant association with type 2 diabetes mellitus affecting lean individuals in 3 independent Japanese sample sets (p = 2.5 x 10(-7); odds ratio, 2.54) and with unstratified T2DM (p = 6.7 x 10(-6); OR, 1.76). The diabetes risk allele frequency was, however, very low among Europeans and no association between the variant and T2DM could be shown in a Danish case-control study. Functional analysis in HEK293 cells demonstrated that the risk T allele increased KCNJ15 expression via increased mRNA stability, which resulted in higher expression of protein compared to the C allele. - Mutation in MTNR1B Bonnefond et al. (2012) performed large-scale exon resequencing of the MTNR1B gene (600804) in 7,632 Europeans, including 2,186 individuals with type 2 diabetes mellitus, and identified 36 very rare variants associated with T2D. Among the very rare variants, partial or total loss-of-function variants but not neutral ones contributed to T2D (odds ratio, 5.67; p = 4.09 x 10(-4)). Genotyping 4 variants with complete loss of melatonin-binding and signaling capabilities (A42P, 600804.0001; L60R, 600804.0002; P95L, 600804.0003; and Y308S, 600804.0004) as a pool in 11,854 additional French individuals, including 5,967 with T2D, demonstrated their association with T2D (odds ratio, 3.88; p = 5.37 x 10(-3)). Bonnefond et al. (2012) concluded that their study established a firm functional link between MTNR1B and T2D risk.