Genetic determinants of type 2 diabetes mellitus.

Type 2 diabetes refers to a group of disparate metabolic diseases, which are typically characterized by insulin resistance in peripheral tissues, together with impaired insulin secretion from pancreatic beta-cells. The complexity of type 2 diabetes is related to factors such as genetic heterogeneity, interactions between genes, and the modulating role played by the environment. Recent progress has included defining the molecular basis of monogenic forms of type 2 diabetes, such as familial partial lipodystrophy and the subtypes of maturity-onset diabetes of the young (MODY), and also the identification of chromosomal regions that may harbor type 2 diabetes susceptibility genes. Many common variants in functional and positional candidate genes, including ADRB3, PPARG, ENPP1, and CAPN10, have also been studied for their possible role as determinants of type 2 diabetes, with varying levels of agreement between studies. The availability of a relatively complete sequence of the human genome will increase the amount of genetic information that can be used to evaluate hypotheses for the genetic basis of type 2 diabetes. To make sense of human type 2 diabetes in the post-genomic era, it is essential to have well-defined phenotypes in addition to sufficient numbers of individuals with the appropriate pedigree structure from families and/or communities.

Variation of candidate genes in triglyceride metabolism.

After more than a decade of study, investigators are grappling for a consensus regarding the relationship between variation in candidate genes and plasma triglyceride concentration. Certain variants of LPL--both rare variants, in the case of loss-of-function mutations in kindreds with chylomicronemia, and common variants, in the case of the D9N and N291S variants--appear to be fairly consistently associated with an elevated plasma triglyceride level. In addition, the variation of the recognition site for Sstl within the 3'-untranslated region of APOC3 has consistently shown an association with a variation in plasma triglycerides. The LPL and APOC3 variants thus have at least a chance in future clinical applications, but this will require more study. Common variants of some other promising candidate genes, such as HL, have not shown as consistent an association with the variation in plasma triglyceride level. Finally, studies of variants of newer candidates, such as the mitochondrial genome, LMNA, and IL-6, indicate that many different genes might be important determinants of plasma triglyceride concentration in the general population. As always, the associations of genes with a complex intermediate trait such as plasma triglyceride level depend upon interactions with modulatory factors such as genetic background and/or secondary genetic effects, in addition to the effects of gender, age, hormone replacement, and postprandial status. A key attribute for increasing confidence in the biologic or potential clinical validity of the associations of candidate gene variation with plasma triglyceride will be the development of assays that will provide a more direct mechanistic link between the genetic variant and the elevated plasma triglyceride.

Association of PON2 variation with birth weight in Trinidadian neonates of South Asian ancestry.

Variation in the PON1 and PON2 genes has been shown to be associated with coronary heart disease risk in adults of South Asian origin. In this group, low birth weight is also associated with coronary heart disease risk. We therefore hypothesized that variation in PON1 and PON2 genes may be associated with variation in birth weight. This relationship was examined in 290 consecutive Trinidadian neonates of different ethnic origins. We found that variation in PON2 was significantly associated with variation in birth weight in Trinidadian neonates of South Asian origin. Among the neonates of South Asian origin, those who were homozygous for PON2 A148/A148 had significantly lower birth weight, by approximately 200 g, compared with those with the other two genotypes (P < 0.05). For neonates of South Asian origin, PON2 A148/A148 homozygotes were significantly more prevalent in those comprising the lowest tertile for birth weight than those comprising the highest tertile (0.41 versus 0.24, P < 0.05). There were no significant associations of PON2 variation with any phenotype in other ethnic groups. We conclude that among neonates of South Asian origin, homozygosity for PON2 A148/A148, is associated with significantly lower birth weight. This suggests that genetic factors in the fetus may be important determinants of neonatal birth weight and possibly of more distal adult phenotypes, such as coronary heart disease.

The ADD1 G460W polymorphism is not associated with variation in blood pressure in Canadian Oji-Cree.

Since adducin modulates cellular sodium retention, its follows that ADD1, which encodes the alpha-subunit of adducin, is an attractive candidate gene for blood pressure variation. Association studies examining the relationship between polymorphism at ADD1 codon 460 (G460W) and both hypertension and blood pressure, which were performed in a variety of human population samples derived from different genetic backgrounds, have given inconsistent results. We examined the association between the ADD1 G460W polymorphism and variation in blood pressure in a sample of non-diabetic, largely normotensive Canadian Oji-Cree from an isolated community in Northern Ontario. Among 481 Oji-Cree subjects, we measured blood pressure and related clinical phenotypes and determined genotypes of ADD1 G460W. We observed an allele frequency of 0.08 for the ADD1 W460 variant, which is among the lowest so far observed in human populations. We found significant associations between variation in both systolic and diastolic blood pressure and gender, age, body mass index (BMI), and treatment for hypertension. However, we found no association between the ADD1 W460 allele and increased blood pressure, nor did we observe a higher frequency of the W460 allele in a hypertensive subgroup compared with normotensive subjects. While the low sample frequency of ADD1 W460 is consistent with the low sample prevalence of hypertension, the absence of a specific association with both blood pressure and hypertension suggests that the ADD1 W460 variant is not an important determinant of blood pressure among individuals of this genetic background.

Lipoprotein-genotype associations in Trinidadian neonates

OBJECTIVES: We hypothesized that common variation in the angiotensinogen (AGT), beta-3-adrenergic receptor. intestinal fatty acid-binding protein, serum paraoxonase, paraoxonase-2, hepatic lipase, apolipoprotein E (APOE), and Werner helicase (WRN) genes would be associated with variation in biochemical phenotypes in a previously unstudied neonatal sample. DESIGN AND METHODS: We examined associations of both nongenetic and genetic variables with plasma lipoprotein traits in neonates from Trinidad. RESULTS: Among nongenetic variables, we found significant associations between plasma concentrations of 1.) lipoprotein (a) [Lp(a)] and both ethnicity (p=0.037) and birth weight (p=0.001); 2)total cholesterol and gender (p=0.010); 3)triglyceride and birth weight (p=0.035); and 4)apolipoprotein A1 and gender (p=0.016). Among genetic variables, we found that: 1)common variation on chromosome 1q in AGT codon 235 was significantly associated with variation in plasma apolipoproteins Al (p<0.0001); and 3)common variation in APOE at codons 112 and 158 was significantly associated with variation in plasma triglycerides (p=0.013). CONCLUSIONS: The associations with AGT and WRN are novel and may have resulted either from direct influence of the genetic variants or through linkage disequilibrium with other functional loci, such as the familial combined hyperlipidemia locus on chromosome 1q in the case of AGT. Despite the fact that there are some limitations in making determinations from cord blood, the results suggest that there may be genetic determinants of plasma lipoproteins in neonates. (AU)

Association of PON2 variation with birth weight in Trinidadian neonates of South Asian ancestry

Variation in the PON1 and PON2 genes has been shown to be associated with coronary heart disease risk in adults of South Asian origin. In this group, low birth weight is also associated with coronary heart disease risk. We therefore hypothesized that variation in PON1 and PON2 genes may be associated with variation in birth weight. This relationship was examined in 90 consecutive Trinidadian neonates of different ethnic origins. We found that variation in PON2 was significantly associated with variation in birth weight in Trinidadian neonates of south Asian origin. Among the neonates of South Asian origin, those who were homozygous for PON A148/A148 had significantly lower birth weight, by approximately 00 g, compared with those with the other two genotypes (P < 0.05). For neonates of south Asian origin, PON2 A148/A148 homozygotes were significantly more prevalent in those comprising the lowest tertile for birth weight than those comprising the highest tertile (0.41 versus 0.24, P < 0.05). There were no significant associations of PON variation with any phenotype in other ethnic groups. We conclude that among neonates of South Asian origin, homozygosity for PON2 A148/A148, is associated with significantly lower birth weight. This suggests that genetic factors in the fetus may be important determinants of neonatal birth weight and possibly of more distal adult phenotypes, such as coronary heart disease.(AU)

Lipoprotein-genotype associations in Trinidadian neonates.

OBJECTIVES: We hypothesized that common variation in the angiotensinogen (AGT), beta-3-adrenergic receptor, intestinal fatty acid-binding protein, serum paraoxonase, paraoxonase-2, hepatic lipase, apolipoprotein E (APOE), and Werner helicase (WRN) genes would be associated with variation in biochemical phenotypes in a previously unstudied neonatal sample. DESIGN AND METHODS: We examined associations of both nongenetic and genetic variables with plasma lipoprotein traits in neonates from Trinidad. RESULTS: Among nongenetic variables, we found significant associations between plasma concentrations of: 1) lipoprotein(a) [Lp(a)] and both ethnicity (p = 0.037) and birth weight (p = 0.001); 2) total cholesterol and gender (p = 0.010); 3) triglyceride and birth weight (p = 0.035); and 4) apolipoprotein AI and gender (p = 0.016). Among genetic variables, we found that: 1) common variation on chromosome 1q in AGT codon 235 was significantly associated with variation in plasma apolipoproteins AI (p<0.0001) and B (p = 0.013); 2) common variation in WRN at codon 1367 was significantly associated with variation in plasma Lp(a) (p<0.0001); and 3) common variation in APOE at codons 112 and 158 was significantly associated with variation in plasma triglycerides (p = 0.013). CONCLUSIONS: The associations with AGT and WRN are novel and may have resulted either from a direct influence of the genetic variants or through linkage disequilibrium with other functional loci, such as the familial combined hyperlipidemia locus on chromosome 1q in the case of AGT. Despite the fact that there are some limitations in making determinations from cord blood, the results suggest that there may be genetic determinants of plasma lipoproteins in neonates.