Biomedical subjects

Samir S Deeb

Publications and source records attributed to Samir S Deeb.

At least 19 recordsLinked to original sources

PubMed2006

Genetics of variation in human color vision and the retinal cone mosaic.

Variation in human color vision is mainly caused by one common polymorphism (Ser180Ala) in the L pigment, and to the frequent presence of hybrid genes that encode pigments with various spectral properties. Both recombination and gene conversion between the highly homologous L and M pigment genes have generated wide variation in genotype and color vision phenotype. The S, M and L cones are distributed randomly in the central retina. Unlike S cones, M and L cones vary widely in number within the central retina. Determining the number of the three classes of cone and their special distribution in the living retina has significantly advanced the ability to correlate the cone mosaic in normal and color-defective subjects with the color vision phenotype. The transcription factors NR2E3, TRbeta2 and RXRgamma play crucial roles in establishment of the retinal cone mosaic during eye development.

Animals↗

PubMed2006

Transcriptional regulation of the human hepatic lipase (LIPC) gene promoter.

Hepatic lipase (HL) plays a key role in the metabolism of plasma lipoproteins, and its level of activity requires tight regulation, given the association of both low and high levels with atherosclerosis and coronary artery disease. However, little is known about the factors responsible for HL expression. Here, we report that the human hepatic lipase gene (LIPC) promoter is regulated by hepatocyte nuclear factor 4alpha (HNF4alpha), peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), apolipoprotein A-I regulatory protein-1 (ARP-1), and hepatocyte nuclear factor 1alpha (HNF1alpha). Reporter analysis showed that HNF4alpha directly regulates the LIPC promoter via two newly identified direct repeat elements, DR1 and DR4. PGC-1alpha is capable of stimulating the HNF4alpha-dependent transactivation of the LIPC promoter. ARP-1 displaces HNF4alpha from the DR1 site and blocks its ability to activate the LIPC promoter. Induction by HNF1alpha requires the HNF1 binding site and upon cotransfection with HNF4alpha leads to an additive effect. In addition, the in vivo relevance of HNF4alpha in LIPC expression is shown by the ability of the HNF4alpha antagonist Medica 16 to repress endogenous LIPC mRNA expression. Furthermore, disruption of Hnf4alpha in mice prevents the expression of HL mRNA in liver. The overall effect these transcription factors have on HL expression will ultimately depend on the interplay between these various factors and their relative intracellular concentrations.

Animals↗

PubMed2005

Common hepatic lipase gene promoter variant predicts the degree of neointima formation after carotid endarterectomy: impact of plaque composition and lipoprotein phenotype.

BACKGROUND: The common -514 C-T promoter polymorphism of the hepatic lipase gene (LIPC) and the cholesteryl ester transfer protein (CETP) gene TaqIB polymorphism affect atherogenesis. We investigated the potential relationship between these polymorphisms and the maximum-intima-media thickness (M-IMT) after carotid endarterectomy. METHODS: The LIPC and CETP genotypes were determined by PCR in 68 patients undergoing endarterectomy. Plaque specimens were analysed for cell composition by immunocytochemistry. Six month after surgery the M-IMT of the revascularized vessel was assessed by B-mode ultrasonography. RESULTS: The CC carriers had denser LDL particles (p<0.0005), an abundance of macrophages (p<0.0005), fewer SMCs in the carotid plaque (p<0.0005), and higher prevalence of cerebrovascular events (72% versus 28%, p=0.002) compared to CT/TT carriers. After endarterectomy, CC carriers showed a lower M-IMT than the CT/TT group (1.36 mm versus 1.76 mm, p=0.04). No association between the CETP polymorphism and either carotid plaque cellular composition or M-IMT was observed. In a multivariate analysis, M-IMT was associated with plaque cell composition (macrophages, r=-0.39; SMC, r=0.44; p<0.005 for both) but not with pre-operative LDL-C, HDL-C, triglycerides, or LDL density. CONCLUSIONS: The LIPC promoter -514 C-T polymorphism is associated with a significantly reduced development of neointima after surgery. This effect seems to be mediated by scarcity of SMC in the plaque of CC carriers who display an excess prevalence of cerebrovascular events prior endarterectomy but are at low risk for restenosis. The pre-operative lipid phenotype plays a marginal role in the neointima formation.

Carotid Stenosis↗

PubMed2004

Apolipoprotein L-I is positively associated with hyperglycemia and plasma triglycerides in CAD patients with low HDL.

Apolipoprotein L-I (apoL-I) is present on a subset of HDL particles and is positively correlated with plasma triglycerides (TGs). We measured plasma apoL-I levels in coronary artery disease (CAD) subjects with low HDL who were enrolled in an angiographic CAD prevention trial. At baseline, apoL-I levels (n = 136; range, 2.2-64.1 mug/ml) were right skewed with a large degree of variability. Multivariate analysis for biological determinants of apoL-I revealed that the log of VLDL-TG (+0.17; P < 0.05) and hyperglycemia (HG; +0.26; P < 0.005) independently predicted apoL-I level. Hyperglycemic patients (n = 24) had mean apoL-I levels >50% higher than normoglycemic subjects (n = 112; 13.2 vs. 8.3 mug/ml, respectively; P < 0.001). No relationship between apoL-I level and change in CAD was found (r = 0.06, P = 0.49). Simvastatin-niacin therapy did not alter apoL-I levels (n = 34; P = 0.27), whereas antioxidant vitamins alone increased apoL-I by >50% (n = 36; P < 0.01). Genotyping of a known apoL-I polymorphism (Lys166Glu) did not independently account for any of the variability in apoL-I levels. In conclusion, we found TG and HG to be the strongest predictors of apoL-I within a dyslipidemic CAD population. These data provide further characterization of the novel HDL-associated apoL-I.

Aged↗

PubMed2004

Analysis of the human hexokinase II promoter in vivo: lack of insulin response within 4.0 kb.

To locate regulatory element(s) that mediate(s) the effect of insulin on hexokinase II (HKII) gene transcription, we have generated several transgenic mouse lines harboring 97, 254, 505, 819 or 4077 bp of the proximal promoter of the human HKII gene driving the expression of a luciferase reporter gene. Luciferase activities indicate that major promoter elements responsible for the basal activity and tissue-specificity of the human HKII gene expression are located within the 505-bp segment of the promoter. To induce the promoter constructs by endogenous insulin released from the pancreatic beta-cells, transgenic mice were given repeated intraperitoneal injections of D-glucose. Significant induction of luciferase activity was not observed in any of the transgenic mouse lines even though the endogenous HKII mRNA was induced 2.7-fold upon treatment. Thus, our results suggest a lack of insulin response in the 4.0-kb region of the proximal promoter of the human HKII gene in mice.

Animals↗

PubMed2004

X-linked high myopia associated with cone dysfunction.

OBJECTIVE: Bornholm eye disease (BED) consists of X-linked high myopia, high cylinder, optic nerve hypoplasia, reduced electroretinographic flicker with abnormal photopic responses, and deuteranopia. The disease maps to chromosome Xq28 and is the first designated high-grade myopia locus (MYP1). We studied a second family from Minnesota with a similar X-linked phenotype, also of Danish descent. All affected males had protanopia instead of deuteranopia. METHODS: X chromosome genotyping, fine-point mapping, and haplotype analysis of the DNA from 22 Minnesota family individuals (8 affected males and 5 carrier females) and 6 members of the original family with BED were performed. Haplotype comparisons and mutation screening of the red-green cone pigment gene array were performed on DNA from both kindreds. RESULTS: Significant maximum logarithm of odds scores of 3.38 and 3.11 at theta = 0.0 were obtained with polymorphic microsatellite markers DXS8106 and DXYS154, respectively, in the Minnesota family. Haplotype analysis defined an interval of 34.4 cM at chromosome Xq27.3-Xq28. Affected males had a red-green pigment hybrid gene consistent with protanopia. We genotyped Xq27-28 polymorphic markers of the family with BED, and narrowed the critical interval to 6.8 cM. The haplotypes of the affected individuals were different from those of the Minnesota pedigree. Bornholm eye disease-affected individuals showed the presence of a green-red hybrid gene consistent with deuteranopia. CONCLUSIONS: Because of the close geographic origin of the 2 families, we expected affected individuals to have the same haplotype in the vicinity of the same mutation. Mapping studies, however, suggested independent mutations of the same gene. The red-green and green-red hybrid genes are common X-linked color vision defects, and thus are unrelated to the high myopia and other eye abnormalities in these 2 families. CLINICAL RELEVANCE: X-linked high myopia with possible cone dysfunction has been mapped to chromosome Xq28 with intervals of 34.4 and 6.8 centimorgan for 2 families of Danish origin.

Adolescent↗

PubMed2004

Molecular genetics of colour vision deficiencies.

Common variation in colour vision exists among both colour normal and colour deficient subjects. Differences at a few amino acid positions that influence the spectra of the L and M cone pigments account for most of this variation. The genes encoding the L and M photopigments are arranged in head-to-tail arrays on the X-chromosome, beginning with the L and followed by one or more M pigment genes. The L and M pigment genes are highly homologous, which predisposed them to unequal crossing over (recombination) resulting in gene deletions and in formation of L/M hybrid genes that encode a variety of pigments with either L-like or M-like spectra that account for the majority of colour vision defects. Only the first two pigment genes of the L/M array are expressed in the retina and, therefore, need to be considered in predicting colour vision. A common single amino acid polymorphism (serine or alanine) at position 180 of the L-pigment plays an important role both in variation in normal colour vision and in the severity of colour vision defects. Blue cone monochromacy is a rare form of colour vision deficiency that results from mutations that abolish function of both the L and M pigment genes. All the above defects are inherited as X-linked recessive traits. Tritanopia is also a rare autosomal dominant colour vision defect caused by mutations in the S pigment gene located on chromosome 7. Total colour blindness (achromatopsia or rod monochromacy) is a rare autosomal recessive trait caused by mutations in genes encoding the proteins of the photoreceptor cation channel or cone transducin that are essential for function of all classes of cone.

Color Vision Defects↗

PubMed2003

Ethnic differences in hepatic lipase and HDL in Japanese, black, and white Americans: role of central obesity and LIPC polymorphisms.

Hepatic lipase activity (HLA) is a determinant of HDL levels, and a polymorphism in the hepatic lipase gene (LIPC) promoter (C-514T) has been hypothesized to account for higher HDL in blacks and Japanese compared with whites. To determine whether the polymorphism contributes to ethnic differences in HDL, we compared LIPC allele frequencies and HLA in Japanese American (JA; n = 84), black American (BA; n = 94), and white American (WA; n = 110) men and women. The LIPC polymorphism was associated with HLA in all cohorts (BA, P = 0.012; JA, P = 0.008; WA, P = 0.009). WA men had 49% and 58% higher HLA than BA and JA men, respectively (both P < 0.05), yet no differences in HLA were found between the women. The higher HLA in the WA men remained after adjustment for the LIPC polymorphism's effect on HLA (P = 0.037) but was erased after adjustment for waist-to-hip-ratio (P = 0.46). Although the WA men had lower HDL and HDL(3) than the JA and BA men (all P < 0.05), there were no differences in HDL(2), implying that variance in HLA may not underlie the ethnic differences in HDL levels. These results suggest that 1) the LIPC promoter polymorphism contributes to variation in HLA and HDL(2) in the three ethnic groups; 2) WA men had higher HLA than BA and JA men, related to ethnic differences in central adiposity but not LIPC allele frequency; and 3) the higher HLA in WA men did not contribute to the ethnic differences in HDL, as the differences in HDL were made up entirely of differences in HDL(3) and not HDL(2).

Asian People↗

PubMed2003

Evidence of linkage of HDL level variation to APOC3 in two samples with different ascertainment.

The APOA1-C3-A4-A5 gene complex encodes genes whose products are implicated in the metabolism of HDL and/or triglycerides. Although the relationship between polymorphisms in this gene cluster and dyslipidemias was first reported more than 15 years ago, association and linkage results have remained inconclusive. This is due, in part, to the oligogenic and multivariate nature of dyslipidemic phenotypes. Therefore, we investigate evidence of linkage of APOC3 and HDL using two samples of dyslipidemic pedigrees: familial combined hyperlipidemia (FCHL) and isolated low-HDL (ILHDL). We used a strategy that deals with several difficulties inherent in the study of complex traits: by using a Bayesian Markov Chain Monte Carlo (MCMC) approach we allow for oligogenic trait models, as well as simultaneous incorporation of covariates, in the context of multipoint analysis. By using this approach on extended pedigrees we provide evidence of linkage of APOC3 and HDL level variation in two samples with different ascertainment. In addition to APOC3, we estimate that two to three genes, each with a substantial effect on total variance, are responsible for HDL variation in both data sets. We also provide evidence, using the FCHL data set, for a pleiotropic effect between HDL, HDL3 and triglycerides at the APOC3 locus.

Apolipoproteins C↗

PubMed2003

The cone visual pigments of an Australian marsupial, the tammar wallaby (Macropus eugenii): sequence, spectral tuning, and evolution.

Studies on marsupial color vision have been limited to very few species. There is evidence from behavioral, electroretinographic (ERG), and microspectrophotometric (MSP) measurements for the existence of both dichromatic and trichromatic color vision. No studies have yet investigated the molecular mechanisms of spectral tuning in the visual pigments of marsupials. Our study is the first to determine the mRNA sequence, infer the amino acid sequence, and determine, by in vitro expression, the spectra of the cone opsins of a marsupial, the tammar wallaby (Macropus eugenii). This yielded some information on mechanisms and evolution of spectral tuning of these pigments. The tammar wallaby retina contains only short-wavelength sensitive (SWS) and middle-wavelength sensitive (MWS) pigment mRNAs. This predicts dichromatic color vision, which is consistent with conclusions from previous behavioral studies ( Hemmi 1999). We found that the wallaby has a SWS1 class pigment of 346 amino acids. Sequence comparison with eutherian SWS pigments predicts that this SWS1 pigment absorbs maximally (lambdamax) at 424 nm and, therefore, is a blue rather than a UV pigment. This (lambdamax) is close to that of the in vitro-expressed wallaby SWS pigment (lambdamax of 420 +/- 2 nm) and to that determined behaviorally (420 nm). The difference from the mouse UV pigment (lambdamax of 359 nm) is largely accounted for by the F86Y substitution, in agreement with in vitro results comparing a variety of other SWS pigments. This suggests that spectral tuning employing F86Y substitution most likely arose independently in the marsupials and ungulates as a result of convergent evolution. An apparently different mechanism of spectral tuning of the SWS1 pigments, involving five amino acid positions, evolved in primates. The wallaby MWS pigment has 363 amino acids. Species comparisons at positions critical to spectral tuning predict a lambdamax near 530 nm, which is close to that of the in vitro-expressed pigment (529 +/- 1 nm), but quite different from the value of 539 nm determined by microspectrophotometry. Introns interrupt the coding sequences of the wallaby, mouse, and human MWS pigment sequences at the same corresponding nucleotide positions. However, the length of introns varies widely among these species.

Amino Acid Sequence↗

PubMed2003

Hepatic lipase and dyslipidemia: interactions among genetic variants, obesity, gender, and diet.

Hepatic lipase (HL) plays a central role in LDL and HDL remodeling. High HL activity is associated with small, dense LDL particles and with reduced HDL2 cholesterol levels. HL activity is determined by an HL gene promoter polymorphism, by gender (lower in premenopausal women), and by visceral obesity with insulin resistance. The activity is affected by dietary fat intake and selected medications. There is evidence for an interaction of the HL promoter polymorphism with visceral obesity, dietary fat intake, and with lipid-lowering medications in determining the level of HL activity. The dyslipidemia with high HL activity is a potentially proatherogenic lipoprotein profile in the metabolic syndrome, in Type 2 diabetes, and in familial combined hyperlipidemia.

Diabetes Mellitus, Type 2↗

PubMed2003

Hepatic lipase: a marker for cardiovascular disease risk and response to therapy.

PURPOSE OF REVIEW: Hepatic lipase plays a key role in the metabolism of pro-atherogenic and anti-atherogenic lipoproteins affecting their plasma level as well as their physico-chemical properties. However, controversial evidence exists concerning whether hepatic lipase is pro or anti-atherogenic. The goal of this review is to summarize recent evidence that connects the enzyme to cardiovascular disease. The potential impact of genetic determinants of hepatic lipase activity in modulating both the development of coronary and carotid atherosclerosis will be discussed based on hepatic lipase proposed roles in lipoprotein metabolism. RECENT FINDINGS: Twenty to 30% of individual variation of hepatic lipase activity is accounted for by the presence of a common polymorphism in the promoter region (-514 C to T) of the hepatic lipase gene (LIPC). This polymorphism, via its impact on hepatic lipase synthesis and activity, appears to contribute to (1) individual susceptibility to cardiovascular disease: the presence of the T allele (low hepatic lipase activity) may carry a marginally increased risk of atherosclerosis; (2) carotid plaque composition and individual susceptibility to cerebrovascular events: the presence of the C allele (high hepatic lipase activity) is associated with increased carotid intima-media thickness and abundance of macrophages in the carotid plaque (unstable plaque); and (3) response of cardiovascular disease patients to lipid-lowering therapy: patients with the CC genotype have the greatest clinical benefit from intensive lipid-lowering therapy. SUMMARY: Convincing evidence shows that hepatic lipase plays a key role in remnant lipoprotein catabolism as well as in remodeling of LDL and HDL particles. The anti or pro-atherogenic role of hepatic lipase is likely to be modulated by the concurrent presence of other lipid abnormalities (i.e. increased LDL cholesterol levels) as well as by the genetic regulation of other enzymes involved in lipoprotein metabolism. Characterization of patients by their LIPC genotype will contribute to a better definition of individual risk of coronary and cerebrovascular events, specifically in patients with qualitative (small, atherogenic LDL and low HDL2 cholesterol) rather than quantitative lipid abnormalities for whom the routine lipid profile may underestimate the risk of coronary and cerebrovascular disease.

Animals↗

PubMed2003

Genetics of color vision deficiencies.

The normal X-chromosome-linked color vision gene array is composed of a single red pigment gene followed by one or more green pigment genes. The high degree of homology between these genes predisposed them to unequal recombination, leading to gene deletions or the formation of red-green hybrid genes that explain the majority of the common red-green color vision deficiencies. Gene expression studies suggest that only the two most proximal genes of the array are expressed in the retina. The severity of the color vision defect is roughly related to the difference in absorption maxima of the photopigments encoded by the first two genes of the array. A single amino acid polymorphism (Ser180Ala) in the red pigment accounts for the subtle difference in normal color vision and influences the severity of color vision deficiency. Blue cone monochromacy is a rare disorder that involves absence of red and green cone function. It is caused either by deletion of a critical region that regulates expression of the red/green gene array, or by mutations that inactivate the red and green pigment genes. Total color blindness is another rare disease that involves complete absence of all cone function. A number of mutations in the genes encoding the cone-specific alpha- and beta-subunits of the cation channel and the alpha-subunit of transducin have been implicated in this disorder.

Color Perception Tests↗

PubMed2003

Köbberling type of familial partial lipodystrophy: an underrecognized syndrome.

OBJECTIVE: The phenotypic expression of partial lipodystrophy is present in two familial syndromes: familial partial lipodystrophy type 1 (FPLD1), with fat loss from the extremities, and central obesity and FPLD type 2, with fat loss from the extremities, abdomen, and thorax. The latter disorder is associated with mutations in the LMNA gene. FPLD1 is thought to be rare. Here, we report 13 subjects with FPLD1, suggesting that this syndrome is more common than previously thought. RESEARCH DESIGN AND METHODS: Fasting glucose, plasma lipids, leptin, HbA(1c), and anthropomorphic measurements were evaluated in 13 subjects with clinical features of FPLD1 and are compared with two age-matched control groups, with and without diabetes. RESULTS: Only women with clinical features of FPLD1 have been identified. Although they lack extremity and gluteal subcutaneous fat, they do have truncal obesity. Skinfold thickness on the arm and leg was significantly less than that in control subjects. The ratio of skinfold thickness from abdomen to thigh was significantly higher in subjects, suggesting an easy method for identifying affected patients. FPLD1 subjects also had components of the metabolic syndrome, including hypertension, insulin resistance, and severe hypertriglyceridemia resulting in pancreatitis. Premature coronary artery disease was present in 31% of subjects. None of the subjects had coding mutations in the LMNA gene or in the gene coding for peroxisome proliferator-activated receptor (PPAR)-gamma. CONCLUSIONS: FPLD1 is more common than previously described, but the diagnosis is often missed. Early recognition and intensive treatment of hyperlipidemia and diabetes in FPLD1 is important for prevention of pancreatitis and early cardiovascular disease.

Anthropometry↗

PubMed2002

Association between the --514 C-->T polymorphism of the hepatic lipase gene promoter and unstable carotid plaque in patients with severe carotid artery stenosis.

OBJECTIVE: We investigated the potential association between -514 C-->T polymorphism in the promoter of the hepatic lipase gene (LIPC) and the prevalence of inflammatory cells in the plaque of patients with severe carotid artery stenosis. BACKGROUND: This common LIPC polymorphism has been related to the presence of an atherogenic lipoprotein pattern. METHODS: We studied 68 consecutive patients undergoing carotid endarterectomy. The LIPC genotype was determined by polymerase chain reaction. Endarterectomy specimens were examined by immunocytochemistry using monoclonal antibodies for smooth muscle cells, macrophages, or lymphocytes. RESULTS: In 50 of 68 patients who had evidence of previous ipsilateral ischemic events, 36 (72%) were carriers of the CC genotype, whereas only 14 (28%) were carriers of the CT/TT genotype (p = 0.002). Among the 18 patients without evidence of events, the two genotypes were equally distributed (9 vs. 9). The low-density lipoprotein (LDL) particles were denser in CC than in CT/TT genotype carriers (flotation rate: 0.315 +/- 0.025 vs. 0.356 +/- 0.019, p < 0.0005). The CC genotype was associated with an abundance of macrophages (6.7 +/- 3.5 vs. 2.1 +/- 2.1 cells/area unit in the CT/TT group, p < 0.0005) and a reduced number of smooth muscle cells (6.9 +/- 6.2 vs. 14.5 +/- 6.4 in the CT/TT group, p < 0.0005) in the plaque. An inverse relationship was found between LDL buoyancy and the number of macrophages in the plaque (r = -0.639, p < 0.0005). CONCLUSION: We provide evidence, for the first time, that LIPC promoter -514 C-->T polymorphism, by modulating LDL density, significantly affects the number of macrophages in the plaque and possibly affects the occurrence of cerebrovascular events in patients with carotid artery stenosis.

Aged↗

PubMed2002

The molecular basis of dichromatic color vision in males with multiple red and green visual pigment genes.

We investigated the genotypic variation in 50 red-green color vision deficient males (27 deuteranopes and 23 protanopes) of middle European ancestry who possess multiple genes in the X-linked photopigment gene array. We have previously shown that only the first two genes of the array are expressed and contribute to the color vision phenotype. Therefore, the hypothesis is that the first two genes possessed by multigene-dichromats encode pigments of identical or nearly identical spectral sensitivity: one gene normal (R or G) and the other a hybrid (G/R or R/G). The spectral sensitivities of the encoded pigments were inferred from published in vitro and in vivo data. The color vision phenotype was assessed by standard anomaloscopy. Most genotypes (92%) included hybrid genes whose sequence and position and whose encoded pigment correlated exactly with the phenotype. However, one and possibly two of the protanopes had gene arrays consistent with protanomaly rather than protanopia, since two spectrally different pigments may be encoded by their arrays. Two of the deuteranopes had only R- and G-photopigment genes, without any detectable G/R-hybrid genes or any as-of-yet identified point mutation or coding/promoter sequence deletions. Further, an unexpectedly high number of multigene-deuteranopes (11%) had the C203R mutation in their most upstream G-pigment gene, suggesting a founder effect of middle European origin for this mutation. About half of the protanopes possessed an upstream R/G-hybrid gene with different exon 2 coding sequences than their downstream G-pigment gene(s), which is inconsistent with published data implying that a single amino acid substitution in exon 2 can confer red-green color discrimination capacity on multigene-protans by altering the optical density of the cones.

Color Perception↗

PubMed2002

Differential effect of PPARgamma2 variants in the development of type 2 diabetes between native Japanese and Japanese Americans.

Common type 2 diabetes mellitus is a disorder that is though to develop by interaction between genetic and environmental factors. Among these factors, peroxisome proliferator-activated receptor (PPAR)gamma gene was identified as a genetic element which variant form, Pro12Ala, was shown to have differential metabolic activity than the wild type. To elucidate the mechanism of interaction between genetic and environmental factors in development of type 2 diabetes, we analyzed prevalence and metabolic status in the context of the variant form of PPARgamma in 105 native Japanese and 145 Japanese American, both should have different environmental factors. The observed frequency of Pro-allele in Japanese American with diabetes was significantly higher than those with normal glucose tolerance (NGT) (P=0.015), while that in native Japanese with diabetes was not different from those with NGT. Alternatively, Japanese Americans with diabetes with Pro/Pro genotype had significantly higher BMI (P=0.024) and higher fasting serum insulin (P=0.043) level than native Japanese, showing that individuals with Ala-allele could be more sensitive to insulin than those with Pro/Pro genotype. The data with emigrants suggests the possible interaction of gene-environment in the development of type 2 diabetes.

Aged↗

PubMed2002

Structural and functional consequences of missense mutations in exon 5 of the lipoprotein lipase gene.

Missense mutations in exon 5 of the LPL gene are the most common reported cause of LPL deficiency. Exon 5 is also the region with the strongest homology to pancreatic and hepatic lipase, and is conserved in LPL from different species. Mutant LPL proteins from post-heparin plasma from patients homozygous for missense mutations at amino acid positions 176, 188, 194, 205, and 207, and from COS cells transiently transfected with the corresponding cDNAs were quantified and characterized, in an attempt to determine which aspect of enzyme function was affected by each specific mutation. All but one of the mutant proteins were present, mainly as partially denatured LPL monomer, rendering further detailed assessment of their catalytic activity, affinity to heparin, and binding to lipoprotein particles difficult. However, the fresh unstable Gly(188)-->Glu LPL and the stable Ile(194)-->Thr LPL, although in native conformation, did not express lipase activity. It is proposed that many of the exon 5 mutant proteins are unable to achieve or maintain native dimer conformation, and that the Ile(194)-->Thr substitution interferes with access of lipid substrate to the catalytic pocket. These results stress the importance of conformational evaluation of mutant LPL. Absence of catalytic activity does not necessarily imply that the substituted amino acid plays a specific direct role in catalysis.

Adult↗