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Haplotypes in the Lipoprotein Lipase Gene Influence Fasting Insulin and Discovery of a New Risk Haplotype

Division of Endocrinology, Diabetes, and Metabolism (M.O.G.) and Medical Genetics Institute (M.O.G., K.D.T., X.G., J.C., Y.-D.I.C., J.I.R.), Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Medicine (M.O.G., Y.-D.I.C., J.I.R.), David Geffen School of Medicine at University of California, Los Angeles, California 90095; Department of Preventive Medicine and Biometrics (J.E.H.), University of Colorado Health Sciences Center, Denver, Colorado 80262; Department of Medicine (S.M.H.), University of Texas Health Sciences Center at San Antonio, San Antonio, Texas 78229; Department of Public Health Sciences (L.E.W.), Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157; and Department of Physiology and Biophysics (R.N.B.), Keck School of Medicine, University of Southern California, Los Angeles, California 90033

Address all correspondence and requests for reprints to: Mark O. Goodarzi, M.D., Ph.D., Cedars-Sinai Medical Center Division of Endocrinology, Diabetes, and Metabolism, 8700 Beverly Boulevard, Becker B-131, Los Angeles, California 90048. E-mail: mark.goodarzi{at}cshs.org.

Context: Prior studies of Mexican Americans described association of lipoprotein lipase (LPL) gene haplotypes with insulin sensitivity/resistance and atherosclerosis. The most common haplotype (haplotype 1) was protective, whereas the fourth most common haplotype (haplotype 4) conferred risk for insulin resistance and atherosclerosis.

Objective: In this study of Hispanics in the Insulin Resistance Atherosclerosis Study Family Study, we sought to replicate LPL haplotype association with insulin sensitivity/resistance.

Design: LPL haplotypes based on 12 single nucleotide polymorphisms were analyzed for association with indexes of insulin sensitivity and other metabolic and adiposity measures.

Setting: This study was conducted in the general community of San Antonio, Texas, and San Luis Valley, Colorado.

Participants: Participants in this study were 978 members of 86 Hispanic families.

Main Outcome Measures: LPL haplogenotype, metabolic phenotypes, and adiposity were measured in this study.

Results: The haplotype structure was identical with that observed in prior studies. Among 978 phenotyped subjects, haplotype 1 was associated with decreased fasting insulin (P = 0.01), and haplotype 4 was associated with increased fasting insulin (P = 0.02) and increased visceral fat mass (P = 0.002). Insulin sensitivity, derived from iv glucose tolerance testing, tended (P > 0.1) to be higher with haplotype 1 (S_I = 1.72) and lower with haplotype 4 (S_I=1.38). Haplotype 2 was associated with increases in fasting insulin, triglycerides (TGs), TG to high-density lipoprotein-cholesterol ratio, and apolipoprotein B (P = 0.01–0.04).

Conclusions: This study independently replicates our prior results of LPL haplotypes 1 and 4 as associated with measures of insulin sensitivity and resistance, respectively. Haplotype 4 may confer insulin resistance by increasing visceral fat. Haplotype 2 was identified as a new risk haplotype, suggesting the complex nature of LPL’s effect on features of the insulin resistance syndrome.

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