A susceptibility locus for early-onset non-insulin dependent (type 2) diabetes mellitus maps to chromosome 20q, proximal to the phosphoenolpyruvate carboxykinase gene
A susceptibility locus for early-onset non-insulin dependent (type 2) diabetes mellitus maps to chromosome 20q, proximal to the phosphoenolpyruvate carboxykinase geneHabib Zouali1,2,+, El Habib Hani2,+, Anne Philippi3, Nathalie Vionnet2, Jacques S. Beckmann4, Florence Demenais3,§ and Philippe Froguel2,§,*
1Fondation Jean Dausset-CEPH, 27 rue Juliette Dodu, 75010 Paris, France, 2CNRS EP10, Institut Pasteur de Lille, 1 rue du Professeur Calmette, 59019 Lille Cedex, France, 3INSERM-U358, Hôpital Saint Louis, 1 avenue Claude Vellefaux, 75010 Paris, France and 4Généthon, 1 rue de l'Internationale, BP 60, 91002 Every Cedex, France
Received November 13, 1996;Revised and Accepted June 20, 1997
Several candidate genes for non-insulin-dependent diabetes mellitus (NIDDM) map on chromosome 20, including the phosphoenolpyruvate carboxykinase gene (PCK1) and one of the maturity onset diabetes of the young genes (MODY1). Thus, we have investigated the entire long arm of chromosome 20. Linkage analyses were conducted in a total sample of 148 NIDDM families (301 NIDDM sib pairs) and in a subset of 42 early onset NIDDM families, where genetic components are likely to play a more important role (55 NIDDM sib pairs diagnosed at or before 45 years of age), using 10 highly polymorphic markers with an average map density of 7.5 cM. Using affected sib pair methods (two-point linkage and multipoint linkage analyses), significant results were obtained with the 20q13 region, in the vicinity of the PCK1 locus, only in the subset of 55 early onset NIDDM sib pairs (multipoint MLS = 2.74, P = 0.0004; MLS = 2.34, P = 0.0009 when using a conservative weighting procedure). Moreover, another region spanning the ribophorin II (RPNII), phospholipase C (PLC1) and adenosine deaminase (ADA) loci suggested linkage with NIDDM (multipoint MLS of 1.81 in all NIDDM sib pairs, P = 0.003; MLS = 1.31, P = 0.012 when using a conservative weighting procedure). Whereas our study suggests the location of a susceptibility locus for early onset NIDDM in the PCK1 gene region, further investigation in larger data sets is required to confirm these results and assess the role of other regions on chromosome 20q in human NIDDM.
It is widely accepted that non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous metabolic disorder with a complex pattern of inheritance. NIDDM exhibits a combination of two major alterations, insulin resistance and pancreatic [beta]-cell dysfunction, but the primary defect is still largely unknown (1 ). Candidate gene approaches and genome-wide scans are powerful tools to search for NIDDM susceptibility loci. In this regard, recent genome-wide searches led to mapping of major susceptibility loci for NIDDM to chromosome 2q in Mexican-Americans and to chromosome 12q in Finnish families (2 ,3 ). However, these two chromosomal regions do not appear to be major contributors to NIDDM in the French NIDDM families, illustrating the difficulties of mapping common multifactorial traits (4 ,5 ).
On the other hand, and so far, the intensive search for NIDDM candidate genes potentially involved in insulin secretion and/or insulin action has only provided clues for limited subtypes of NIDDM. This has led to the identification of rare Mendelian sub-entities and few genetic variants having separately relatively modest effects on insulin secretion and/or insulin action, therefore accounting for no more than 5% of the familial clustering of NIDDM (6 -9 ). Insulin resistance is considered to be the earliest detectable clinical defect in the pre-diabetic state (10 ) and segregation analyses in several ethnic groups strongly suggest that major loci may be involved in the familial clustering of insulin resistance (11 -13 ). Therefore, investigating genes of the insulin pathways may potentially help to elucidate some forms of human NIDDM. The cytosolic phosphoenolpyruvate carboxykinase gene (PCK1) located on chromosome 20q13.3 (14 ) encodes a key regulatory enzyme (PEPCK) in liver glucose metabolism. This enzyme governs the rate limiting step of gluconeogenesis and thus in part hepatic glucose output. As demonstrated in transgenic mice, over-expression of PEPCK enzyme leads to hyperglycemia, insulin resistance and NIDDM (15 ), and a similar mechanism may be expected to cause insulin resistance with increased hepatic gluconeogenesis in human NIDDM. Thus, PCK1 is a strong candidate gene for NIDDM, which is characterized by abnormally increased and non-suppressible hepatic glucose production (1 ,10 ).
Preliminary genetic studies of several candidate genes for insulin resistance showed some indication of linkage between a PCK1 intragenic microsatellite marker and NIDDM in a limited set of 42 French NIDDM families with multiple cases of NIDDM (16 ). It is noteworthy that two other diabetogenes also map to chromosome 20q, both centromeric to the PCK1 locus, namely the MODY1 gene, causing a subtype of maturity onset diabetes of the young, and the agouti signaling protein gene (ASP), which is the human homolog of a murine gene responsible for an obesity-diabetes syndrome in mice (17 ,18 ). This prompted us to investigate the entire chromosome 20q in our collection of French Caucasian NIDDM families. A sample of 148 families, ascertained through at least two NIDDM siblings (including the original set of 42 multiple case NIDDM families), was genotyped for 10 polymorphic markers spanning a 67 cM region on the long arm of chromosome 20q with an average map density of 7.5 cM.
We report here suggestive evidence for linkage of early onset NIDDM to the chromosome 20q13 region, in the vicinity of the PCK1 locus in a subset of 55 NIDDM sib pairs diagnosed at or before 45 years of age. In addition, our data indicate a possible linkage of NIDDM to the 20q12-13.11 region, proximal to PCK1, spanning the ribophorin II (RPNII), phospholipase C (PLC1) and adenosine deaminase (ADA) loci.
This study was conducted in a total sample of 148 multiplex NIDDM pedigrees, including 156 sibships with a maximum of 301 NIDDM sib pairs available for genotyping. Affected status was defined as having overt NIDDM according to the WHO criteria (individuals with fasting plasma glucose >7.8 mM and/or >11 mM after a 2 h glucose load and/or if treated by oral hypoglycemic agents or by insulin at least 1 year after diagnosis) (19 ). Since NIDDM is a heterogeneous disorder and, as reported in a previous study, the contribution of the genetic component to NIDDM decreases as the age at diagnosis increases (20 ), we selected a subset of 42 sibships including at least two siblings with NIDDM diagnosed at or before the age of 45 years, where genetic factors may be easier to detect. This subset of families, designated in this paper `early onset NIDDM', included a total of 55 early onset NIDDM sib pairs. We did not consider those sib pairs diagnosed after the age of 45 years separately, as these are probably a mixture of early and late onset cases (early onset diabetic patients remaining frequently undiagnosed for a long period of time). Indeed, analysis of this late-onset subset would increase the number of statistical tests without any likely gain with respect to the whole sample. Available parents and siblings (affected and unaffected) were genotyped for 10 markers with an average heterozygosity of 0.77 +- 0.06 (mean +- SD), estimated from the data (Fig. 1 ).
Following these two-point linkage analyses, multipoint mapping, based on the MLS method (25 ), was carried out on the two sets of NIDDM sib pairs, using the whole map of 10 markers. In all NIDDM pairs the MLS reached 1.81 (1.31 when weighted, 0.003 < P < 0.012) at a location linked to RPNII, with a 1 LOD unit confidence interval of 28 cM, contained within the region spanning the loci from D20S112 to ADA (Fig. 2 ). In the 55 early onset NIDDM pairs the peak MLS was 2.74 (2.34 when weighted, 0.0004 < P < 0.0009) at a location 7 cM proximal to PCK1, with a 1 LOD unit confidence interval of 24 cM, spanning the D20S176, D20S196, D20S100 and PCK1 loci (Fig. 3 ).
Given this latter result, a direct involvement of PCK1 in early onset NIDDM was suggested. Since the PCK1 gene is essentially regulated in a negative manner by insulin, we screened for mutations in the PCK1 gene promoter sequences. Thus, a 579 bp segment located at the 5'-end of the structural gene and containing the necessary regulatory elements accounting for the normal pattern of gene expression, especially inhibition by insulin, was directly screened by SSCP in early onset NIDDM patients. However, we did not find any DNA polymorphism in the probands studied (data not shown).
This study shows suggestive evidence for linkage of early onset NIDDM with a 24 cM region on 20q13, including the PCK1 locus. Measurement of the contribution of each sib pair to the multipoint MLS of 2.74 at the PCK1 locus indicates that the LOD scores corresponding to the initial set of 25 sib pairs and the second set of 30 sib pairs are 1.85 (P = 0.003) and 0.88 (P = 0.035) respectively, both in favor of linkage. It is common usage to weight non-independent sib pairs from sibships with s affecteds if s > 2. However, a recent simulation study showed that the weighting procedure, which multiplies the LOD score of each sib pair by 2/s, as implemented in the computer program Mapmaker/Sibs, leads to conservative tests, especially when parents are not genotyped (27 ). Since analyses were repeated on two data sets, the early onset sample and the whole sample, it is also common usage to multiply the P values by the number of samples analyzed to correct for multiple testing. The P value of 0.0004 associated with the MLS of 2.74 would thus become equal to 0.0008, still close to the conservative threshold of suggestive linkage (P = 0.0007) recommended by Lander and Kruglyak for a dense map in a complete genome scan (28 ).
From an initial pool of 278 multiplex NIDDM families, we have selected 46 multiple case pedigrees. Family information was collected in France through a multimedia campaign and clinical data for each family member were obtained during a standardized clinical examination performed at the Endocrinology Department of the Hôpital Saint Louis, Paris, or by the subject's personal physician. Four of these families were excluded from the study because both parents had NIDDM. Subjects were considered affected if they presented NIDDM as defined by WHO criteria (19 ). The 42 selected families presented NIDDM cases in at least two consecutive generations. To increase the sample size, a second set of 116 NIDDM families (smaller in size than those in the first set), with at least one NIDDM sib pair, was selected. Ten families with both parents affected were excluded and only 106 families were included in the study, making a total of 148 families when added to the initial set. Criteria used to select our family samples comprised exclusion of linkage to the MODY3 locus on chromosome 12q (4 ) and absence of mutations in the glucokinase gene and a tRNALeu mutation in mitochondrial DNA when testing at least one affected individual from each family. In the total set of 148 NIDDM families studied there were 393 family members presenting NIDDM; the first set of 42 NIDDM families and the total set have been previously described (4 ,16 ). All 393 NIDDM subjects were tested for fasting glucose levels, and 16% of the affected members from these families who were not being treated for NIDDM consented to oral glucose tolerance testing. Among all NIDDM patients of the total set, 69% were being treated with oral hypoglycemic agents and 15% with insulin. The total sample of 148 families included 156 sibships with at least two NIDDM cases available for genotyping, making an overall sample size of 301 NIDDM sib pairs. Since the genetic component is suggested to play a more important role in early onset NIDDM, we selected a subset of 42 sibships with at least two sibs with NIDDM diagnosed at or before age 45 years, including a total of 55 early onset NIDDM sib pairs (39% of affected family members in the whole sample were diagnosed for NIDDM at or before the age of 45 years). The cut-off point of 45 years of age was chosen as in our previous linkage studies (4 ,29 ), since true age at onset of NIDDM is difficult to know accurately and 45 years seemed a reasonable choice to define an actual early onset subgroup. Characteristics of NIDDM patients in this subset and the whole sample of sib pairs are as follows: mean age at diagnosis of NIDDM 36.9 +- 6.9 in the early onset group and 47.7 +- 11.8 in the whole set; proportions of males among all patients 57 and 51% respectively (not significantly different, P = 0.47); mean body mass indices (BMI) similar, being respectively 27.1 +- 4.0 and 27.0 +- 4.4. Moreover, comparison of the early onset (55 NIDDM sib pairs diagnosed at or before age 45) and late onset (246 NIDDM sib pairs diagnosed after age 45) subgroups did not show any significant difference in terms of sex ratio, mean BMI, waist/hip ratio, blood glucose and insulin levels or cholesterol and triglycerides levels. The proportions of families with no, one or two parents genotyped are respectively 77, 19 and 4% in the whole sample of 156 families and 69, 26 and 5% in the subset of 42 early onset families. Moreover, the distributions of these sibships according to the number of affected sibs s available for genotyping is as follows: the total of 156 sibships includes 109 sibships with s = 2, 37 with s = 3, six with s = 4, three with s = 5 and one with s = 6, while the 42 early onset sibships include 37 sibships with s = 2, four with s = 3 and one with s = 4. The number of genotyped sib pairs differed slightly according to the marker studied and are presented in Tables 1 and 2 .
DNA from individuals of NIDDM families was extracted from peripheral blood leukocytes by standard procedures (40 ). All family members were genotyped by PCR using highly polymorphic simple tandem repeat DNA polymorphisms (STRPs) located within or in the vicinity of the PCK1, ADA, PLC1 and RPNII genes as previously described (41 -44 ). Six Généthon anonymous markers (D20S173, D20S112, D20S119, D20S176, D20S100 and D20S196) were also investigated (45 ). The PCR reactions were carried out with unlabeled primers and dNTPs and the PCR products were separated by electrophoresis on a 6% denaturing polyacrylamide gel containing 8 M urea. Electrophoresed PCR products were then transferred by blotting onto Hybond N+ nylon membranes which were then hybridized in a non-radioactive labeling procedure using one of the primers used in DNA amplification (46 ).
Evidence for linkage was sought using three non-parametric affected sib pair methods which were shown to display different statistical properties (21 ). The Haseman-Elston sib pair method (22 ,23 ) consists of estimating the mean proportion of alleles shared identical by descent (IBD) among affected sib pairs, using all marker information available in parents and siblings (affected and unaffected). This mean proportion is tested against the expected value of 0.5, under the null hypothesis of no linkage, by a one-sided t-test with degrees of freedom (df) equal to (n - 2) (n being the total number of affected pairs). This method is implemented in the computer program Sibpal of the Sage package (47 ). The second method, based on the number of shared and non-shared alleles among affected sib pairs computed from informative meioses (heterozygous parents and IBD status unambiguously determined in sib pairs) either observed or inferred from marker information in the data (J.Terwilliger, personal communication). The number of shared and non-shared alleles are equal under the null hypothesis of no linkage, whereas there are more shared than non-shared alleles when there is linkage. This is tested by a one-sided [chi]2 test with 1 df. This method has been recently implemented in the program Sibpair of the Analyze package (distributed by J.Terwilliger). The third method is a maximum likelihood method which estimates the IBD probabilities among affected sib pairs from observed marker information and compares it with the expected distribution (1/4, 1/2, 1/4) when there is no linkage using a LOD score test (MLS method; 24 ). The power of this method can be increased by imposing constraints on IBD probabilities based on the `possible triangle' (25 ) and 2ln(10) times the MLS is distributed as a mixture of [chi]2 values with 1 df and 2 df. The MLS was computed using the computer program Mapmaker/Sibs (25 ). The latter two methods, as implemented in the computer programs, make it possible to correct for the non-independence of multiple affected sib pairs from the same sibship by weighting the contribution of each sib pair by 2/s (s being the number of affected sibs). To compute empirical P values, marker data were simulated in affected sib pairs under the null hypothesis of no linkage using observed marker information in parents and unaffected siblings. Multipoint mapping was conducted using the MLS approach and the computer program Mapmaker/Sibs with and without weighting sib pairs from multiple affected sibships (26 ).
Marker allelic frequencies were estimated using all family information from the data set with the ILink program of the Linkage package (48 ).
In this study we have genotyped the PCK1 and RPNII markers in the CEPH pedigrees and positioned them with respect to a subset of polymorphic markers using multipoint mapping analyses with the Linkage package of programs (48 ).
A 579 bp segment of the PCK1 promoter region (from -547 to +32), encompassing all the PCK1 regulatory elements, including the insulin response element (49 ), was subdivided into four small overlapping segments (<250 bp, Table 3 ). Each fragment of this regulatory sequence was screened for mutations by PCR amplification followed by SSCP analysis in 41 affected individuals with NIDDM diagnosed at or before 45 years of age and 40 unrelated normoglycemic control individuals. Genomic DNA extracted using the standard procedures was amplified in a total volume of 25 [mu]l under the following PCR conditions: an initial denaturation at 94oC for 6 min, 30 cycles of 94oC for 30 s, 60oC for 30 s and 72oC for 30 s for all fragments except fragment 2 (amplified at 58oC in a 35 cycle PCR reaction) and a final extension step at 72oC for 6 min. For SSCP analysis, 1 [mu]l PCR product was denatured in 1 [mu]l formamide loading buffer and then directly loaded onto a preprepared polyacrylamide gel (Pharmacia, PhastSystemtm) and run under each fragment's optimized conditions. Gels were silver stained and checked for the presence of an abnormal pattern of migration of the PCR fragments.
We thank our patients for their cooperation. We are indebted to Dr G.I.Bell for his helpful reading and suggestions on the manuscript and to L.Zekiri for secretarial assistance. This work was supported by the French Ministry of Research, the Centre National de la Recherche Scientifique, the Institut de Recherches Internationales-Servier, the Institut National de la Santé et de la Recherche Médicale, the Direction of Clinical Research of Assistance Publique-Hôpitaux de Paris and Glaxo-Welcome. This work was supported partially by the BIOMED II program no. BMH4-CT950662 and the Groupe de Recherches et d'Etudes sur les Génomes. The results in this work were obtained using the SAGE program package, which is supported by a US Public Health Service Resource Grant (1-P41-RR03655). We are also grateful to GIS Infobiogen for providing us with additional computer facilities.
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+The two first authors contributed equally to this work
§The two last authors were equally responsible for this work
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