SNP43 of CAPN10 and the risk of type 2 Diabetes in African-Americans: the Atherosclerosis Risk in Communities Study.

Recently, an A-to-G variant in intron 3 (SNP43) of the calcium-activated neutral protease 10 gene (CAPN10) was identified as a possible type 2 diabetes susceptibility gene through positional cloning in Mexican-Americans. We conducted cross-sectional and prospective studies to evaluate the relation between SNP43 and type 2 diabetes and related traits in middle-aged African-American participants of the Atherosclerosis Risk in Communities Study, a population-based longitudinal study. At baseline, 269 prevalent diabetes cases and 1,159 nondiabetic control subjects were studied. Those with the G/G genotype were more likely to have diabetes than those with the A/G or A/A genotype (odds ratio [OR] 1.41, 95% CI 1.00-1.99, P = 0.05). In the prospective study, 166 of the control subjects developed incident diabetes over 9 years of follow-up. The incidence of diabetes for individuals with the G/G genotype did not differ significantly from those with at least one copy of the A allele (23.3 vs. 19.5 per 1,000 person years, P = 0.29). Pooling prevalent and incident diabetic cases together, individuals with the G/G genotype were approximately 40% more likely to have diabetes than those without (OR 1.38, 95% CI 1.04-1.83, P = 0.03). Because of the high frequency of the G allele (0.88), approximately 25% of the susceptibility to type 2 diabetes in African-Americans may be attributed to the G/G genotype at SNP43 of CAPN10, although most of the subjects with the G/G genotype did not develop diabetes over the 9 years of follow-up. We conclude from this large prospective study that the G allele of SNP43 of CAPN10 or another allele or gene that is in linkage disequilibrium with it increases susceptibility to type 2 diabetes in African-Americans.     

Linkage but not association of calpain-10 to type 2 diabetes replicated in northern Sweden

We present data from a genome-wide scan identifying genetic factors conferring susceptibility to type 2 diabetes. The linkage analysis was based on 59 families from northern Sweden, consisting of a total of 129 cases of type 2 diabetes and 19 individuals with impaired glucose tolerance. Model-free linkage analysis revealed a maximum multipoint logarithm of odds score of 3.19 for D2S2987 at 267.7 cM (P=0.00058), suggesting that a gene conferring susceptibility to type 2 diabetes in the northern Swedish population resides in the 2q37 region. These data replicate, in a European population, previously identified linkage of marker loci in this region to type 2 diabetes in Mexican Americans. In contrast, no evidence in support of association to the previously identified single nucleotide polymorphisms in the calpain-10 gene was observed in a case-control cohort derived from the same population.     

Linkage of calpain 10 to type 2 diabetes: the biological rationale

The follow-up studies to the original report of association of variation at calpain 10 (CAPN10) with type 2 diabetes in the Mexican-American population of Starr County, Texas, encompass a broad range of science. There are association studies on genetic variation at CAPN10 in different human populations over a range of phenotypes related to type 2 diabetes, physiological studies on the biological functions of calpain proteases, and evolutionary studies on CAPN10 and the NIDDM1 region. We review here the studies published to date on CAPN10, as well as the latest findings from positional cloning studies on a number of other complex disorders. Collectively, these studies provide perspective on the challenges of moving from the linkage mapping and positional cloning studies on which we have been focused to an understanding of the biology shaping the relationship of genotype to phenotype at loci influencing susceptibility to complex disorders like type 2 diabetes.     

Association of the diabetes gene calpain-10 with subclinical atherosclerosis: the Mexican-American Coronary Artery Disease Study

The powerful relation between atherosclerosis and diabetes may have a common genetic basis. However, few genes predisposing to both have been identified. Calpain-10 (CAPN10) was the first gene for type 2 diabetes identified by positional cloning, wherein a combination of haplotypes conferred increased risk of diabetes. We sought to determine whether CAPN10 influences subclinical atherosclerosis. Among nondiabetic subjects from 85 Mexican-American families with a history of coronary artery disease, subclinical atherosclerosis was assessed by common carotid artery intima-media thickness (IMT), insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and insulin secretion was estimated by the oral glucose tolerance test. These phenotypes were tested for association with CAPN10 haplotypes. Haplotype 1112 (of single nucleotide polymorphisms [SNPs] 44, 43, 56, and 63) was associated with increased IMT, while haplotype 1221 was associated with decreased IMT. The 112/121 haplotype combination (of SNPs 43, 56, and 63), originally found to confer increased risk for diabetes, was associated with the largest IMT in our study population. CAPN10 was also associated with both insulin sensitivity and insulin secretion. Covariate analysis suggested that CAPN10 affects IMT independently of these diabetes-related phenotypes. The fact that the diabetes gene CAPN10 also influences the risk for atherosclerosis shows that inherited factors may underlie the frequent co-occurrence of these two conditions.     

Further evidence for a susceptibility locus for type 2 diabetes on chromosome 20q13.1-q13.2

We previously reported suggestive linkage between type 2 diabetes and markers in a region on chromosome 20q using data from a collection of 29 Caucasian families in which type 2 diabetes with middle-age-onset was segregated as an autosomal-dominant disorder. To map more precisely the susceptibility locus (or loci) within this broad region, we increased the family collection and genotyped all families for additional markers, both within the critical region and spaced over the rest of chromosome 20. Altogether 526 individuals (including 241 with diabetes) from the total collection of 43 families were included in the study. All individuals were genotyped for 23 highly polymorphic markers. Positive evidence for linkage was found for a 10-cM region on the long arm of chromosome 20q13.1-q13.2 between markers D20S119 and D20S428. The strongest evidence in two-point as well as multipoint linkage analysis (P = 1.8 x 10(-5)) occurred at the position corresponding to marker D20S196. The individuals with diabetes in the seven most strongly linked families had high serum insulin levels during fasting and 2-h post-glucose load periods. We did not find any evidence for linkage between type 2 diabetes and any other region on chromosome 20. In conclusion, our larger and more comprehensive study showed very strong evidence for a susceptibility gene for insulin-resistant type 2 diabetes located on the long arm of chromosome 20 around marker D20S196.     

Physical and genetic mapping of IDDM8 on chromosome 6q27

Genome-wide mapping studies have provided evidence of a type 1 diabetes susceptibility gene (IDDM8) that is located on chromosome 6q27. However, association studies of IDDM8 have so far been negative. The purpose of this investigation was to determine a linkage disequilibrium (LD) map in the chromosome 6q27 region and to better localize IDDM8. A physical map of nearly 1 Mb containing the chromosome 6 telomere was constructed, and polymorphic markers spanning this region were defined. Haplotypes composed of the markers in LD were tested for association with type 1 diabetes in 266 families. A microsatellite marker allele and multiple haplotypes were associated with IDDM8, which suggests localization of this type 1 diabetes susceptibility gene to the terminal 200 kb of chromosome 6.     

A single nucleotide polymorphism in MGEA5 encoding O-GlcNAc-selective N-acetyl-beta-D glucosaminidase is associated with type 2 diabetes in Mexican Americans

Excess O-glycosylation of proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc) may be involved in the pathogenesis of type 2 diabetes. The enzyme O-GlcNAc-selective N-acetyl-beta-d glucosaminidase (O-GlcNAcase) encoded by MGEA5 on 10q24.1-q24.3 reverses this modification by catalyzing the removal of O-GlcNAc. We have previously reported the linkage of type 2 diabetes and age at diabetes onset to an overlapping region on chromosome 10q in the San Antonio Family Diabetes Study (SAFADS). In this study, we investigated menangioma-expressed antigen-5 (MGEA5) as a positional candidate gene. Twenty-four single nucleotide polymorphisms (SNPs), identified by sequencing 44 SAFADS subjects, were genotyped in 436 individuals from 27 families whose data were used in the original linkage report. Association tests indicated significant association of a novel SNP with the traits diabetes (P = 0.0128, relative risk = 2.77) and age at diabetes onset (P = 0.0017). The associated SNP is located in intron 10, which contains an alternate stop codon and may lead to decreased expression of the 130-kDa isoform, the isoform predicted to contain the O-GlcNAcase activity. We investigated whether this variant was responsible for the original linkage signal. The variance attributed to this SNP accounted for approximately 25% of the logarithm of odds. These results suggest that this variant within the MGEA5 gene may increase diabetes risk in Mexican Americans.     

Genetic and nongenetic regulation of CAPN10 mRNA expression in skeletal muscle

The gene encoding calpain-10 (CAPN10) has been identified as a candidate gene for type 2 diabetes. Our aim was to study the impact of genetic (heritability and polymorphisms) and nongenetic (insulin, free fatty acids, and age) factors on CAPN10 mRNA expression in skeletal muscle using two different study designs. Muscle biopsies were obtained before and after hyperinsulinemic-euglycemic clamps from 166 young and elderly monozygotic and dizygotic twins as well as from 15 subjects with normal (NGT) or impaired glucose tolerance (IGT) exposed to an Intralipid infusion. We found hereditary effects on both basal and insulin-exposed CAPN10 mRNA expression. Carriers of the type 2 diabetes-associated single nucleotide polymorphism (SNP)-43 G/G genotype had reduced CAPN10 mRNA levels compared with subjects carrying the SNP-43 A-allele. Age had no significant influence on CAPN10 mRNA levels. Insulin had no significant effect on CAPN10 mRNA levels, neither in the twins nor in the basal state of the Intralipid study. However, after a 24-h infusion of Intralipid, we noted a significant increase in CAPN10 mRNA in response to insulin in subjects with NGT but not in subjects with IGT. In conclusion, we provide evidence that mRNA expression of CAPN10 in skeletal muscle is under genetic control. Glucose-tolerant but not glucose-intolerant individuals upregulate their CAPN10 mRNA levels in response to prolonged exposure to fat.     

Haplotypes of transcription factor 7-like 2 (TCF7L2) gene and its upstream region are associated with type 2 diabetes and age of onset in Mexican Americans

TCF7L2 acts as both a repressor and transactivator of genes, as directed by the Wnt signaling pathway. Recently, several highly correlated sequence variants located within a haplotype block of the TCF7L2 gene were observed to associate with type 2 diabetes in three Caucasian cohorts. We previously reported linkage of type 2 diabetes in the San Antonio Family Diabetes Study (SAFADS) cohort consisting of extended pedigrees of Mexican Americans to the region of chromosome 10q harboring TCF7L2. We therefore genotyped 11 single nucleotide polymorphisms (SNPs) from nine haplotype blocks across the gene in 545 SAFADS subjects (178 diabetic) to investigate their role in diabetes pathogenesis. We observed nominal association between four SNPs (rs10885390, rs7903146, rs12255372, and rs3814573) in three haplotype blocks and type 2 diabetes, age at diagnosis, and 2-h glucose levels (P = 0.001-0.055). Furthermore, we identified a common protective haplotype defined by these four SNPs that was significantly associated with type 2 diabetes and age at diagnosis (P = 4.2 x 10(-5), relative risk [RR] 0.69; P = 6.7 x 10(-6), respectively) and a haplotype that confers diabetes risk that contains the rare alleles at SNPs rs10885390 and rs12255372 (P = 0.02, RR 1.64). These data provide evidence that variation in the TCF7L2 genomic region may affect risk for type 2 diabetes in Mexican Americans, but the attributable risk may be lower than in Caucasian populations.     

Suggestive evidence for association of human chromosome 18q12-q21 and its orthologue on rat and mouse chromosome 18 with several autoimmune diseases

Some immune system disorders, such as type 1 diabetes, multiple sclerosis (MS), and rheumatoid arthritis (RA), share common features: the presence of autoantibodies and self-reactive T-cells, and a genetic association with the major histocompatibility complex. We have previously published evidence, from 1,708 families, for linkage and association of a haplotype of three markers in the D18S487 region of chromosome 18q21 with type 1 diabetes. Here, the three markers were typed in an independent set of 627 families and, although there was evidence for linkage (maximum logarithm of odds score [MLS] = 1.2; P = 0.02), no association was detected. Further linkage analysis revealed suggestive evidence for linkage of chromosome 18q21 to type 1 diabetes in 882 multiplex families (MLS = 2.2; lambdas = 1.2; P = 0.001), and by meta-analysis the orthologous region (also on chromosome 18) is linked to diabetes in rodents (P = 9 x 10(-4)). By meta-analysis, both human chromosome 18q12-q21 and the rodent orthologous region show positive evidence for linkage to an autoimmune phenotype (P = 0.004 and 2 x 10(-8), respectively, empirical P = 0.01 and 2 x 10(-4), respectively). In the diabetes-linked region of chromosome 18q12-q21, a candidate gene, deleted in colorectal carcinoma (DCC), was tested for association with human autoimmunity in 3,380 families with type 1 diabetes, MS, and RA. A haplotype ("2-10") of two newly characterized microsatellite markers within DCC showed evidence for association with autoimmunity (P = 5 x 10(-6)). Collectively, these data suggest that a locus (or loci) exists on human chromosome 18q12-q21 that influences multiple autoimmune diseases and that this association might be conserved between species.     

Genome-wide linkage scan in Gullah-speaking African American families with type 2 diabetes: the Sea Islands Genetic African American Registry (Project SuGAR)

OBJECTIVE—The Gullah-speaking African American population from the Sea Islands of South Carolina is characterized by a low degree of European admixture and high rates of type 2 diabetes and diabetic complications. Affected relative pairs with type 2 diabetes were recruited through the Sea Islands Genetic African American Registry (Project SuGAR).RESEARCH DESIGN AND METHODS—We conducted a genome-wide linkage scan, genotyping 5,974 single nucleotide polymorphisms in 471 affected subjects and 50 unaffected relatives from 197 pedigrees. Data were analyzed using a multipoint engine for rapid likelihood inference and ordered subsets analyses (OSAs) for age at type 2 diabetes diagnosis, waist circumference, waist-to-hip ratio, and BMI. We searched for heterogeneity and interactions using a conditional logistic regression likelihood approach.RESULTS—Linkage peaks on chromosome 14 at 123–124 cM were detected for type 2 diabetes (logarithm of odds [LOD] 2.10) and for the subset with later age at type 2 diabetes diagnosis (maximum LOD 4.05). Two linkage peaks on chromosome 7 were detected at 44–45 cM for type 2 diabetes (LOD 1.18) and at 78 cM for type 2 diabetes (LOD 1.64) and the subset with earlier age at type 2 diabetes diagnosis (maximum LOD 3.93). The chromosome 14 locus and a peak on 7p at 29.5 cM were identified as important in the multilocus model. Other regions that provided modest evidence for linkage included chromosome 1 at 167.5 cM (LOD 1.51) and chromosome 3 at 121.0 cM (LOD 1.61).CONCLUSIONS—This study revealed a novel type 2 diabetes locus in an African American population on 14q that appears to reduce age of disease onset and confirmed two loci on chromosome 7.There is little information available regarding genes contributing to type 2 diabetes in the indigenous or diasporic populations of sub-Saharan Africa. To date, there have been only three reported linkage scans for type 2 diabetes in populations of African descent: two in African Americans (1,2) and one in African families from Ghana and Nigeria (3). Although there have been several recent genome-wide association studies (GWASs) conducted in primarily European populations, none has been reported for African Americans, and relatively few diabetes genes have been found in African American populations using candidate gene approaches (4). Consequently, we have few insights into genetic susceptibility factors in African Americans contributing to greater type 2 diabetes prevalence.To better understand the genetics of type 2 diabetes in African Americans, we have studied Gullah-speaking African Americans living in coastal communities and on the sea islands of South Carolina. The ancestors of the Gullahs derived from the “grain coast” of West Africa and were forcibly imported because their rice-growing expertise was critical for the culture of this cash crop on low country plantations (5). Gullah-speaking African Americans have high rates of type 2 diabetes, characterized by relatively high rates of diabetic complications, early age of onset, and a high relative risk to siblings, λ_S, of type 2 diabetes at 3.3 (6). The diet is uniformly rich in animal fats, suggesting diabetes and obesity susceptibility alleles may more predictably produce a corresponding phenotype. Although there has been some emigration to northern American cities, there has been little immigration of African Americans born elsewhere into the Sea Islands. Studies of admixture indicate that the Gullah people are the most homogeneous population of African descent in the U.S., with Caucasian admixture below 3.5% (6–8), the lowest documented for any African American population. Analyses of mitochondrial and Y-chromosomal markers show that the genetic distance between the Gullah and Sierra Leonean tribes is measurably shorter than other African American populations (8–10).Given the relatively low European admixture, diet high in animal fats, and increased prevalence and familial clustering of diabetes, studies of families from this population were anticipated to provide unique insights into predominantly “African”-derived diabetes loci. Thus, we initiated the Sea Islands Genetic African American Registry (Project SuGAR). Type 2 diabetes–affected sibling, half-sibling, or parent-child pairs were recruited and assessed for medical, anthropometrical, and metabolic phenotypes in affected and nonaffected family members to conduct a whole-genome linkage scan. This scan is the first to be conducted for type 2 diabetes in African Americans using the higher resolution single nucleotide polymorphism (SNP) linkage panel.     

Linkage analysis of diabetes status among hypertensive families: the Hypertension Genetic Epidemiology Network study

Type 2 diabetes susceptibility is determined by multiple genetic and environmental factors. Genome-wide linkage scans have localized common regions, possibly harboring susceptibility genes on chromosomes 1, 2, 12, and 20. Variability in linkage findings underscores the probable genetic heterogeneity of type 2 diabetes. Thus, we conducted a genome scan of diabetes status using maximum likelihood methods that model affection status by a liability threshold model. Hypertensive sibships and their offspring and/or parents in the Hypertension Genetic Epidemiology Network study were recruited from five field centers. The diabetes phenotype was derived using the World Health Organization criteria and adjusted for race/study center, age, age2, sex, and with and without percent body fat. In total, 567 diabetic participants were identified in 437 families. Variance component linkage analysis was performed among 1,545 Caucasians and 1,608 African Americans using race-specific marker allele frequencies. We detected a quantitative trait loci (QTLs) influencing diabetes variance (logarithm of odds = 3.4) on chromosome 22, which overlaps a positive type 2 diabetes finding among Canadian Oji-Cree Indians. We also observed suggestive evidence for linkage on chromosomes 1, 2, 5, 8, 14, 17, and 19. The identification and replication of type 2 diabetes QTLs will bring us closer to the detection of functional genes that influence diabetes susceptibility.     

Role of a proline insertion in the insulin promoter factor 1 (IPF1) gene in African Americans with type 2 diabetes

African Americans have twice the prevalence of type 2 diabetes as Caucasians and much greater genetic diversity. We identified an inframe insertion of a proline in the insulin promoter factor 1 (IPF1) gene (InsCCG243), which was relatively common (minor allele frequency approximately 0.08) in African Americans and showed a trend to association with type 2 diabetes in preliminary studies. An earlier French study identified InsCCG243 as a cause of autosomal dominant diabetes. To determine the role of this variant in African Americans, we examined an additional population from North Carolina (n = 368) and a subset of African-American participants from the Atherosclerosis Risk in Communities (ARIC) study (n = 1,741). We also looked for segregation in 66 African-American families and for a role in insulin secretion in 112 nondiabetic subjects. InsCCG243 did not increase the risk of type 2 diabetes (P = 0.16 in North Carolina; P = 0.97 in the ARIC study) and did not segregate with type 2 diabetes in families. However, we found suggestive evidence for reduced insulin response to glucose (P = 0.05). Neither indirect measures of beta-cell mass nor beta-cell compensation were altered (P > 0.1). InsCCG243 does not act in a dominant, highly penetrant fashion in African Americans and is not a significant risk factor for type 2 diabetes in this population.     

Mapping genes influencing type 2 diabetes risk and BMI in Japanese subjects

We have carried out an autosomal genome scan for genes contributing to the development of type 2 diabetes and affecting BMI in the Japanese population (164 families, 256 affected sib-pairs). We found 12 regions that showed nominally significant multipoint evidence of linkage with type 2 diabetes (i.e. logarithm of odds [LOD] score >0.59, P < 0.05): chromosome 1 29.9 cM; chromosome 2 169.6 and 236.8 cM; chromosome 4 104.9 cM; chromosome 5 114.8 cM; chromosome 6 42.3 cM; chromosome 8 15.3 and 93.3 cM; chromosome 9 140.0 cM; chromosome 11 131.6 cM; chromosome 17 36.1 cM; and chromosome 21 48.0 cM. Twelve regions showed nominal multipoint evidence for linkage with log-transformed BMI (lnBMI): chromosome 2 167.9 and 210.5 cM; chromosome 3 185.7 cM; chromosome 4 118.9 and 145.6 cM; chromosome 5 131.9 cM; chromosome 7 7.4 cM; chromosome 10 70.0 cM; chromosome 15 12.8 cM; chromosome 16 30.0 cM; and chromosome 17 47.8 and 100.2 cM. Although none of the regions achieved genome-wide levels of significance, simulation studies showed that we observed more linkage signals than expected if there were no loci contributing to type 2 diabetes or BMI. Eight of the regions showing nominal evidence for linkage with type 2 diabetes have been reported in other genome scans, and seven of the regions showing linkage with lnBMI have shown linkage with BMI and BMI-related traits in other studies. Thus, our results may replicate findings in other studies. They may also indicate new regions of the genome that are involved in the regulation of blood glucose levels or body weight.     

A genome-wide search for type 2 diabetes susceptibility genes in West Africans: the Africa America Diabetes Mellitus (AADM) Study

The incidence of type 2 diabetes is growing rapidly, not only in developed countries but also worldwide. We chose to study type 2 diabetes in West Africa, where diabetes is less common than in the U.S., reasoning that in an environment where calories are less abundant, incident cases of type 2 diabetes might carry a proportionately greater genetic component. Through the Africa America Diabetes Mellitus (AADM) study, we carried out a genome-wide linkage analysis of type 2 diabetes in a cohort of 343 affected sibling pairs (691 individuals) enrolled from five West African centers in two countries (Ghana: Accra and Kumasi; Nigeria: Enugu, Ibadan, and Lagos). A total of 390 polymorphic markers were genotyped, and multipoint linkage analysis was conducted using the GENEHUNTER-PLUS and ASM programs. Suggestive evidence of linkage was observed in four regions on three chromosomes (12, 19, and 20). The two largest logarithm of odds scores of 2.63 and 1.92 for chromosomes 20q13.3 and 12q24, respectively, are particularly interesting because these regions have been reported to harbor diabetes susceptibility genes in several other populations and ethnic groups. Given the history of forced migration of West African populations during the slave trade, these results should have considerable relevance to the study of type 2 diabetes in African Americans.     

Genetics of the APM1 locus and its contribution to type 2 diabetes susceptibility in French Caucasians

We have carried out a detailed reexamination of the genetics of the APM1 locus and its contribution to the genetic basis of type 2 diabetes susceptibility in the French Caucasian population. The G allele of single nucleotide polymorphism -11426 in the APM1 promoter showed modest association with type 2 diabetes (odds ratio 1.44 [95% CI 1.04-1.98]; P = 0.03), providing corroborative evidence that single nucleotide polymorphisms in the APM1 promoter region contribute to the genetic risk of type 2 diabetes. A "sliding window" analysis identified haplotypes 1-1-1, 1-1-1-1, and 1-1-1-1-1 as being strongly protective against type 2 diabetes (P 相似文献   

Young-onset type 2 diabetes families are the major contributors to genetic loci in the Diabetes UK Warren 2 genome scan and identify putative novel loci on chromosomes 8q21, 21q22, and 22q11

A young onset of type 2 diabetes is likely to result, in part, from greater genetic susceptibility. Young-onset families may therefore represent a group in which genes are more easily detectable by linkage. To test this hypothesis, we conducted age at diagnosis (AAD) stratified linkage analyses in the Diabetes UK Warren 2 sibpairs. In the previously published unstratified analysis, evidence for linkage (logarithm of odds [LOD] >1.18) was found at seven loci. The LOD scores at these seven loci were higher in the 245 families with AAD <55 years (L55) compared with the 328 families with AAD >55 years (G55). Five of these seven loci (1q24-25, 5q13, 8p21-22, 8q24.2, and 10q23.2) had LOD scores >1.18 in the L55 subset but only one (8p21-22) did in the G55 subset. Two additional loci (8q21.13 and 21q22.2) showed evidence for linkage in the L55 subset alone. Another locus (22q11) showed evidence for linkage in a subset of families with AAD <45 years. Using a locus-counting approach, the L55 subset had significantly more loci (P approximately 0.01) than expected under the null hypothesis of no linkage across the LOD score range 0.59-3.0. In contrast, the G55 subset contained no more susceptibility loci than that expected by chance. In conclusion, young-onset families provide both disproportionate evidence for linkage to known loci and evidence for additional novel loci. Our data confirm our hypothesis that families segregating young-onset type 2 diabetes represent a more powerful resource for defining susceptibility genes by linkage.     

Variants in the calpain-10 gene predispose to insulin resistance and elevated free fatty acid levels

The calpain-10 gene (CAPN10) has been associated with type 2 diabetes, but information on molecular and physiological mechanisms explaining this association is limited. Here we addressed this question by studying the role of CAPN10 for phenotypes associated with type 2 diabetes and free fatty acid (FFA) metabolism. Among 395 type 2 diabetic patients and 298 nondiabetic control subjects from Finland, the SNP-43 allele 1 (P = 0.011), SNP-63 allele 2 (P = 0.010), and the haplotype combination SNP-44/43/19/63 1121/1121 (P = 0.028) were associated with type 2 diabetes. The SNP-43 genotypes 11 and 12 were associated with higher fasting insulin and homeostasis model assessment (HOMA) insulin resistance index among control subjects (P = 0.021 and P = 0.0076) and with elevated FFA among both control subjects (P = 0.0040) and type 2 diabetic patients (P = 0.0025). Multiple regression analysis further indicated that SNP-43 is an independent predictor of FFA levels (P = 0.0037). Among 80 genotype discordant sibling pairs, the SNP-43 allele 1 was associated with elevated fasting serum insulin and HOMA index (P = 0.013 and P = 0.0068). None of the four SNPs showed distorted transmission of alleles to patients with type 2 diabetes in a qualitative transmission disequilibrium test, including 108 trios. Because FFA and insulin resistance are known to predict type 2 diabetes, the finding that variation in the CAPN10 gene influences FFA levels and insulin resistance may provide an explanation for how the CAPN10 gene increases susceptibility to type 2 diabetes.     

Analysis of quantitative lipid traits in the genetics of NIDDM (GENNID) study

Coronary heart disease (CHD) is the leading cause of death among individuals with type 2 diabetes. Dyslipidemia contributes significantly to CHD in diabetic patients, in whom lipid abnormalities include hypertriglyceridemia, low HDL cholesterol, and increased levels of small, dense LDL particles. To identify genes for lipid-related traits, we performed genome-wide linkage analyses for levels of triglycerides and HDL, LDL, and total cholesterol in Caucasian, Hispanic, and African-American families from the Genetics of NIDDM (GENNID) study. Most lipid traits showed significant estimates of heritability (P < 0.001) with the exception of triglycerides and the triglyceride/HDL ratio in African Americans. Variance components analysis identified linkage on chromosome 3p12.1-3q13.31 for the triglyceride/HDL ratio (logarithm of odds [LOD] = 3.36) and triglyceride (LOD = 3.27) in Caucasian families. Statistically significant evidence for linkage was identified for the triglyceride/HDL ratio (LOD = 2.45) on 11p in Hispanic families in a region that showed suggestive evidence for linkage (LOD = 2.26) for triglycerides in this population. In African Americans, the strongest evidence for linkage (LOD = 2.26) was found on 19p13.2-19q13.42 for total cholesterol. Our findings provide strong support for previous reports of linkage for lipid-related traits, suggesting the presence of genes on 3p12.1-3q13.31, 11p15.4-11p11.3, and 19p13.2-19q13.42 that may influence traits underlying lipid abnormalities associated with type 2 diabetes.