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24-h ambulatory blood pressure is linked to chromosome 18q21-22 and genetic variation of NEDD4L associates with cross-sectional and longitudinal blood pressure in Swedes.

https://arctichealth.org/en/permalink/ahliterature81774
Source
Kidney Int. 2006 Aug;70(3):562-9
Publication Type
Article
Date
Aug-2006
Author
Fava C.
von Wowern F.
Berglund G.
Carlson J.
Hedblad B.
Rosberg L.
Burri P.
Almgren P.
Melander O.
Author Affiliation
Department of Clinical Sciences, University Hospital MAS, Malmö, Sweden.
Source
Kidney Int. 2006 Aug;70(3):562-9
Date
Aug-2006
Language
English
Publication Type
Article
Keywords
Adult
Alternative Splicing
Antihypertensive Agents - therapeutic use
Blood Pressure - genetics
Blood Pressure Monitoring, Ambulatory
Chromosomes, Human, Pair 18
Circadian Rhythm
Cross-Sectional Studies
Female
Genetic Predisposition to Disease - epidemiology
Genotype
Humans
Hypertension - drug therapy - epidemiology - genetics
Insulin - blood
Linkage (Genetics)
Longitudinal Studies
Male
Middle Aged
Phenotype
Polymorphism, Single Nucleotide
Risk factors
Sweden - epidemiology
Ubiquitin-Protein Ligases - genetics
Variation (Genetics)
Abstract
Numerous linkage studies have indicated chromosome 18q21-22 as a locus of importance for blood pressure regulation. This locus harbors the neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) gene, which is instrumental for the regulation of the amiloride-sensitive epithelial sodium channel (ENaC). In a linkage study of 16 markers (including two single nucleotide polymorphism markers located within the NEDD4L gene) on chromosome 18 between 70-104 cM and ambulatory blood pressure (ABP), in 118 families, the strongest evidence of linkage was found for 24 h and day-time systolic ABP at the NEDD4L locus (82.25 cM) (P=0.0014). In a large population sample (n=4001), we subsequently showed that a NEDD4L gene variant (rs4149601), which by alternative splicing leads to varying expression of a functionally crucial C2 domain, was associated with diastolic blood pressure (DBP) (P=0.03) and DBP progression over time (P=0.04). A genotype combination of the rs4149601 and an intronic NEDD4L marker (rs2288774) was associated with systolic blood pressure (SBP) (P=0.01), DBP (P=0.04), and progression of both SBP (P=0.03) and DBP (P=0.05) over time. A quantitative transmission disequilibrium test in the family material of the rs4149601 supported this NEDD4L variant as being at least partially causative of the linkage result. In conclusion, our findings suggest that the chromosome 18 linkage peak at 82.25 cM is explained by genetic NEDD4L variation affecting cross-sectional and longitudinal blood pressure, possibly as a consequence of altered NEDD4L interaction with ENaC.
PubMed ID
16788695 View in PubMed
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Common variants in MODY genes increase the risk of gestational diabetes mellitus.

https://arctichealth.org/en/permalink/ahliterature82024
Source
Diabetologia. 2006 Jul;49(7):1545-51
Publication Type
Article
Date
Jul-2006
Author
Shaat N
Karlsson E
Lernmark A
Ivarsson S
Lynch K
Parikh H
Almgren P
Berntorp K
Groop L
Author Affiliation
Department of Clinical Sciences/Diabetes and Endocrinology, Malmö University Hospital, Lund University, Malmö, Sweden. nael.shaat@med.lu.se
Source
Diabetologia. 2006 Jul;49(7):1545-51
Date
Jul-2006
Language
English
Publication Type
Article
Keywords
Adult
Diabetes Mellitus, Type 2 - genetics
Diabetes, Gestational - genetics
Female
Gene Frequency
Genetic Predisposition to Disease
Glucokinase - genetics
Hepatocyte Nuclear Factor 1-alpha - genetics
Hepatocyte Nuclear Factor 4 - genetics
Humans
Linkage Disequilibrium
Polymorphism, Single Nucleotide
Pregnancy
Sweden
Abstract
AIMS/HYPOTHESIS: Impaired beta cell function is the hallmark of gestational diabetes mellitus (GDM) and MODY. In addition, women with MODY gene mutations often present with GDM, but it is not known whether common variants in MODY genes contribute to GDM. SUBJECTS AND METHODS: We genotyped five common variants in the glucokinase (GCK, commonly known as MODY2), hepatocyte nuclear factor 1-alpha (HNF1A, commonly known as MODY3) and 4-alpha (HNF4A commonly known as MODY1) genes in 1,880 Scandinavian women (648 women with GDM and 1,232 pregnant non-diabetic control women). RESULTS: The A allele of the GCK -30G-->A polymorphism was more common in GDM women than in control subjects (odds ratio [OR] 1.28 [95% CI 1.06-1.53], p=0.008, corrected p value, p=0.035). Under a recessive model [AA vs GA+GG], the OR increased further to 2.12 (95% CI 1.21-3.72, p=0.009). The frequency of the L allele of the HNF1A I27L polymorphism was slightly higher in GDM than in controls (1.16 [95% CI 1.001-1.34], p=0.048, corrected p value, p=0.17). However, the OR increased under a dominant model (LL+IL vs II; 1.31 [95% CI 1.08-1.60], p=0.007). The rs2144908, rs2425637 and rs1885088 variants, which are located downstream of the primary beta cell promoter (P2) of HNF4A, were not associated with GDM. CONCLUSIONS/INTERPRETATION: The -30G-->A polymorphism of the beta-cell-specific promoter of GCK and the I27L polymorphism of HNF1A seem to increase the risk of GDM in Scandinavian women.
Notes
Erratum In: Diabetologia. 2006 Sep;49(9):2226-7
PubMed ID
16752173 View in PubMed
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A common variant upstream of the PAX6 gene influences islet function in man.

https://arctichealth.org/en/permalink/ahliterature131235
Source
Diabetologia. 2012 Jan;55(1):94-104
Publication Type
Article
Date
Jan-2012
Author
Ahlqvist E
Turrini F
Lang ST
Taneera J
Zhou Y
Almgren P
Hansson O
Isomaa B
Tuomi T
Eriksson K
Eriksson JG
Lyssenko V
Groop L
Author Affiliation
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, CRC at Skåne University Hospital, 205 02 Malmö, Sweden. Emma.Ahlqvist@med.lu.se
Source
Diabetologia. 2012 Jan;55(1):94-104
Date
Jan-2012
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Aged
Cohort Studies
Diabetes Mellitus, Type 2 - genetics - metabolism - physiopathology
Down-Regulation
Eye Proteins - genetics - metabolism
Female
Finland
Genetic Association Studies
Homeodomain Proteins - genetics - metabolism
Humans
Insulin Resistance
Islets of Langerhans - metabolism - physiopathology
Linkage Disequilibrium
Male
Middle Aged
Oligonucleotide Array Sequence Analysis
Paired Box Transcription Factors - genetics - metabolism
Polymorphism, Single Nucleotide
Proprotein Convertase 1 - genetics - metabolism
RNA, Messenger - metabolism
Repressor Proteins - genetics - metabolism
Tissue Culture Techniques
Young Adult
Abstract
Impaired glucose tolerance and impaired insulin secretion have been reported in families with PAX6 mutations and it is suggested that they result from defective proinsulin processing due to lack of prohormone convertase 1/3, encoded by PCSK1. We investigated whether a common PAX6 variant would mimic these findings and explored in detail its effect on islet function in man.
A PAX6 candidate single nucleotide polymorphism (rs685428) was associated with fasting insulin levels in the Diabetes Genetics Initiative genome-wide association study. We explored its potential association with glucose tolerance and insulin processing and secretion in three Scandinavian cohorts (N?=?8,897 individuals). In addition, insulin secretion and the expression of PAX6 and transcriptional target genes were studied in human pancreatic islets.
rs685428 G allele carriers had lower islet mRNA expression of PAX6 (p?=?0.01) and PCSK1 (p?=?0.001) than AA homozygotes. The G allele was associated with increased fasting insulin (p (replication)?=?0.02, p (all)?=?0.0008) and HOMA-insulin resistance (p (replication)?=?0.02, p (all)?=?0.001) as well as a lower fasting proinsulin/insulin ratio (p (all)?=?0.008) and lower fasting glucagon (p?=?0.04) and gastric inhibitory peptide (GIP) (p?=?0.05) concentrations. Arginine-stimulated (p?=?0.02) insulin secretion was reduced in vivo, which was further reflected by a reduction of glucose- and potassium-stimulated insulin secretion (p?=?0.002 and p?=?0.04, respectively) in human islets in vitro.
A common variant in PAX6 is associated with reduced PAX6 and PCSK1 expression in human islets and reduced insulin response, as well as decreased glucagon and GIP concentrations and decreased insulin sensitivity. These findings emphasise the central role of PAX6 in the regulation of islet function and glucose metabolism in man.
PubMed ID
21922321 View in PubMed
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Polymorphisms in the gene encoding the voltage-dependent Ca(2+) channel Ca (V)2.3 (CACNA1E) are associated with type 2 diabetes and impaired insulin secretion.

https://arctichealth.org/en/permalink/ahliterature84135
Source
Diabetologia. 2007 Dec;50(12):2467-75
Publication Type
Article
Date
Dec-2007
Author
Holmkvist J.
Tojjar D.
Almgren P.
Lyssenko V.
Lindgren C M
Isomaa B.
Tuomi T.
Berglund G.
Renström E.
Groop L.
Author Affiliation
Department of Clinical Sciences-Diabetes and Endocrinology, CRC, Malmö University Hospital MAS, Lund University, Malmo, Sweden, johan.holmkvist@med.lu.se.
Source
Diabetologia. 2007 Dec;50(12):2467-75
Date
Dec-2007
Language
English
Publication Type
Article
Abstract
AIMS/HYPOTHESIS: Glucose-stimulated insulin secretion is dependent on the electrical activity of beta cells; hence, genes encoding beta cell ion channels are potential candidate genes for type 2 diabetes. The gene encoding the voltage-dependent Ca(2+) channel Ca(V)2.3 (CACNA1E), telomeric to a region that has shown suggestive linkage to type 2 diabetes (1q21-q25), has been ascribed a role for second-phase insulin secretion. METHODS: Based upon the genotyping of 52 haplotype tagging single nucleotide polymorphisms (SNPs) in a type 2 diabetes case-control sample (n = 1,467), we selected five SNPs that were nominally associated with type 2 diabetes and genotyped them in the following groups (1) a new case-control sample of 6,570 individuals from Sweden; (2) 2,293 individuals from the Botnia prospective cohort; and (3) 935 individuals with insulin secretion data from an IVGTT. RESULTS: The rs679931 TT genotype was associated with (1) an increased risk of type 2 diabetes in the Botnia case-control sample [odds ratio (OR) 1.4, 95% CI 1.0-2.0, p = 0.06] and in the replication sample (OR 1.2, 95% CI 1.0-1.5, p = 0.01 one-tailed), with a combined OR of 1.3 (95% CI 1.1-1.5, p = 0.004 two-tailed); (2) reduced insulin secretion [insulinogenic index at 30 min p = 0.02, disposition index (D (I)) p = 0.03] in control participants during an OGTT; (3) reduced second-phase insulin secretion at 30 min (p = 0.04) and 60 min (p = 0.02) during an IVGTT; and (4) reduced D (I) over time in the Botnia prospective cohort (p = 0.05). CONCLUSIONS/INTERPRETATION: We conclude that genetic variation in the CACNA1E gene contributes to an increased risk of the development of type 2 diabetes by reducing insulin secretion.
PubMed ID
17934712 View in PubMed
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