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.     

A genome-wide scan for childhood obesity-associated traits in French families shows significant linkage on chromosome 6q22.31-q23.2

We conducted a genome-wide search for childhood obesity-associated traits, including BMI >/==" BORDER="0">95th percentile (PCT95), 97th percentile (PCT97), and 99th percentile (PCT99) as well as age of adiposity rebound (AAR), which corresponds to the beginning of the second rise in childhood adiposity. A set of 431 microsatellite markers was genotyped in 506 subjects from 115 multiplex French Caucasian families, with at least one child with a BMI >/==" BORDER="0">95th percentile. Among these 115 pedigrees, 97 had at least two sibs with a BMI >/==" BORDER="0">95th percentile. Fine-mapping was performed in the seven most positive loci. Nonparametric multipoint analyses revealed six regions of significant or suggestive linkage on chromosomes 2q33.2-q36.3, 6q22.31-q23.2, and 17p13 for PCT95, PCT97, or PCT99 and 15q12-q15.1, 16q22.1-q24.1, and 19p13.3-p13.11 for AAR. The strongest evidence of linkage was detected on chromosome 6q22.31 for PCT97 (maximum likelihood score: 4.06) at the marker D6S287. This logarithm of odds score meets genome-wide significance tested through simulation (empirical genome-wide P = 0.01 [0.0027-0.0254]). Six independent ge-nome scans in adults have reported quantitative trait loci on 6q linked to energy or glucose homeostasis-associated phenotypes. Possible candidate genes in this region include SIM1, MCHR2, and PC-1.     

Genome-wide scan for type 1 diabetic nephropathy in the Finnish population reveals suggestive linkage to a single locus on chromosome 3q

Diabetic nephropathy (DN) is the primary cause of morbidity and mortality in patients with type 1 as well as type 2 diabetes, and accounts for 40% of end-stage renal disease in the Western world. Familial clustering of DN suggests importance of genetic factors in the development of the disease. In the present study, we performed a two-stage genome-wide scan to search for chromosomal loci containing susceptibility genes for nephropathy in patients with type 1 diabetes. In total, 83 discordant sib pairs (DSPs), sibs concordant for type 1 diabetes but discordant for nephropathy, were collected from Finland, a homogeneous population with one of the highest incidences of type 1 diabetes. To map loci for DN, we applied DSP analysis to detect linkage. In the initial scan, 73 DSPs were typed using 900 markers with an average intermarker distance of approximately 4 cM. Multipoint DSP analysis identified five chromosome regions (3q, 4p, 9q, 16q, and 22p) with maximum logarithm of odds (LOD) score (MLS) >or=1.0 (corresponding to a nominal P-value 相似文献   

Genome-wide scan for type 2 diabetes loci in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21-q25

We conducted an autosomal genome scan to map loci for type 2 diabetes in a Hong Kong Chinese population. We studied 64 families, segregating type 2 diabetes, of which 57 had at least one member with an age at diagnosis of 0.59, P(pointwise) < 0.05): chromosome 1 at 173.9 cM (LOD = 3.09), chromosome 3 at 26.3 cM (LOD = 1.27), chromosome 4 at 135.3 cM (LOD = 2.63), chromosome 5 at 139.3 cM (LOD = 0.84), chromosome 6 at 178.9 cM (LOD = 1.91), chromosome 12 at 48.7 cM (LOD = 1.99), and chromosome 18 at 28.1 cM (LOD = 1.00). Simulation studies showed genome-wide significant evidence for linkage of the chromosome 1 region (P(genome-wide) = 0.036). We have confirmed the results of previous studies for the presence of a susceptibility locus on chromosome 1q21-q25 (173.9 cM) and suggest the locations of other loci that may contribute to the development of type 2 diabetes in Hong Kong Chinese.     

A genome-wide scan in families with maturity-onset diabetes of the young: evidence for further genetic heterogeneity

Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non-insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15-20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of beta-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169-175 cM), and to chromosomes 3 (heterogeneity LOD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Our results provide evidence for further heterogeneity in MODY.     

Genome-wide and fine-mapping linkage studies of type 2 diabetes and glucose traits in the Old Order Amish: evidence for a new diabetes locus on chromosome 14q11 and confirmation of a locus on chromosome 1q21-q24

We conducted a genome scan using a 10-cM map to search for genes linked to type 2 diabetes in 691 individuals from a founder population, the Old Order Amish. We then saturated two regions on chromosomes 1 and 14 showing promising linkage signals with additional markers to produce a approximately 2-cM map for fine mapping. Analyses of both discrete traits (type 2 diabetes and the composite trait of type 2 diabetes and/or impaired glucose homeostasis [IGH]), and quantitative traits (glucose levels during a 75-g oral glucose challenge, designated glucose 0-180 and HbA(1c)) were performed. We obtained significant evidence for linkage to type 2 diabetes in a novel region on chromosome 14q11 (logarithm of odds [LOD] for diabetes = 3.48, P = 0.00005). Furthermore, we observed evidence for the existence of a diabetes-related locus on chromosome 1q21-q24 (LOD for type 2 diabetes/IGH = 2.35, P = 0.0008), a region shown to be linked to diabetes in several other studies. Suggestive evidence for linkage to glucose traits was observed on three other regions: 14q11-q13 (telomeric to that above with LOD = 1.82-1.85 for glucose 150 and 180), 1p31 (LOD = 1.28-2.30 for type 2 diabetes and glucose 120-180), and 18p (LOD = 3.07, P = 0.000085 for HbA(1c) and LOD = 1.50 for glucose 0). In conclusion, our findings provide evidence that type 2 diabetes susceptibility genes reside on chromosomes 1, 14, and 18.     

Examination of candidate chromosomal regions for type 2 diabetes reveals a susceptibility locus on human chromosome 8p23.1

In a panel of large Caucasian pedigrees, we genotyped markers in eight chromosomal regions previously reported as supporting linkage with type 2 diabetes. We previously reported significant linkage on chromosome 20q (maximum logarithm of odds score [MLS] = 2.79) in this panel. In the present analysis, candidate regions on 1q, 2q, 3q, 5q, 9q, and 10q yielded little evidence for linkage; a region on 2p (MLS = 1.64, P = 0.01 at position 9.0 cM) gave suggestive evidence of linkage; and a region on 8p (MLS = 3.67, P = 2.8 x 10(-5), at position 7.6 cM) gave significant evidence of linkage. Conditional analyses were performed for both 2p and 8p regions and the region reported on 20q. The MLS for 2p increased from 1.64 to 1.79 (empirical P = 0.142) when conditioned for heterogeneity on 20q. The case was similar for 8p, where the MLS increased from 3.67 to 4.51 (empirical P = 0.023) when conditioned on families without evidence of linkage at 20q. In conclusion, our data support a type 2 diabetes susceptibility locus on chromosome 8p that appears to be independent from other susceptibility loci. Although we were able to replicate linkage in our pedigrees on chromosome 2p, we did not find evidence of linkage for regions on 1q, 2q, 3q, 5q, 9q, or 10q.     

Evidence of a novel type 2 diabetes locus 50 cM centromeric to NIDDM2 on chromosome 12q.

To replicate the recent finding of a type 2 diabetes locus (NIDDM2) on 12q, families segregating early-onset autosomal-dominant type 2 diabetes were screened for linkage. Included were 26 Caucasian and 6 non-Caucasian pedigrees with an average age at diabetes diagnosis of 37 +/- 18 years. Affected (n = 233) and nonaffected (n = 152) family members were genotyped for 17 markers covering 90 cM on chromosome 12q. While no evidence for linkage was detected at the NIDDM2 locus, a linkage peak was observed 50 cM centromeric to NIDDM2 at markers D12S375 and D12S1052. In a nonparametric analysis, the Z(all) score was 2.9 (P = 0.015) at D12S375, and increased to 3.8 (P = 0.007) among Caucasian families. Further increase in significance was observed in pedigrees with poor insulin response, with a maximum Z(all) of 6.2 (P = 0.002) at D12S375. Suggestive evidence of linkage was also detected by the parametric analysis, with the heterogeneity logarithm of odds score peaking at 2.5 (alpha = 0.15) between D12S375 and D12S1052. In summary, our data indicate that the NIDDM2 locus does not play a major role in early-onset autosomal-dominant type 2 diabetes. Rather, they strongly suggest that a previously undetected type 2 diabetes locus exists 50 cM from NIDDM2 on 12q.     

Extension of type 2 diabetes genome-wide association scan results in the diabetes prevention program

OBJECTIVE— Genome-wide association scans (GWASs) have identified novel diabetes-associated genes. We evaluated how these variants impact diabetes incidence, quantitative glycemic traits, and response to preventive interventions in 3,548 subjects at high risk of type 2 diabetes enrolled in the Diabetes Prevention Program (DPP), which examined the effects of lifestyle intervention, metformin, and troglitazone versus placebo.RESEARCH DESIGN AND METHODS— We genotyped selected single nucleotide polymorphisms (SNPs) in or near diabetes-associated loci, including EXT2, CDKAL1, CDKN2A/B, IGF2BP2, HHEX, LOC387761, and SLC30A8 in DPP participants and performed Cox regression analyses using genotype, intervention, and their interactions as predictors of diabetes incidence. We evaluated their effect on insulin resistance and secretion at 1 year.RESULTS— None of the selected SNPs were associated with increased diabetes incidence in this population. After adjustments for ethnicity, baseline insulin secretion was lower in subjects with the risk genotype at HHEX rs1111875 (P = 0.01); there were no significant differences in baseline insulin sensitivity. Both at baseline and at 1 year, subjects with the risk genotype at LOC387761 had paradoxically increased insulin secretion; adjustment for self-reported ethnicity abolished these differences. In ethnicity-adjusted analyses, we noted a nominal differential improvement in β-cell function for carriers of the protective genotype at CDKN2A/B after 1 year of troglitazone treatment (P = 0.01) and possibly lifestyle modification (P = 0.05).CONCLUSIONS— We were unable to replicate the GWAS findings regarding diabetes risk in the DPP. We did observe genotype associations with differences in baseline insulin secretion at the HHEX locus and a possible pharmacogenetic interaction at CDKNA2/B.The increasing incidence of diabetes continues to have a tremendous impact on diabetes-related morbidity and mortality around the world. Although much emphasis has been placed on the contribution of a Western lifestyle characterized by increasing caloric intake and physical inactivity to the diabetes epidemic, the role genetics plays in the development of diabetes is generally poorly understood. Additional insight into the contribution of genetic variants to diabetes incidence, gene-lifestyle interactions, and pharmacological response to antidiabetes medications is required to slow this tragic epidemic.The recent implementation of genome-wide association scans (GWASs) as an investigative tool has resulted in a qualitative leap in identifying diabetes-related genes (1,2). These surveys, which are agnostic to candidate genes, can cover ∼80% of common human genome variants with current technology, thus providing unprecedented insight into the genetic architecture of type 2 diabetes. In 2007, the first published type 2 diabetes GWAS confirmed the important impact of TCF7L2 on diabetes incidence (odds ratio [OR] 1.65, P < 1.0 × 10⁻⁷) and identified several new type 2 diabetes loci, SLC30A8 (1.26, P = 5.0 × 10⁻⁷), HHEX (1.21, P = 9.1 × 10⁻⁶), LOC38771 (1.14, P = 2.9 × 10⁻⁴), and EXT (1.26, P = 1.2 × 10⁻⁴) (3). SLC30A8 encodes a zinc transporter protein that carries zinc from the cytoplasm into insulin secretory vesicles within the pancreatic β-cell, an important step in insulin synthesis and secretion (4). HHEX is essential for the development of the pancreas and liver and is a target of the Wnt signaling pathway (5).After the initial GWAS publication, four other high-density scans were published simultaneously by different groups, confirming many of the initial findings. In addition to replicating the prior associations of TCF7L2, HHEX, and SCL30A8, investigators from Iceland identified CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1) as another potential diabetes-related gene (OR 1.2, P = 1.8 × 10⁻⁴) (6). This gene is hypothesized to lead to β-cell degeneration by modulating CDK5/CDK5R1 activity. The Diabetes Genetics Initiative, the Wellcome Trust Case Control Consortium, and the Finland–U.S. Investigation of Type 2 Diabetes Genetics concomitantly published GWASs that were combined in a preliminary meta-analysis of >30,000 samples (7–9). Again, the above findings were confirmed, and novel diabetes loci in or near IGF2BP2 (1.14, P = 8.9 × 10⁻¹⁶) and CDKN2A/B (1.2, P = 7.8 × 10⁻¹⁵) were identified. The EXT2 and LOC387761 gene regions have not been replicated in these or additional studies (10,11). Taken together, these studies support the potential power of GWASs in unraveling the genetic basis of type 2 diabetes.Several studies have attempted to characterize the physiological mechanisms affected by these genetic variants. Pascoe et al. (12) performed 75-g oral glucose tolerance tests (OGTTs) and hyperinsulinemic-euglycemic clamps on 1,276 healthy European subjects and demonstrated that common variants in CDKAL1 and HHEX are associated with decreased pancreatic β-cell function. Grarup et al. (13) reported that variants of HHEX, CDKN2A/B, and IFG2BP2 are associated with type 2 diabetes, and single nucleotide polymorphisms (SNPs) within the HHEX and CDKN2A/B loci impaired glucose-induced insulin release in healthy subjects, emphasizing the central role of pancreatic β-cell dysfunction in disease pathogenesis. Staiger et al. (14) found that the major alleles of the SLC30A8 and the HHEX SNPs associate with reduced insulin secretion stimulated by orally administered glucose but not with insulin resistance; the other reported type 2 diabetes SNPs within the EXT2 and LOC387761 loci did not associate with insulin resistance or β-cell dysfunction. Finally, a quantitative trait analysis of GWAS-identified type 2 diabetes susceptibility loci was recently completed by Palmer et al. (15) in their analysis of the Insulin Resistance Atherosclerosis Family Study (IRAS-FS). This study of 1,268 Hispanic and 581 African American subjects revealed that the increase in diabetes risk associated with variants in GWAS-identified gene regions, including CDKAL1, IGF2BP2, SLC30A8, and LOC387761, is mediated in part via defects primarily in insulin secretion. In Hispanic Americans, the acute insulinogenic response to glucose challenge decreased in high-risk genotype subjects at CDKAL1 (P = 0.005), and the disposition index was reduced in subjects with the high-risk genotype at IGF2BP2 (P = 0.01). Paradoxically, in Hispanic Americans, the previously identified risk allele of LOC387761 was significantly associated with an increased acute insulin response (P = 0.005) and disposition index (P = 0.036). IGF2BP2 rs4402960 was the only GWAS-identified SNP that associated with type 2 diabetes as a categorical trait (P = 0.02). Even fewer studies have attempted to analyze the influence of these genetic variants on response to pharmacological or behavioral interventions (16,17).The current study attempts to replicate and extend recent GWAS findings in the Diabetes Prevention Program (DPP) cohort. As a multiethnic, interventional study of >3,000 people at high risk for diabetes who have been carefully characterized, the DPP provides the opportunity to study insulin dynamics according to genotype and potential drug-genotype interactions. Studying pre-diabetic subjects as opposed to patients with overt diabetes provides insight into the role of genetic variation in the early stages of disease progression. As a longitudinal interventional study, the DPP provides the opportunity to carefully study the impact of genetic variation on insulin secretion and resistance over time. Finally, having multiple treatment arms allows for the identification of potential interactions of genotype with the results of the interventions. Studying gene-treatment interactions helps elucidate mechanisms of disease, identify specific treatments that may ameliorate the genetic predisposition to disease, and focus on subgroups that respond particularly well (or poorly) to specific therapies.     

EIF4A2 is a positional candidate gene at the 3q27 locus linked to type 2 diabetes in French families

One of the most replicated loci influencing type 2 diabetes-related quantitative traits (quantitative trait loci [QTL]) is on chromosome 3q27 and modulates both type 2 diabetes-and metabolic syndrome-associated phenotypes. A QTL for type 2 diabetes age of onset (logarithm of odds [LOD] score = 3.01 at D3S3686, P = 0.0001) was identified in a set of French families. To assess genetic variation underlying both age-of-onset QTL and our previous type 2 diabetes linkage in a 3.87-Mb interval, we explored 36 single nucleotide polymorphisms (SNPs) in two biologically relevant candidate genes for glucose homeostasis, kininogen (KNG1), and eukaryotic translation initiation factor 4alpha2 (EIF4A2). Analysis of 148 families showed significant association of a frequent SNP, rs266714, located 2.47 kb upstream of EIF4A2, with familial type 2 diabetes (family-based association test, P = 0.0008) and early age of onset (P = 0.0008). This SNP also contributes to both age-of-onset QTL (1.13 LOD score decrease P = 0.02) and type 2 diabetes linkage (genotype identical-by-descent sharing test, P = 0.02). However, no association was observed in three independent European diabetic cohorts. EIF4A2 controls specific mRNA translation and protein synthesis rate in pancreatic beta-cells, and our data indicates that EIF4A2 is downregulated by high glucose in rat beta-INS832/13 cells. The potential role of EIF4A2 in glucose homeostasis and its putative contribution to type 2 diabetes in the presence of metabolic stress will require further investigation.     

A genome-wide linkage scan for genes controlling variation in renal function estimated by serum cystatin C levels in extended families with type 2 diabetes

We performed a variance components linkage analysis of renal function, measured as glomerular filtration rate (GFR), in 63 extended families with multiple members with type 2 diabetes. GFR was estimated from serum concentrations of cystatin C and creatinine in 406 diabetic and 428 nondiabetic relatives. Results for cystatin C were summarized because they are superior to creatinine results. GFR aggregates in families with significant heritability (h(2)) in diabetic (h(2) = 0.45, P < 1 x 10(-5)) and nondiabetic (h(2) = 0.36, P < 1 x 10(-3)) relatives. Genetic correlation (r(G) = 0.35) between the GFR of diabetic and nondiabetic relatives was less than one (P = 0.01), suggesting that genes controlling GFR variation in these groups are different. Linkage results supported this interpretation. In diabetic relatives, linkage was strong on chromosome 2q (logarithm of odds [LOD] = 4.1) and suggestive on 10q (LOD = 3.1) and 18p (LOD = 2.2). In nondiabetic relatives, linkage was suggestive on 3q (LOD = 2.2) and 11p (LOD = 2.1). When diabetic and nondiabetic relatives were combined, strong evidence for linkage was found only on 7p (LOD = 4.0). In conclusion, partially distinct sets of genes control GFR variation in relatives with and without diabetes on chromosome 2q, possibly on 10q and 18p in the former, and on 7p in both. None of these genes overlaps with genes controlling variation in urinary albumin excretion.     

An X-chromosome scan reveals a locus for fat distribution in chromosome region Xp21-22

Several groups have completed autosomal genome scans for human obesity, but only two have examined the X chromosome. A French group reported linkage of BMI to Xp and Xq markers, and a Finnish group reported linkage of BMI to Xq. We scanned the X chromosome in two cohorts, 190 European-American families (940 members) and 43 African-American families (208 members). We examined five correlated obesity phenotypes, BMI, body fat percentage, hip and waist circumferences, and plasma leptin concentration. We also examined leptin resistance (leptin/BMI) and fat patterning (waist-to-hip ratio [WHR]). Variables were adjusted for age within generation, race, and sex. We genotyped 20 markers with average spacing of 10 cM and no interval >22 cM and conducted nonparametric analyses. Suggestive linkage was found for WHR only. Linkage was supported in both family sets, and support was especially strong for females. Z scores for analyses of female phenotypes were 2.69, 1.73, and 2.37 (P = 0.0036, 0.0418, and 0.0089) for African-Americans, European-Americans, and the combined sample, respectively. The peaks were 51-73 cM from the p terminus, 14-34 cM distal of the French report in Xp22. Our results suggest that a quantitative trait locus influencing fat distribution in women may lie in chromosome region Xp21-22; however, the linked interval is large and differs substantially from that of the French and Finnish groups. Given the positive but divergent results, it would be worthwhile for others to examine the X chromosome.     

Evidence for a novel type 1 diabetes susceptibility locus on chromosome 8

Type 1 diabetes results from a combination of genetic susceptibility and environmental exposures. Susceptibility loci other than HLA and the insulin gene remain to be identified to account for the degree of familial clustering observed in this disorder. Early genome-wide scans provided suggestive evidence of linkage on chromosome 8q, prompting detailed analysis of this region. A total of 20 microsatellite markers spanning an 88-cM region of 8q11-24 were genotyped in 24 type 1 diabetes pedigrees from Wisconsin that contained 39 affected sib-pairs. Multipoint linkage analyses provided close to suggestive evidence of linkage, with a multipoint logarithm of odds score (MLS) of 2.4 and Genehunter nonparametric logarithm of odds score (NPL) of 2.7 (P = 0.003). There is also evidence of linkage disequilibrium at peak marker D8S1823 for the 217bp allele (P = 0.037) using the pedigree disequilibrium test. Although our sample size was small, the multiple tests were consistent and our preliminary results suggested that 8q24 may harbor a novel population-specific type 1 diabetes susceptibility gene. Continued investigation of this region for a novel type 1 diabetes susceptibility gene appears justified.     

Linkage and association mapping of a chromosome 1q21-q24 type 2 diabetes susceptibility locus in northern European Caucasians

We have identified a region on chromosome 1q21-q24 that was significantly linked to type 2 diabetes in multiplex families of Northern European ancestry and also in Pima Indians, Amish families, and families from France and England. We sought to narrow and map this locus using a combination of linkage and association approaches by typing microsatellite markers at 1.2 and 0.5 cM densities, respectively, over a region of 37 cM (23.5 Mb). We tested linkage by parametric and nonparametric approaches and association using both case-control and family-based methods. In the 40 multiplex families that provided the previous evidence for linkage, the highest parametric, recessive logarithm of odds (LOD) score was 5.29 at marker D1S484 (168.5 cM, 157.5 Mb) without heterogeneity. Nonparametric linkage (NPL) statistics (P = 0.00009), SimWalk2 Statistic A (P = 0.0002), and sib-pair analyses (maximum likelihood score = 6.07) all mapped to the same location. The one LOD CI was narrowed to 156.8-158.9 Mb. Under recessive, two-point linkage analysis, adjacent markers D1S2675 (171.5 cM, 158.9 Mb) and D1S1679 (172 cM, 159.1 Mb) showed LOD scores >3.0. Nonparametric analyses revealed a second linkage peak at 180 cM near marker D1S1158 (163.3 Mb, NPL score 3.88, P = 0.0001), which was also supported by case-control (marker D1S194, 178 cM, 162.1 Mb; P = 0.003) and family-based (marker ATA38A05, 179 cM, 162.5 Mb; P = 0.002) association studies. We propose that the replicated linkage findings actually encompass at least two closely spaced regions, with a second susceptibility region located telomeric at 162.5-164.7 Mb.     

A genome-wide linkage scan for genes controlling variation in urinary albumin excretion in type II diabetes

The main hallmark of diabetic nephropathy is elevation in urinary albumin excretion. We performed a genome-wide linkage scan in 63 extended families with multiple members with type II diabetes. Urinary albumin excretion, measured as the albumin-to-creatinine ratio (ACR), was determined in 426 diabetic and 431 nondiabetic relatives who were genotyped for 383 markers. The data were analyzed using variance components linkage analysis. Heritability (h2) of ACR was significant in diabetic (h2=0.23, P=0.0007), and nondiabetic (h2=0.39, P=0.0001) relatives. There was no significant difference in genetic variance of ACR between diabetic and nondiabetic relatives (P=0.16), and the genetic correlation (rG=0.64) for ACR between these two groups was not different from 1 (P=0.12). These results suggested that similar genes contribute to variation in ACR in diabetic and nondiabetic relatives. This hypothesis was supported further by the linkage results. Support for linkage to ACR was suggestive in diabetic relatives and became significant in all relatives for chromosome 22q (logarithm of odds, LOD=3.7) and chromosome 7q (LOD=3.1). When analyses were restricted to 59 Caucasian families, support for linkage in all relatives increased and became significant for 5q (LOD=3.4). In conclusion, genes on chromosomes 22q, 5q and 7q may contribute to variation in urinary albumin excretion in diabetic and nondiabetic individuals.     

Meta-analysis of genome-wide linkage studies of quantitative lipid traits in families ascertained for type 2 diabetes

Dyslipidemia is a major risk factor for coronary heart disease, which is the predominant cause of mortality in individuals with type 2 diabetes. To date, nine linkage studies for quantitative lipid traits have been performed in families ascertained for type 2 diabetes, individually yielding linkage results that were largely nonoverlapping. Discrepancies in linkage findings are not uncommon and are typically due to limited sample size and heterogeneity. To address these issues and increase the power to detect linkage, we performed a meta-analysis of all published genome scans for quantitative lipid traits conducted in families ascertained for type 2 diabetes. Statistically significant evidence (i.e., P < 0.00043) for linkage was observed for total cholesterol on 7q32.3-q36.3 (152.43-182 cM; P = 0.00004), 19p13.3-p12 (6.57-38.05 cM; P = 0.00026), 19p12-q13.13 (38.05-69.53 cM; P = 0.00001), and 19q13.13-q13.43 (69.53-101.1 cM; P = 0.00033), as well as LDL on 19p13.3-p12 (P = 0.00041). Suggestive evidence (i.e., P < 0.00860) for linkage was also observed for LDL on 19p12-q13.13, triglycerides on 7p11-q21.11 (63.72-93.29 cM), triglyceride/HDL on 7p11-q21.11 and 19p12-q13.13, and LDL/HDL on 16q11.2-q24.3 (65.2-130.4 cM) and 19p12-q13.13. Linkage for lipid traits has been previously observed on both chromosomes 7 and 19 in several unrelated studies and, together with the results of this meta-analysis, provide compelling evidence that these regions harbor important determinants of lipid levels in individuals with type 2 diabetes.     

Genome-wide linkage scan of a large family with IgA nephropathy localizes a novel susceptibility locus to chromosome 2q36

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and an important cause of ESRD. Familial clustering of cases suggests genetic predisposition to this disease. Two recent genome-wide studies in IgAN have identified a major susceptibility locus on chromosome 6q22 (IGAN1) and two additional loci with suggestive linkage signals on chromosomes 4q26-31 and 17q12-22. A large four-generation family with 14 affected individuals has been clinically ascertained and excluded from linkage to these loci. A genome-wide linkage scan was performed on this family with GeneChip Mapping 10K 2.0 Arrays using an "affected-only" strategy. By nonparametric analysis, two regions of suggestive linkage (multipoint logarithm of odds [LOD] scores >2) were identified on chromosomes 2q36 and 13p12.3. By parametric analysis (assuming an autosomal dominant inheritance, a disease allele frequency of 0.001, phenocopy rate of 0.01, and penetrance of 75%), a significant linkage to chromosome 2q36 (maximum multipoint LOD score 3.47) was found. Nine simple sequence repeat markers then were genotyped in 21 members (included all of the affected individuals), and significant linkage to chromosome 2q36 over a region of 12.2 cM (maximum multipoint LOD score 3.46) was confirmed. Recombination events in two affected individuals, as detected by haplotype analysis, delineated a critical interval of approximately 9 cM (equivalent to approximately 7 Mb) between D2S1323 and D2S362. Taken together, these data provide strong evidence for a novel disease susceptibility locus for familial IgAN.