Type 2 Diabetes Genetic Predisposition, Obesity, and All-cause Mortality Risk in the U.S.

A Multiethnic Analysis

Aaron Leong; Bianca Porneala; Josée Dupuis; Jose C. Florez; James B. Meigs

Diabetes Care. 2016;39(4):539-546.

Abstract and Introduction

Abstract

Objective Type 2 diabetes (T2D) is associated with increased mortality in ethnically diverse populations, although the extent to which this association is genetically determined is unknown. We sought to determine whether T2D-related genetic variants predicted all-cause mortality, even after accounting for BMI, in the Third National Health and Nutrition Examination Survey.

Research Design and Methods We modeled mortality risk using a genetic risk score (GRS) from a weighted sum of risk alleles at 38 T2D-related single nucleotide polymorphisms. In age-, sex-, and BMI-adjusted logistic regression models, accounting for the complex survey design, we tested the association with mortality in 6,501 participants. We repeated the analysis within ethnicities (2,528 non-Hispanic white [NHW], 1,979 non-Hispanic black [NHB], and 1,994 Mexican American [MA]) and within BMI categories (<25, 25–30, and ≥30 kg/m²). Significance was set at P < 0.05.

Results Over 17 years, 1,556 participants died. GRS was associated with mortality risk (OR 1.04 [95% CI 1.00–1.07] per T2D-associated risk allele, P = 0.05). Within ethnicities, GRS was positively associated with mortality risk in NHW and NHB, but not in MA (0.95 [0.90–1.01], P = 0.07). The negative trend in MA was largely driven by those with BMI <25 kg/m² (0.91 [0.82–1.00]). In NHW, the positive association was strongest among those with BMI ≥30 kg/m² (1.07 [1.02–1.12]).

Conclusions In the U.S., a higher T2D genetic risk was associated with increased mortality risk, especially among obese NHW. The underlying genetic basis for mortality likely involves complex interactions with factors related to ethnicity, T2D, and body weight.

Introduction

The escalating type 2 diabetes (T2D) epidemic is a major public health concern.^[1] In the U.S., the rate of increase in T2D is projected to be disproportionately higher among certain ethnic minorities.^[2,3] Epidemiologic studies^[3–6] have shown that T2D is associated with increased all-cause mortality risk. Given that T2D is partly genetically determined,^[7,8] genetic factors that increase T2D susceptibility may also raise mortality risk through T2D or its related complications.

The T2D epidemic parallels the rising prevalence of obesity, on a genetic background of varying permissibility. Responsible for this coepidemic are social-behavioral influences (e.g., urbanization, efficient transportation networks, increase in sedentary work, advent of modern technology, reliance on electronic transactions and Internet-based social connections),^[9–11] coupled with the growing consumption of conveniently prepared and readily available food and beverages rich in poorly satiating calories.^[9,10,12] As social, behavioral, and lifestyle factors are associated with both T2D and mortality,^[13–17] these modifiable risk factors may partly explain the T2D-mortality relationship. Although genetic factors are fixed from birth and potentially exert their effects throughout life, modifiable factors can act as environmental exposures that amplify or nullify these genetic effects. Obesity, reflecting energy balance and capturing these modifiable factors, is a fundamental effect modifier in any genetic study of T2D risk^[18] that has to be accounted for in our increasingly obesogenic environment.^[19] Here, we tested the hypothesis that carrying a higher aggregate genetic burden of T2D risk, modeled using a genetic risk score (GRS), predicted all-cause mortality independently of BMI, the principal physical reflection of this obesogenic environment, in the Third National Health and Nutrition Examination Survey (NHANES III).

Investigations have also suggested an "obesity paradox," where a higher BMI is associated with lower mortality risk in individuals with T2D or other chronic conditions.^[20,21] It has also been shown that genetic effects on T2D susceptibility are stronger in leaner individuals than in heavier counterparts;^[22,23] such findings may be particularly relevant to individuals of certain nonwhite ethnicities in whom normal-weight T2D is more likely to develop.^[24] Conversely, individuals with a higher T2D genetic predisposition may be more susceptible to the metabolic derangements and health consequences of obesity. Thus, in secondary analyses we tested whether T2D genetic-mortality associations differed by BMI category (normal weight, overweight, and obese), and whether obesity-associated mortality risk differed by T2D genetic risk.

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Table 1. Baseline characteristics accounting for sampling weights and complex survey design by ethnicity in the NHANES III Survey DNA Bank (NHANES III, 1991–1994)
	All ethnicities (N = 6,501)	NHW (N = 2,528)	NHB (N = 1,979)	MA (N = 1,994)
Ethnicity, %	—	81.1 (77.3–84.9)	12.7 (9.3–16.1)	6.2 (4.4–8.1)
Age, years	41.2 (39.8–42.7)	42.5 (40.6–44.4)	37.2 (35.6–38.8)	33.3 (32.1–34.5)
≥45 years of age, %	37.4 (33.3–41.6)	40.3 (35.0–45.5)	27.9 (23.7–32.0)	20.3 (17.7–23.0)
20–44 years of age, %	62.6 (58.4–66.7)	59.7 (54.5–65.0)	72.1 (68.0–76.3)	79.7 (77.0–82.3)
Women, %	51.5 (49.9–53.1)	51.2 (49.3–53.2)	54.8 (52.2–57.4)	48.5 (46.8–50.2)
Unweighted GRS	37.8 (37.6–38.0)	37.9 (37.7–38.2)	36.2 (36.1–36.4)	39.3 (39.0–39.6)
Weighted GRS	37.6 (37.4–37.8)	37.5 (37.3–37.8)	37.7 (37.5–37.8)	39.0 (38.7–39.3)
BMI, kg/m²	26.3 (26.0–26.7)	26.0 (25.6–26.4)	27.7 (27.1–28.3)	27.5 (27.1–27.8)
BMI categories, %
<25 kg/m²	46.8 (43.9–49.7)	48.4 (45.0–51.8)	39.6 (36.4–42.8)	39.6 (37.1–42.2)
25–30 kg/m²	30.8 (28.8–32.9)	30.4 (28.0–32.9)	31.2 (29.5–32.8)	35.4 (32.2–38.5)
≥30 kg/m²	22.4 (20.2–24.6)	21.1 (18.6–23.7)	29.3 (26.5–32.0)	25.0 (23.5–36.5)
Educational attainment, %
<12 years	30.2 (26.8–33.6)	25.9 (22.6–29.2)	41.8 (37.1–46.5)	62.5 (57.5–67.5)
12 years	31.4 (29.1–33.7)	31.7 (28.7–34.8)	33.5 (30.4–36.6)	23.1 (20.3–25.8)
>12 years	38.4 (33.4–43.4)	42.4 (37.0–47.7)	24.7 (20.2–29.2)	14.4 (11.4–17.5)
Insurance coverage, %	86.6 (84.6–88.6)	89.4 (87.1–91.7)	81.0 (77.2–84.8)	58.6 (53.3–63.8)
Family history, %	19.5 (17.5–21.6)	18.2 (16.0–20.4)	25.3 (22.8–27.7)	25.5 (22.9–28.1)
Smoking, %
Never	26.2 (23.2–29.3)	26.0 (22.3–29.7)	30.4 (28.3–32.4)	21.5 (19.1–23.9)
Former	25.0 (22.9–27.1)	27.1 (24.6–29.5)	13.87 (11.8–15.9)	19.9 (17.4–22.3)
Current	48.7 (45.9–51.5)	46.9 (43.5–50.5)	55.8 (52.5–59.1)	58.6 (55.4–61.9)
Alcohol consumption, %
Nondrinker	47.2 (43.6–50.8)	45.8 (41.73–49.81)	55.4 (52.1–58.7)	50.5 (48.5–52.5)
>0 to <3 drinks/week	24.9 (22.8–27.1)	25.9 (23.35–28.41)	19.2 (16.9–21.4)	23.1 (20.2–26.0)
≥3 drinks/week	27.9 (25.3–30.4)	28.4 (25.23–31.47)	25.4 (22.9–28.0)	26.4 (23.6–29.1)
PA level, %
No activity	27.4 (24.1–30.8)	26.3 (22.6–30.1)	31.2 (27.9–34.2)	35.0 (32.1–38.0)
>0 to <5 times/week	44.5 (40.9–48.1)	45.9 (41.9–50.0)	38.1 (34.6–41.6)	38.1 (35.6–40.9)
≥5 times/week	28.1 (25.5–30.7)	27.8 (24.8–30.7)	30.9 (27.6–34.2)	26.9 (23.8–30.0)
HEI	64.3 (63.4–65.1)	64.8 (63.8–65.7)	60.3 (59.5–61.1)	65.9 (64.5–67.4)
Diabetes, %	8.8 (7.4–10.3)	8.5 (7.0–10.1)	10.8 (8.6–13.1)	8.7 (7.6–9.8)
Hypertension, %	21.1 (18.7–23.6)	21.1 (18.1–24.1)	26.0 (22.9–29.0)	12.5 (10.1–14.8)
WC (cm)	90.3 (89.5–91.1)	89.8 (88.9–90.7)	92.0 (90.7–93.4)	92.7 (92.0–93.4)
TC (mmol/L)	5.13 (5.08–5.17)	5.12 (5.07–5.17)	5.11 (5.03–5.19)	5.17 (5.11–5.24)
HDL (mmol/L)	1.30 (1.28–1.33)	1.29 (1.26–1.32)	1.41 (1.38–1.44)	1.26 (1.23–1.29)

Values are reported as the mean (95% CI). For all variables, procedures to account for sampling probabilities and complex sampling design were applied. Continuous variables were adjusted for age and sex.

Table 2. Death rates by BMI categories, T2D genetic risk groups, and ethnicity, and causes of death by ethnicity in the NHANES III DNA Bank (NHANES III, 1991–1994), accounting for sampling weights and complex survey design
	All ethnicities (N = 6,501)	NHW (N = 2,528)	NHB (N = 1,979)	MA (N = 1,994)
Death rate, per 1,000 person-years (95% CI)	11.2 (9.5–12.9)	11.7 (9.6–13.7)	10.9 (9.3–12.6)	6.2 (5.1–7.2)
BMI categories, per 1,000 person-years (95% CI)
<25 kg/m²	8.1 (6.7–9.7)	8.3 (6.5–10.1)	9.0 (6.7–11.4)	3.9 (3.1–4.8)
25–30 kg/m²	12.8 (10.5–15.1)	13.4 (10.6–16.3)	12.3 (10.2–14.4)	7.0 (5.6–8.5)
≥30 kg/m²	15.7 (13.4–18.0)	17.3 (14.4–20.2)	11.7 (8.8–14.7)	8.6 (6.0–11.1)
T2D genetic risk groups, per 1,000 person-years (95% CI)
GRS < ethnic-specific median	10.6 (8.3–12.8)	11.0 (8.2–13.8)	9.6 (7.4–11.8)	6.7 (5.4–8.0)
GRS ≥ ethnic-specific median	11.9 (10.0–13.7)	12.3 (10.0–14.6)	12.2 (10.7–13.8)	5.6 (4.1–7.2)
Cause of death, % (95% CI)
CVD	39.2 (35.5–42.9)	39.8 (35.5–44.1)	35.4 (32.5–38.2)	37.0 (29.5–44.6)
Cancer	21.2 (17.8–24.6)	20.9 (16.9–24.8)	24.5 (20.5–28.5)	17.9 (13.0–22.9)
External	2.2 (1.6–2.9)	1.8 (1.2–2.5)	3.8 (1.3–6.4)	6.3 (1.0–11.5)
Other	37.4 (33.2–41.6)	37.5 (32.5–42.5)	36.3 (32.1–40.6)	38.8 (32.2–45.4)

Cause-specific death was ascertained for CVD (ICD-9 codes 390–434 and 436–459; ICD-10 codes I00–I99), cancer (ICD-9 codes 140–208; ICD-10 codes C00–C97), and external (ICD-9 codes E800–E999.9, ICD-10 codes V, W, X, and Y).

Table 3. Estimated mortality risk per T2D risk allele by ethnicity in the NHANES III DNA Bank (NHANES III, 1991–1994), accounting for sampling weights and complex survey design
	All ethnicities (N = 6,501)			NHW (N = 2,528)			NHB (N = 1,979)			MA (N = 1,994)
	OR	95% CI	P	OR	95% CI	P	OR	95% CI	P	OR	95% CI	P
Unadjusted for BMI	1.04	(1.00–1.07)	0.07	1.04	(0.99–1.09)	0.09	1.04	(1.01–1.06)	0.002	0.95	(0.90–1.00)	0.07
Adjusted for BMI	1.04	(1.00–1.07)	0.05	1.04	(1.00–1.09)	0.08	1.04	(1.01–1.06)	0.002	0.95	(0.90–1.01)	0.07
Fully adjusted model*	1.04	(1.00–1.08)	0.05	1.04	(1.00–1.10)	0.06	1.03	(1.01–1.06)	0.007	0.95	(0.89–1.01)	0.10

All models were adjusted for age, sex, and ethnicity. BMI, BMI categories (normal weight, BMI <25 kg/m²; overweight, BMI 25–30 kg/m²; obese, BMI ≥30 kg/m²). *Fully adjusted model includes BMI, family history, educational attainment, insurance coverage, PA, HEI, smoking status, alcohol consumption, TC, HDL cholesterol level, WC, and hypertension.