WO2009052418A1

WO2009052418A1 - Methods of using genetic variants in the lipoprotein lipase gene to determine liver enzyme levels and insulin resistance

Info

Publication number: WO2009052418A1
Application number: PCT/US2008/080359
Authority: WO
Inventors: Jerome I. Rotter; Kent D. Taylor; Mark O. Goodarzi; Yii Der I. Chen; Xiuqing Guo
Original assignee: Cedars-Sinai Medical Center
Priority date: 2007-10-19
Filing date: 2008-10-17
Publication date: 2009-04-23

Abstract

The invention relates to methods of diagnosing and/or predicting susceptibility to metabolic syndrome and associated traits by determining the presence or absence of genetic variants at the lipoprotein lipase (LPL) gene. In one embodiment, the invention provides a method of diagnosing and/or predicting susceptibility to liver enzyme levels by determining the presence or absence of LPL genetic variants.

Description

METHODS OF USING GENETIC VARIANTS IN THE LIPOPROTEIN LIPASE GENE TO DETERMINE LIVER ENZYME LEVELS AND INSULIN RESISTANCE

GOVERNMENT RIGHTS This invention was made with U.S. Government support on behalf of the Insulin

Resistance Atherosclerosis Study Family Study (IRASFS): Molecular Genetics of Glucose Homeostasis and Fat (NHLBI HL060894). The U.S. Government may have certain rights in this invention.

FIELD OF THE INVENTION

The invention relates generally to the field of metabolism and, more specifically, to genetic methods for diagnosing liver enzyme levels and/or metabolic syndrome.

BACKGROUND All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

Metabolic syndrome affects an estimated 50 million people in the United States alone. Those with metabolic syndrome, also called insulin resistance syndrome, have an increased risk of diabetes, and diseases that are related to plaque build ups in artery walls such as coronary heart disease. Although the specific causes of metabolic syndrome are not completely understood, primary risk factors include abdominal obesity, and insulin resistance where the body is unable to use insulin efficiently. Elevated liver enzyme levels, likely a reflection of fatty liver, have also been associated with insulin resistance and metabolic syndrome. Family studies have shown that both the metabolic syndrome and liver enzymes are heritable, with heritability and co- heritability analyses indicating significant evidence for a genetic contribution to liver enzyme levels.

Lipoprotein lipase (LPL) has the ability to hydrolyze circulating triglycerides and thus allow uptake of free fatty acids in adipose tissue and muscle where lipid accumulation influences obesity and insulin-stimulated glucose uptake. LPL is also expressed in vascular wall macrophages where it influences atherosclerosis, and has been previously shown to be associated with insulin resistance. Thus, LPL is a possible candidate gene for insulin resistance and other metabolic traits.

Although there have been some associations found between risk factors and metabolic traits, the exact cause and contribution factors for many of the metabolic diseases are largely unknown. Thus, there is need in the art to determine genes, allelic variants, biological pathways, and other factors that contribute to metabolic traits, including but not limited to metabolic syndrome and insulin resistance.

SUMMARY OF THE INVENTION

BRIEF DESCRIPTION OF FIGURES

Exemplary embodiments are illustrated in referenced figures. It is intended that the embodiments and figures disclosed herein are to be considered illustrative rather than restrictive.

Figure 1 depicts a haplotype block of the LPL gene.

Figure 2 depicts a table describing results found for the LPL haplotype frequency. Figure 3 (a) and (b) depicts graphs demonstrating the LPL haplotypic association with levels of liver enzyme and insulin resistance. GGT designates the enzyme gamma-glutamyl transferase. HOMA designates homeostasis model assessment.

DESCRIPTION OF INVENTION

All references cited herein are incorporated by reference in their entirety as though fully set forth. Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York, NY 1994); March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 4th ed., J. Wiley & Sons (New York, NY 1992); and Sambrook and Russel, Molecular Cloning: A Laboratory Manual 3rd ed., Cold Spring Harbor Laboratory Press (Cold Spring Harbor, NY 2001 ), provide one skilled in the art with a general guide to many of the terms used in the present application.

One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. Indeed, the present invention is in no way limited to the methods and materials described.

"Haplotype" as used herein refers to a set of single nucleotide polymorphisms (SNPs) on a gene or chromatid that are statistically associated.

As used herein, "LPL" means lipoprotein lipase gene. An example of LPL is described herein as SEQ. ID. NO.: 3.

As used herein, the term "haplotype H2" means the haplotype designated H2 and may be identified by the minor alleles of SNPs rs8292 (SEQ. ID. NO.: 1) and/or rs3200218 (SEQ. ID. NO.: 2).

As used herein, "metabolic syndrome⁹⁹ is a collection of health risks and conditions that may increase the chance of developing, and relate to, heart disease, stroke and diabetes.

As used herein, "Hispanic American" means all American persons of Mexican, Puerto Rican, Cuban, Central, Latin or South American, Portuguese or other Spanish culture of origin. As used herein, the term "biological sample" means any biological material from which nucleic acid molecules can be prepared. As non-limiting examples, the term material encompasses whole blood, plasma, saliva, cheek swab, or other bodily fluid or tissue that contains nucleic acid.

As disclosed herein, the inventors evaluated the role of genetic variants in the LPL gene on liver enzyme (LE) levels. 1017 non-diabetic individuals from 88 large Hispanic American (HA) families were recruited through the Insulin Resistance Atherosclerosis Study Family Study at two clinical sites (San Antonio, TX and San Luis Valley, CO). Three liver enzymes: aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) were measured. None of the subjects self-reported a high alcohol consumption. Twelve single nucleotide polymorphisms (SNPs) in the LPL gene (all in the same block) were genotyped on these samples. The generalized estimating equation methods were used in the association analysis. After adjusting for age, sex, and body mass index, the second most common haplotype, which accounts for 18.8% of the sample and is identified by the minor alleles in SNP rs8292 and rs3200218, was significantly associated with increased GGT (40.8±2.1 vs 35.8±1.3, p=0.009), ALT (11.9±0.5 vs 10.4±0.3, p=0.010), and AST/ALT ratio (p=0.007). This is the same haplotype that has been previously reported being significantly associated with increased fasting insulin and triglycerides in the HA sample (Goodarzi MO, et al. J Clin Endocrinol Metab 92: 293-296, 2007). The results show that the LPL gene is a common genetic determinant for LEs and IR in the Hispanic American population, and that variation in LEs is a genetically determined component of the metabolic syndrome.

In one embodiment, the present invention provides methods of diagnosing and/or predicting susceptibility to metabolic syndrome and traits thereof by determining the presence or absence in the individual of variants in the LPL gene. In another embodiment, the present invention provides methods of diagnosing and/or predicting susceptibility to metabolic syndrome and traits thereof by determining the presence or absence of haplotype H2 in the LPL gene. In another embodiment, the present invention provides methods of diagnosing and/or predicting susceptibility to metabolic syndrome and traits thereof by determining the presence or absence of the minor alleles in SNPs rs8292 (SEQ. ID. NO.: 1) and/or rs3200218 (SEQ. ID. NO.: 2) of the LPL gene. In another embodiment, the individual is an Hispanic American.

In another embodiment, determining the presence or absence of haplotype H2 in the LPL gene is part of an overall treatment regimen for metabolic syndrome and traits thereof. In one embodiment, the present invention provides methods of prognosis of metabolic syndrome and traits thereof by determining the presence or absence in the individual of variants in the LPL gene. In another embodiment, the present invention provides methods of prognosis of metabolic syndrome and traits thereof by determining the presence or absence of haplotype H2 in the LPL gene. In another embodiment, the present invention provides methods of prognosis of metabolic syndrome and traits thereof by determining the presence or absence of the minor alleles in SNPs rs8292 (SEQ. ID. NO.: 1) and/or rs3200218 (SEQ. ID. NO.: 2) of the LPL gene. In another embodiment, the individual is an Hispanic American. In one embodiment, the present invention provides methods of diagnosing and/or predicting susceptibility to insulin resistance and/or elevated liver enzyme levels by determining the presence or absence in the individual of variants in the LPL gene. In another embodiment, the present invention provides methods of diagnosing and/or predicting susceptibility to insulin resistance and/or elevated liver enzyme levels by determining the presence or absence of haplotype H2 in the LPL gene. In another embodiment, the present invention provides methods of diagnosing and/or predicting susceptibility to insulin resistance and/or elevated liver enzyme levels by determining the presence or absence of the minor alleles in SNPs rs8292 (SEQ. ID. NO.: 1) and/or rs3200218 (SEQ. ID. NO.: 2) of the LPL gene. In another embodiment, the presence of haplotype H2 in the LPL gene is associated with the elevation of liver enzymes aspartate aminotransferase, alanine aminotransferase, and/or gamma-glutamyl transferase. In another embodiment, the individual is an Hispanic American.

In another embodiment, determining the presence or absence of haplotype H2 in the LPL gene is part of an overall treatment regimen for insulin resistance, in conjunction with elevated liver enzyme levels.

In one embodiment, the present invention provides methods of prognosis of insulin resistance and/or elevated liver enzyme levels by determining the presence or absence in the individual of variants in the LPL gene. In another embodiment, the present invention provides methods of prognosis of insulin resistance and/or elevated liver enzyme levels by determining the presence or absence of haplotype H2 in the LPL gene. In another embodiment, the present invention provides methods of prognosis of insulin resistance and/or elevated liver enzyme levels by determining the presence or absence of the minor alleles in SNPs rs8292 (SEQ. ID. NO.: 1) and/or rs3200218 (SEQ. ID. NO.: 2) of the LPL gene. In another embodiment, the presence of haplotype H2 in the LPL gene is associated with the elevation of liver enzymes aspartate aminotransferase, alanine aminotransferase, and/or gamma-glutamyl transferase. In another embodiment, the individual is an Hispanic American.

The methods may include the steps of obtaining a biological sample containing nucleic acid from the individual and determining the presence or absence of a SNP and/or a haplotype in the biological sample. The methods may further include correlating the presence or absence of the SNP and/or the haplotype to a genetic risk, a susceptibility for metabolic syndrome and metabolic traits thereof including but not limited to insulin resistance, as described herein. The methods may also further include recording whether a genetic risk, susceptibility for metabolic syndrome and metabolic traits thereof including but not limited to insulin resistance exists in the individual. The methods may also further include a prognosis of metabolic syndrome and metabolic traits thereof based upon the presence or absence of the SNP and/or haplotype. The methods may also further include a treatment of metabolic syndrome and metabolic traits thereof based upon the presence or absence of the SNP and/or haplotype.

In one embodiment, a method of the invention is practiced with whole blood, which can be obtained readily by non-invasive means and used to prepare genomic DNA, for example, for enzymatic amplification or automated sequencing. In another embodiment, a method of the invention is practiced with tissue obtained from an individual such as tissue obtained during surgery or biopsy procedures.

A variety of methods can be used to determine the presence or absence of a genetic variant allele or haplotype. As an example, enzymatic amplification of nucleic acid from an individual may be used to obtain nucleic acid for subsequent analysis. The presence or absence of a variant allele or haplotype may also be determined directly from the individual's nucleic acid without enzymatic amplification. Analysis of the nucleic acid from an individual, whether amplified or not, may be performed using any of various techniques. Useful techniques include, without limitation, polymerase chain reaction based analysis, sequence analysis and electrophoretic analysis. As used herein, the term "nucleic acid" means a polynucleotide such as a single or double-stranded DNA or RNA molecule including, for example, genomic DNA, cDNA and mRNA. The term nucleic acid encompasses nucleic acid molecules of both natural and synthetic origin as well as molecules of linear, circular or branched configuration representing either the sense or antisense strand, or both, of a native nucleic acid molecule. The presence or absence of a variant allele or haplotype may involve amplification of an individual's nucleic acid by the polymerase chain reaction. Use of the polymerase chain reaction for the amplification of nucleic acids is well known in the art (see, for example, Mullis et al. (Eds.), The Polymerase Chain Reaction, Birkhauser, Boston, (1994)). A TaqmanB allelic discrimination assay available from Applied Biosystems may be useful for determining the presence or absence of a variant allele. In a TaqmanB allelic discrimination assay, a specific, fluorescent, dye-labeled probe for each allele is constructed. The probes contain different fluorescent reporter dyes such as FAM and VICTM to differentiate the amplification of each allele. In addition, each probe has a quencher dye at one end which quenches fluorescence by fluorescence resonant energy transfer (FRET). During PCR, each probe anneals specifically to complementary sequences in the nucleic acid from the individual. The 5¹ nuclease activity of Taq polymerase is used to cleave only probe that hybridize to the allele. Cleavage separates the reporter dye from the quencher dye, resulting in increased fluorescence by the reporter dye. Thus, the fluorescence signal generated by PCR amplification indicates which alleles are present in the sample. Mismatches between a probe and allele reduce the efficiency of both probe hybridization and cleavage by Taq polymerase, resulting in little to no fluorescent signal. Improved specificity in allelic discrimination assays can be achieved by conjugating a DNA minor grove binder (MGB) group to a DNA probe as described, for example, in Kutyavin et al., "3'-minor groove binder-DNA probes increase sequence specificity at PCR extension temperature, "Nucleic Acids Research 28:655- 661 (2000)). Minor grove binders include, but are not limited to, compounds such as dihydrocyclopyrroloindole tripeptide (DPI,).

Sequence analysis also may also be useful for determining the presence or absence of an IL23R variant allele or haplotype.

Restriction fragment length polymorphism (RFLP) analysis may also be useful for determining the presence or absence of a particular allele (Jarcho et al. in Dracopoli et al., Current Protocols in Human Genetics pages 2.7.1-2.7.5, John Wiley & Sons, New York; lnnis et al.,(Ed.), PCR Protocols, San Diego: Academic Press, Inc. (1990)). As used herein, restriction fragment length polymorphism analysis is any method for distinguishing genetic polymorphisms using a restriction enzyme, which is an endonuclease that catalyzes the degradation of nucleic acid and recognizes a specific base sequence, generally a palindrome or inverted repeat. One skilled in the art understands that the use of RFLP analysts depends upon an enzyme that can differentiate two alleles at a polymorphic site.

Allele-specific oligonucleotide hybridization may also be used to detect a disease-predisposing allele. Allele-specific oligonucleotide hybridization is based on the use of a labeled oligonucleotide probe having a sequence perfectly complementary, for example, to the sequence encompassing a disease-predisposing allele. Under appropriate conditions, the allele-specific probe hybridizes to a nucleic acid containing the disease-predisposing allele but does not hybridize to the one or more other alleles, which have one or more nucleotide mismatches as compared to the probe. If desired, a second allele-specific oligonucleotide probe that matches an alternate allele also can be used. Similarly, the technique of allele-specific oligonucleotide amplification can be used to selectively amplify, for example, a disease-predisposing allele by using an allele- specific oligonucleotide primer that is perfectly complementary to the nucleotide sequence of the disease-predisposing allele but which has one or more mismatches as compared to other alleles (Mullis et al., supra, (1994)). One skilled in the art understands that the one or more nucleotide mismatches that distinguish between the disease-predisposing allele and one or more other alleles are preferably located in the center of an allele-specific oligonucleotide primer to be used in allele-specific oligonucleotide hybridization. In contrast, an allele-specific oligonucleotide primer to be used in PCR amplification preferably contains the one or more nucleotide mismatches that distinguish between the disease-associated and other alleles at the 3' end of the primer.

A heteroduplex mobility assay (HMA) is another well known assay that may be used to detect a SNP or a haplotype. HMA is useful for detecting the presence of a polymorphic sequence since a DNA duplex carrying a mismatch has reduced mobility in a polyacrylamide gel compared to the mobility of a perfectly base-paired duplex (Delwart et al., Science 262:1257-1261 (1993); White et al., Genomics 12:301-306 (1992)).

The technique of single strand conformational, polymorphism (SSCP) also may be used to detect the presence or absence of a SNP and/or a haplotype (see Hayashi, K., Methods Applic. 1 :34-38 (1991)). This technique can be used to detect mutations based on differences in the secondary structure of single-strand DNA that produce an altered electrophoretic mobility upon non-denaturing gel electrophoresis. Polymorphic fragments are detected by comparison of the electrophoretic pattern of the test fragment to corresponding standard fragments containing known alleles.

Denaturing gradient gel electrophoresis (DGGE) also may be used to detect a SNP and/or a haplotype. In DGGE, double-stranded DNA is electrophoresed in a gel containing an increasing concentration of denaturant; double-stranded fragments made up of mismatched alleles have segments that melt more rapidly, causing such fragments to migrate differently as compared to perfectly complementary sequences (Sheffield et al., "Identifying DNA Polymorphisms by Denaturing Gradient Gel Electrophoresis" in lnnis et al., supra, 1990).

Other molecular methods useful for determining the presence or absence of a SNP and/or a haplotype are known in the art and useful in the methods of the invention. Other well-known approaches for determining the presence or absence of a SNP and/or a haplotype include automated sequencing and RNAase mismatch techniques (Winter et al., Proc. Natl. Acad. Sci. 82:7575-7579 (1985)). Furthermore, one skilled in the art understands that, where the presence or absence of multiple alleles or haplotype(s) is to be determined, individual alleles can be detected by any combination of molecular methods. See, in general, Birren et al. (Eds.) Genome Analysis: A Laboratory Manual Volume 1 (Analyzing DNA) New York, Cold Spring Harbor Laboratory Press (1997). In addition, one skilled in the art understands that multiple alleles can be detected in individual reactions or in a single reaction (a "multiplex" assay). In view of the above, one skilled in the art realizes that the methods of the present invention for diagnosing or predicting susceptibility to or protection against metabolic syndrome and associated traits may be practiced using one or any combination of the well known assays described above or another art-recognized genetic assay.

One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. Indeed, the present invention is in no way limited to the methods and materials described. For purposes of the present invention, the following terms are defined below. Additionally, one of skill in the art would recognize that the invention can be applied to various metabolic traits, conditions and diseases besides that of metabolic syndrome, insulin resistance and/or elevated liver enzyme levels. It will also be readily apparent to one of skill in the art that the invention can be used in conjunction with a variety of phenotypes, such as serological markers, additional genetic variants, biochemical markers, abnormally expressed biological pathways, and variable clinical manifestations.

EXAMPLES The following examples are provided to better illustrate the claimed invention and are not to be interpreted as limiting the scope of the invention. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to limit the invention. One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of the invention. Example 1

Role of Genetic Variants in the LPL Gene on LE Levels The inventors evaluated the role of genetic variants in the LPL gene on liver enzyme (LE) levels. 1017 non-diabetic individuals from 88 large Hispanic American (HA) families were recruited through the Insulin Resistance Atherosclerosis Study Family Study at two clinical sites (San Antonio, TX and San Luis Valley, CO). Three liver enzymes: aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) were measured. None of the subjects self-reported a high alcohol consumption. Twelve single nucleotide polymorphisms (SNPs) in the LPL gene (all in the same block) were genotyped on these samples. An example of the LPL gene is described herein as SEQ. ID. NO.: 3. The generalized estimating equation methods were used in the association analysis. After adjusting for age, sex, and body mass index, the second most common haplotype, which accounts for 18.8% of the sample and is identified by the minor alleles in SNP rs8292 (SEQ. ID. NO.: 1) and rs3200218 (SEQ. ID. NO.: 2), was significantly associated with increased GGT (40.8±2.1 vs 35.8±1.3, p=0.009), ALT (11.9±0.5 vs 10.4±0.3, p=0.010), and AST/ALT ratio (p=0.007). This is the same haplotype that has been previously reported being significantly associated with increased fasting insulin and triglycerides in the HA sample (Goodarzi MO, et al. J Clin Endocrinol Metab 92: 293-296, 2007). The results show that the LPL gene is a common genetic determinant for LEs and IR in the Hispanic American population, and that variation in LEs is a genetically determined component of the metabolic syndrome.

Example 2 Study Design

1017 non-diabetic individuals from 88 large Hispanic American (HA) families were recruited through the Insulin Resistance Atherosclerosis Study (IRAS) Family Study at two clinical sites (San Antonio, TX and San Luis Valley, CO). Probands were from the IRAS study, with > 3 living siblings, > 5 children, and none of the subjects reporting a high alcohol consumption.

Example 3 Phenotype

Two liver enzymes, aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT), were measured by enzymatic colorimetry. IR was measured by fasting insulin and homeostasis model assessment (HOMA).

Example 4

Genotypes

Twelve single nucleotide polymorphisms (SNPs) in the LPL gene (all in the same block) were genotyped.

Example 5

Statistical Analyses

The generalized estimating equation method was used in the association analysis. Age, sex, and BMI were included as covariates.

Example 6

Conclusions - LPL Gene

The second most common haplotype was significantly associated with increased GGT. The results show that the LPL gene is a common genetic determinant for liver enzymes and IR in the HA population. The results also show that variation in liver enzymes is a genetically determined component of the metabolic syndrome.

Example 7 Haplotypes of LPL locus - Table 1

Table 1 describes haplotypes of the LPL locus, with the haplotypes described as H1 - H5, and corresponding SNPs defined as M1 - M12. "1" is the major allele and "2" is the minor allele.

Table 1.

Various embodiments of the invention are described above in the Description of Invention. While these descriptions directly describe the above embodiments, it is understood that those skilled in the art may conceive modifications and/or variations to the specific embodiments shown and described herein. Any such modifications or variations that fall within the purview of this description are intended to be included therein as well. Unless specifically noted, it is the intention of the inventor that the words and phrases in the specification and claims be given the ordinary and accustomed meanings to those of ordinary skill in the applicable art(s).

The foregoing description of various embodiments of the invention known to the applicant at this time of filing the application has been presented and is intended for the purposes of illustration and description. The present description is not intended to be exhaustive nor limit the invention to the precise form disclosed and many modifications and variations are possible in the light of the above teachings. The embodiments described serve to explain the principles of the invention and its practical application and to enable others skilled in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. Therefore, it is intended that the invention not be limited to the particular embodiments disclosed for carrying out the invention.

While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that, based upon the teachings herein, changes and modifications may be made without departing from this invention and its broader aspects and, therefore, the appended claims are to encompass within their scope all such changes and modifications as are within the true spirit and scope of this invention. Furthermore, it is to be understood that the invention is solely defined by the appended claims. It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including but not limited to," the term "having" should be interpreted as "having at least," the term "includes" should be interpreted as "includes but is not limited to," etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles "a" or "an" limits any particular claim containing such introduced claim recitation to inventions containing only one such recitation, even when the same claim includes the introductory phrases "one or more" or "at least one" and indefinite articles such as "a" or "an" (e.g., "a" and/or "an" should typically be interpreted to mean "at least one" or "one or more"); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should typically be interpreted to mean at least the recited number (e.g., the bare recitation of "two recitations," without other modifiers, typically means at least two recitations, or two or more recitations).

Accordingly, the invention is not limited except as by the appended claims.

Claims

1. A method for evaluating the likelihood of an individual to have or develop metabolic syndrome, comprising: obtaining a DNA sample from the individual; and analyzing the DNA sample for a risk haplotype at the lipoprotein lipase ("LPL") locus in the individual, wherein the presence of the risk haplotype at the LPL locus is predictive of increased metabolic syndrome.

2. The method of claim 1 , wherein the risk haplotype at the LPL locus is haplotype 2.

3. The method of claim 1 , wherein the individual is Hispanic American.

4. A method for diagnosing defective liver function in an individual, comprising: determining the presence of haplotype 2 at the lipoprotein lipase ("LPL) locus in the individual; and diagnosing defective liver function in the individual based upon the presence of haplotype 2 at the LPL locus.

5. The method of claim 4, wherein haplotype 2 at the LPL locus comprises SEQ. ID. NO.: 1 and SEQ. ID. NO.: 2.

6. The method of claim 4, wherein the individual is Hispanic American.

7. A method for diagnosing metabolic syndrome, comprising: determining the presence of a risk haplotype at the lipoprotein lipase ("LPL") locus in the individual; determining the presence of an elevated level of one or more liver enzymes relative to a healthy subject; and diagnosing the metabolic syndrome in the individual based upon the presence of the risk haplotype at the LPL locus and the presence of the elevated level of one or more liver enzyme relative to a healthy subject.

8. The method of claim 7, wherein the risk haplotype at the LPL locus comprises haplotype 2.

9. The method of claim 7, wherein the liver enzymes comprise aspartate aminotransferase, alanine aminotransferase, and/or gamma-glutamyl transferase.

10. The method of claim 7, wherein the individual is Hispanic American.